Towards spike-based machine intelligence with neuromorphic computing.

Guided by brain-like 'spiking' computational frameworks, neuromorphic computing-brain-inspired computing for machine intelligence-promises to realize artificial intelligence while reducing the energy requirements of computing platforms. This interdisciplinary field began with the implementation of silicon circuits for biological neural routines, but has evolved to encompass the hardware implementation of algorithms with spike-based encoding and event-driven representations. Here we provide an overview of the developments in neuromorphic computing for both algorithms and hardware and highlight the fundamentals of learning and hardware frameworks. We discuss the main challenges and the future prospects of neuromorphic computing, with emphasis on algorithm-hardware codesign.

Headache Associated with PPE During COVID-19 Pandemic in Health Care Workers.

PURPOSE: In the pandemic coronavirus disease 2019 (COVID-19), health care workers (HCWs) are at very high risk. Personal protective equipment (PPE) and masks are not only difficult to wear while working but also causes various complications. The present self-administered questionnaire- based study aimed to explore the headache and complications in HCWs on wearing PPE during the COVID-19 pandemic. METHODS: The present study was performed by obtaining a self-administered questionnaire from HCWs, which provides evidence of various complications due to the use of a PPE and mask. RESULTS: Out of a total of 329 respondents, 189(57.45%), 67(20.36%), 238(72.34%), 213(64.74%), 177(53.80%), and 34(10.33%) reported headache, breathlessness, suffocation, nose pain, ear pain, and leg pain respectively. Out of 329 respondents, 47(14.29%) had pre-existing headaches. Headache was significantly high for those who wore PPE for 4-6h (121/133; 87.05%) than that of those who wore up to 4h (18/26; 69.23%). Of the 34(24.46%) required medication who reported headaches wearing PPE. Acetaminophen is quite helpful in most health care workers to decrease headaches. Nose-related complications occur frequently in health care workers after regular shifts for more than 6 days. Gelatinous adhesives patch was a wonderful prophylactic remedy as it was helpful to prevent nose- related complications in 24 HCWs out of 25(96%). CONCLUSIONS: More than half of the HCWs reported headache, suffocation, nose pain, and ear pain. Duration of PPE use of more than 4h is significantly associated with headache. Short duration PPE use prevent HCWs from headache and various ill effects.

Overexpression of P-glycoprotein and MRP-1 are pharmacogenomic biomarkers to determine steroid resistant phenotype in childhood idiopathic nephrotic syndrome.

Steroid remains the keystone therapy for Idiopathic Nephrotic Syndrome (NS). Besides genetic factors and histological changes, pharmacogenomic factors also affect the steroid response. The upregulation of P-glycoprotein (P-gp) and Multidrug resistance-associated protein 1 (MRP-1) modulate the pharmacokinetics of steroids and may contribute to steroid resistance. Flow-cytometric analysis of P-gp, MRP-1 expression and functional activity on peripheral blood mononuclear cells (PBMCs) was carried out in steroid-sensitive nephrotic syndrome (SSNS) (n = 171, male 103, mean age = 8.54 ± 4.3); and steroid-resistant nephrotic syndrome (SRNS) (n = 83, male 43, mean age = 7.43 ± 4.6) patients. The genotypings of MDR-1 gene were carried out using PCR-RFLP. We observed that the percentage expression of P-gp (10.01 ± 2.09 and 3.79 ± 1.13, p < 0.001); and MRP-1 (15.91 ± 3.99 and 7.40 ± 2.33, p < 0.001) on lymphocyte gated population were significantly higher in SRNS than that of SSNS. The functional activity of P-gp and MRP-1 was also significantly escalated in SRNS as compared to SSNS (68.10 ± 13.35 and 28.93 ± 7.57, p < 0.001); (72.13 ± 8.34 and 31.56 ± 8.65, p < 0.001) respectively. AUC-ROC curve analysis revealed that P-gp and MRP-1 expression with a cut-off value of 7.13% and 9.62% predicted SRNS with the sensitivity of 90% and 80.7%; and specificity 90% and 80%, respectively. Moreover, MDR-1 homozygous mutant TT+AA for G2677T/A (rs2032582) was significantly associated with SRNS (p = 0.025, OR = 2.86 CI = 1.14-7.14). The expression of P-gp (9.68 ± 4.99 v/s 5.88 ± 3.38, p = 0.002) was significantly higher in the patients of homozygous mutant alleles compared to wildtype GG. The increased expression and functionality of P-gp and MRP-1 contribute to steroid resistance, and MDR-1 homozygous mutant G2677T/A promotes steroid resistance by inducing P-gp expression in NS.

In situ unsupervised learning using stochastic switching in magneto-electric magnetic tunnel junctions.

Spiking neural networks (SNNs) offer a bio-plausible and potentially power-efficient alternative to conventional deep learning. Although there has been progress towards implementing SNN functionalities in custom CMOS-based hardware using beyond Von Neumann architectures, the power-efficiency of the human brain has remained elusive. This has necessitated investigations of novel material systems which can efficiently mimic the functional units of SNNs, such as neurons and synapses. In this paper, we present a magnetoelectric-magnetic tunnel junction (ME-MTJ) device as a synapse. We arrange these synapses in a crossbar fashion and perform in situ unsupervised learning. We leverage the capacitive nature of write-ports in ME-MTJs, wherein by applying appropriately shaped voltage pulses across the write-port, the ME-MTJ can be switched in a probabilistic manner. We further exploit the sigmoidal switching characteristics of ME-MTJ to tune the synapses to follow the well-known spike timing-dependent plasticity (STDP) rule in a stochastic fashion. Finally, we use the stochastic STDP rule in ME-MTJ synapses to simulate a two-layered SNN to perform image classification tasks on a handwritten digit dataset. Thus, the capacitive write-port and the decoupled-nature of read-write path of ME-MTJs allow us to construct a transistor-less crossbar, suitable for energy-efficient implementation of in situ learning in SNNs. This article is part of the theme issue 'Harmonizing energy-autonomous computing and intelligence'.

Differential alteration in peripheral T-regulatory and T-effector cells with change in P-glycoprotein expression in Childhood Nephrotic Syndrome: A longitudinal study.

INTRODUCTION: Childhood Idiopathic Nephrotic Syndrome (INS) responds to glucocorticoid therapy, however, 60-80% of patients relapse and some of them become steroid non responsive. INS may occur because of T cell dysfunction, abnormal cytokines and podocytopathies which reverse on steroid treatment. The reason of relapses could be imbalances in T cells phenotypes and respective cytokines. Herein, we hypothesize that relapses in INS may occur due to imbalance in T-regulatory and T-effector cell with their respective cytokines and overexpression of P-gp on lymphocytes. METHODS: The frequency of peripheral blood CD4(+)CD25(+)FoxP3(+) Treg, CD4(+)IFN-γ(+) Th1 and CD4(+)IL-4(+) Th2 lymphocytes and their respective cytokines and P-gp expression on peripheral blood lymphocytes (PBLs) were analyzed in INS patients at baseline (n=26), during remission (n=24) and at relapse (n=15). RESULTS: Compared to baseline, the frequency of Tregs was significantly increased at remission and decreased during relapse. In contrast, the frequency of Th1 and Th2 lymphocytes was significantly decreased during remission and increased at the time of relapse. Similarly, expression of P-gp was significantly high at baseline and at the time of relapse as compared to remission. Levels of cytokines IL-10 and TGF-ß in the supernatant of stimulated PBMCs was increased during remission and decreased during relapse. In contrast, levels of IFN-γ and IL-4 were decreased during remission and increased at the time of relapse. CONCLUSIONS: Steroid therapy in INS induces decreased P-gp expression on PBLs along with increased frequency and cytokine response of T-regulatory cells, and reduced frequency and respective cytokine response of Th1 and Th2 cells during remission. However, reversal in the frequency and respective cytokines of T-regs, Th1 and Th2, and P-gp expression on PBLs occurs during relapses on follow-up.

Urinary Kidney injury molecule-1 can predict delayed graft function in living donor renal allograft recipients.

AIM: Delayed graft function is an early complication leading to impaired creatinine clearance, urine formation and determinant of long term graft outcome. The aim of the present study was to determine the earliest predictive cut-off value of uKIM-1 level in patients with delayed graft function and acute tubular necrosis. METHODS: We have determined the serial urinary KIM-1 normalized to urinary creatinine (uKIM-1, pg/mg) level at 0, 6, 12, 18, 24 and 48 h of post-transplant by ELISA methods. RESULT: The normalized uKIM-1 and AUC-ROC, of uKIM-1 were progressively increased up to 48 h in both delayed graft function (DGF) and immediate graft function (IGF). The u KIM-1 values were significantly high at 6, 12, 18, 24 and 48 h in patients with DGF as compared to that of IGF except at half an hour post-transplant values. Although, progressive increase in uKIM-1 values were observed in both groups of patients; there was an overlap of values between two groups up to 12 h. The earliest non-overlapping values of uKIM-1 between the groups were observed at 18 h onwards and minimum difference of 923.43 pg/mg. The earliest predictive AUC-ROC of uKIM-1 in patients with DGF without overlap with IGF was also observed at 18 h post-transplant with specificity of 100% and sensitivity of 89.9%. CONCLUSION: Serial uKIM-1 measurement can be used as non-invasive diagnostic biomarkers to predict the incident of DGF in living donor renal transplant recipients. At 18(th) post-transplant hour uKIM-1 can predict DGF with 100% specificity and 89.9% sensitivity with a cut-off value of normalized KIM-1 of 923.43 pg/mg.

Is basiliximab induction, a novel risk factor for new onset diabetes after transplantation for living donor renal allograft recipients?

AIM: It was found that, by affecting populations of T lymphocytes and regulatory T cells, basiliximab also indirectly affects pancreatic ß-cell function and glucose homeostasis. METHODS: In this prospective observational study, we included all renal transplant recipients from 1 July 2007 to 31 July 2011. The overall incidence of hyperglycaemia (transient hyperglycaemia, impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and new onset diabetes after transplantation (NODAT)) was compared between patients with and without basiliximab induction. RESULTS: Of the 439 eligible study patients, 105 patients received basiliximab induction and 334 patients did not. Overall hyperglycaemia (transient hyperglycaemia, IFG, IGT and NODAT) was detected in 102/334 (30.5%) patients without induction and 44/105 (41.9%) patients with induction (P = 0.03). Of the 102 patients with hyperglycaemia in patients without basiliximab, 46 (45.1%) patients improved, while only 10 (22.7%) of the 44 patients with basiliximab improved (P = 0.016) at the end of 3 months. Finally, NODAT was observed in 56/334 (16.7%) patients without induction and 102/334 (30.5%) patients with induction. Relative risk of NODAT with basiliximab was 2.3 (95% CI 1.4-3.9) compared to that of patients without induction. Basiliximab and hepatitis C virus infection were independent risk factors for NODAT. Risk of NODAT remained high with basiliximab despite adjusting the acute rejections episodes. CONCLUSIONS: Basiliximab induction prevents acute rejection; however, it is associated with increased risk of NODAT.

Community-acquired acute kidney injury in India: data from ISN-acute kidney injury registry.

Background: Acute kidney injury (AKI), particularly community-acquired AKI (CA-AKI), is a major health concern globally. The International Society of Nephrology's "0 by 25" initiative to reduce preventable deaths from AKI to zero by 2025 is not achievable in low and middle income countries, such as India, possibly due to a lack of data and measures to tackle this urgent public health issue. In India, CA-AKI predisposes younger patients to hospitalization, morbidity, and mortality. This is the first multicenter, prospective, cohort study investigating CA-AKI and its consequences in India. Methods: This study included data from patients with CA-AKI (>12 years of age) housed in the Indian Society of Nephrology-AKI registry, involving 9 participating tertiary care centers in India, for the period between November 2016 and October 2019. The etiological spectrum and renal and patient outcomes of CA-AKI at the index visit and at 1-month and 3-month follow-ups were analyzed. The impact of socioeconomic status (SES) on outcomes was also analyzed. Findings: Data from 3711 patients (mean [±SD] age 44.7 ± 16.5 years; 66.6% male) were analyzed. The most common comorbidities included hypertension (21.1%) and diabetes (19.1%). AKI occurred in medical, surgical, and obstetrical settings in 86.7%, 7.3%, and 6%, respectively. The most common causes of AKI were associated with sepsis (34.7%) and tropical fever (9.8%). Mortality at the index admission was 10.8%. Complete recovery (CR), partial recovery (PR), and dialysis dependency among survivors at the time of discharge were 22.1%, 57.7%, and 9.4%, respectively. Overall, at 3 months of follow-up, mortality rate, CR, PR, and dialysis dependency rates were 11.4%, 72.2%, 7.2%, and 1%, respectively. Multivariate analysis revealed that age >65 years, alcoholism, anuria, hypotension at presentation, thrombocytopenia, vasopressor use, transaminitis, and low SES were associated with mortality at the index admission. Interpretation: Sepsis and tropical fever were the most common causes of CA-AKI. Presentation of CA-AKI to tertiary care units was associated with high mortality, and a significant number of patients progressed to CKD. Individuals with a low SES had increased risk of mortality and require immediate attention and intervention. Funding: This study was funded by the Indian Society of Nephrology.

Unravelling the role of Sildenafil and SB204741 in suppressing fibrotic potential of peritoneal fibroblasts obtained from PD patients.

Introduction: Peritoneal fibrosis (PF) results in technique failure in peritoneal dialysis (PD) patients. Peritoneal fibroblasts are characterized by increase in the ACTA2 gene, responsible for alpha smooth muscle actin (α-SΜΑ), extracellular matrix (ECM) production, and inflammatory cytokines production, which are the are key mediators in the pathogenesis of PF. 5-hydroxytryptamine (5-HT; serotonin) induces ECM synthesis in fibroblasts in a transforming growth factor-beta 1 (TGF-ß1) dependent manner. The purpose of our study was to identify the potential mechanism and role of sildenafil and 5HT2B receptor inhibitor (SB204741) combination in attenuating PD-associated peritoneal fibrosis. Methods: Studies were performed to determine the effect of TGF-ß1, sildenafil, and SB204741 on human peritoneal fibroblasts (HPFBs) isolated from the parietal peritoneum of patients in long-term PD patients (n = 6) and controls (n = 6). HPFBs were incubated with TGF-ß1 (10 ng/mL) for 1 h and later with TGF-ß1 (10 ng/mL)/[sildenafil (10 µM) or SB204741 (1 µM)] and their combination for 24 h (post-treatment strategy). In the pre-treatment strategy, HPFBs were pre-treated with sildenafil (10 µM) or SB204741 (1 µM) and a combination of the two for 1 h and later with only TGF-ß1 (10 ng/mL) for 24 h. Results: The anti-fibrotic effects of the combination of sildenafil and SB204741 were greater than that of each drug alone. In TGF-ß1-stimulated HPFBs, pro-fibrotic genes (COL1A1, COL1A2, ACTA2, CTGF, FN1, and TGFB1) exhibited higher expression than in controls, which are crucial targets of sildenafil and SB204741 against peritoneal fibrosis. The synergistic approach played an anti-fibrotic role by regulating the pro- and anti-fibrotic gene responses as well as inflammatory cytokine responses. The combination treatment significantly attenuated peritoneal fibrosis, as evident by the almost complete amelioration of ACTA2 expression, restoration of anti-fibrotic genes (MMP2/TIMP1), and, at least, by reducing the expression of pro-inflammatory cytokines (IFN-γ, IL-4, IL-17, IL-1ß, IL-6, TNF-α, and TGF-ß1) along with an increase in IL-10 levels. Discussion: Taken together, the above research evidences that the combination of sildenafil and SB204741 may have therapeutic potential in suppressing peritoneal fibrosis due to peritoneal dialysis.

Neuromorphic-P2M: processing-in-pixel-in-memory paradigm for neuromorphic image sensors.

Edge devices equipped with computer vision must deal with vast amounts of sensory data with limited computing resources. Hence, researchers have been exploring different energy-efficient solutions such as near-sensor, in-sensor, and in-pixel processing, bringing the computation closer to the sensor. In particular, in-pixel processing embeds the computation capabilities inside the pixel array and achieves high energy efficiency by generating low-level features instead of the raw data stream from CMOS image sensors. Many different in-pixel processing techniques and approaches have been demonstrated on conventional frame-based CMOS imagers; however, the processing-in-pixel approach for neuromorphic vision sensors has not been explored so far. In this work, for the first time, we propose an asynchronous non-von-Neumann analog processing-in-pixel paradigm to perform convolution operations by integrating in-situ multi-bit multi-channel convolution inside the pixel array performing analog multiply and accumulate (MAC) operations that consume significantly less energy than their digital MAC alternative. To make this approach viable, we incorporate the circuit's non-ideality, leakage, and process variations into a novel hardware-algorithm co-design framework that leverages extensive HSpice simulations of our proposed circuit using the GF22nm FD-SOI technology node. We verified our framework on state-of-the-art neuromorphic vision sensor datasets and show that our solution consumes ~2× lower backend-processor energy while maintaining almost similar front-end (sensor) energy on the IBM DVS128-Gesture dataset than the state-of-the-art while maintaining a high test accuracy of 88.36%.

IRIS: Integrated Retinal Functionality in Image Sensors.

Neuromorphic image sensors draw inspiration from the biological retina to implement visual computations in electronic hardware. Gain control in phototransduction and temporal differentiation at the first retinal synapse inspired the first generation of neuromorphic sensors, but processing in downstream retinal circuits, much of which has been discovered in the past decade, has not been implemented in image sensor technology. We present a technology-circuit co-design solution that implements two motion computations-object motion sensitivity and looming detection-at the retina's output that could have wide applications for vision-based decision-making in dynamic environments. Our simulations on Globalfoundries 22 nm technology node show that the proposed retina-inspired circuits can be fabricated on image sensing platforms in existing semiconductor foundries by taking advantage of the recent advances in semiconductor chip stacking technology. Integrated Retinal Functionality in Image Sensors (IRIS) technology could drive advances in machine vision applications that demand energy-efficient and low-bandwidth real-time decision-making.

Protocol and Methods: Role of Levothyroxine on the Progression of Chronic Kidney Disease in Subclinical Hypothyroid Populations (LP-CKD) - A Multicenter Randomized Controlled Trial.

Introduction: Subclinical hypothyroidism (SCH) is highly prevalent and associated with chronic kidney disease (CKD). However, it is still unanswered whether the restoration of euthyroid status in these patients will be beneficial in retarding a decline in glomerular filtration rate in early CKD patients. We aim to evaluate the efficacy of levothyroxine therapy versus placebo in slowing estimated glomerular filtration rate (eGFR) decline among CKD patients (stage 2-4) with SCH. Methods: This study will be a multicentric, double-blind, randomized, parallel-group, placebo-controlled study. A total of 500 CKD patients, 250 patients in the treatment group and 250 patients in the placebo group, will be randomized. The randomization between the treatment arm and placebo arm will be performed as per the computer-generated random number table in a 1:1 ratio. The sample size was calculated based on the assumed reduction in eGFR after 1-year follow-up in the treatment and placebo groups of 10% and 25%, respectively, at a minimum two-sided 99% confidence interval and 90% power of the study and considering 20% loss on follow-up. Each patient will be followed every 3 months for at least 1 year after randomization. Individuals completing 1-year follow-up visits will be considered for analysis. The baseline and follow-up data will be compared between the treatment and placebo groups. The study will evaluate the efficacy and safety of levothyroxine therapy versus placebo in slowing eGFR decline among CKD patients (stage 2-4) with SCH. The primary endpoint will be the end of follow-up of the patients, reduction of eGFR by ≥50% from a baseline of that patient, or development of ESKD or death of the patients. The secondary endpoint will be any cardiovascular event or arrhythmia after the institution of the drug.

ACE-SNN: Algorithm-Hardware Co-design of Energy-Efficient & Low-Latency Deep Spiking Neural Networks for 3D Image Recognition.

High-quality 3D image recognition is an important component of many vision and robotics systems. However, the accurate processing of these images requires the use of compute-expensive 3D Convolutional Neural Networks (CNNs). To address this challenge, we propose the use of Spiking Neural Networks (SNNs) that are generated from iso-architecture CNNs and trained with quantization-aware gradient descent to optimize their weights, membrane leak, and firing thresholds. During both training and inference, the analog pixel values of a 3D image are directly applied to the input layer of the SNN without the need to convert to a spike-train. This significantly reduces the training and inference latency and results in high degree of activation sparsity, which yields significant improvements in computational efficiency. However, this introduces energy-hungry digital multiplications in the first layer of our models, which we propose to mitigate using a processing-in-memory (PIM) architecture. To evaluate our proposal, we propose a 3D and a 3D/2D hybrid SNN-compatible convolutional architecture and choose hyperspectral imaging (HSI) as an application for 3D image recognition. We achieve overall test accuracy of 98.68, 99.50, and 97.95% with 5 time steps (inference latency) and 6-bit weight quantization on the Indian Pines, Pavia University, and Salinas Scene datasets, respectively. In particular, our models implemented using standard digital hardware achieved accuracies similar to state-of-the-art (SOTA) with ~560.6× and ~44.8× less average energy than an iso-architecture full-precision and 6-bit quantized CNN, respectively. Adopting the PIM architecture in the first layer, further improves the average energy, delay, and energy-delay-product (EDP) by 30, 7, and 38%, respectively.

A processing-in-pixel-in-memory paradigm for resource-constrained TinyML applications.

The demand to process vast amounts of data generated from state-of-the-art high resolution cameras has motivated novel energy-efficient on-device AI solutions. Visual data in such cameras are usually captured in analog voltages by a sensor pixel array, and then converted to the digital domain for subsequent AI processing using analog-to-digital converters (ADC). Recent research has tried to take advantage of massively parallel low-power analog/digital computing in the form of near- and in-sensor processing, in which the AI computation is performed partly in the periphery of the pixel array and partly in a separate on-board CPU/accelerator. Unfortunately, high-resolution input images still need to be streamed between the camera and the AI processing unit, frame by frame, causing energy, bandwidth, and security bottlenecks. To mitigate this problem, we propose a novel Processing-in-Pixel-in-memory (P2M) paradigm, that customizes the pixel array by adding support for analog multi-channel, multi-bit convolution, batch normalization, and Rectified Linear Units (ReLU). Our solution includes a holistic algorithm-circuit co-design approach and the resulting P2M paradigm can be used as a drop-in replacement for embedding memory-intensive first few layers of convolutional neural network (CNN) models within foundry-manufacturable CMOS image sensor platforms. Our experimental results indicate that P2M reduces data transfer bandwidth from sensors and analog to digital conversions by [Formula: see text], and the energy-delay product (EDP) incurred in processing a MobileNetV2 model on a TinyML use case for visual wake words dataset (VWW) by up to [Formula: see text] compared to standard near-processing or in-sensor implementations, without any significant drop in test accuracy.

Melding Pharmacogenomic Effect of MDR1 and CYP3A5 Gene Polymorphism on Tacrolimus Dosing in Renal Transplant Recipients in Northern India.

INTRODUCTION: Tacrolimus (TAC) is the mainstay immunosuppressant for renal transplantation. A narrow therapeutic index, multiple drug interactions, and interindividual variability in pharmacokinetics make it obligatory to monitor therapeutic drug levels. The Multidrug resistance gene 1 (MDR1) and CYP3A5 gene polymorphism may blend to achieve the optimal level. The optimal dose as per body weight is difficult to single out in the early posttransplantation period. In this study, we aimed to analyze the melding effect of both gene polymorphisms and to elicit the dose depending on the combination of genetic single nucleotide polymorphisms (SNPs) in northern Indian transplant recipients, for whom data are limited. METHODS: The daily TAC dose, weight-adjusted doses (mg/kg per day), TAC trough blood concentration (average of at least 3 levels), dose normalized with a corresponding dose using TAC concentration/weight-adjusted dose ratio (ng/ml per mg/kg per day) of 248 patients were recorded. All recipients were genotyped for the SNPs of CYP3A5 at intron 3 A6986G (the *3 or *1 allele), MDR1 at exons 12 (C1236T), 21 (G2677A/T), and 26 (C3435T). We analyzed the blending effect of mutant SNPs of the MDR gene and CYP3A5 for optimized TAC levels. RESULTS: Among CYP3A5 genotypic variants, the dose-adjusted TAC level was significantly lower, and the TAC dose required to achieve the target level was significantly higher, in CYP3A5*1*1 (expressor) than that of CYP3A5*1*3 and CYP3A5*3*3. Of the MDR1 gene SNPs, only the G2677T/A homozygous mutant was significantly associated with TAC level, and it was strongly correlated with P-gp expression.The daily TAC dose requirement was highest with a combination of CYP3A5*1*1 and homozygous mutant TT+AA genotype of G2677T/A, and was lowest with CYP3A5*3*3 and wild-type GG of the G2677T/A genotype. CONCLUSION: Both CYP gene and MDR1 gene polymorphism affect TAC dose requirements, and there is a need to look for both in an individual to achieve the target trough concentration.

Reciprocal Relationship Between HDAC2 and P-Glycoprotein/MRP-1 and Their Role in Steroid Resistance in Childhood Nephrotic Syndrome.

Background: Reduced HDACs levels have been reported in steroid resistant chronic obstructive pulmonary disease and bronchial asthma patients. P-glycoprotein (P-gp) over expression in peripheral blood mononuclear cells (PBMCs) has been reported in patients with steroid resistant nephrotic syndrome (NS). Whether and how HDACs and P-gp are linked with each other is not clear, especially in NS patients. Aim: To evaluate mRNA expression of P-gp/MRP-1 and HDAC2 in PBMCs of steroid sensitive (SSNS) and steroid resistant nephrotic syndrome (SRNS) patients, and determine the relationship between expression of HDAC2 and P-gp/ MRP-1in NS patients. Methods: Twenty subjects (10 in each group), SSNS (mean age 7.54 ± 3.5 years), and SRNS (mean age 8.43 ± 3.8 years) were recruited. mRNA expression of HDAC2 and P-gp/MRP-1 was studied by quantitative real time PCR. PBMCs were treated with Theophylline, 1 µM, and Trichostatin A, 0.8 µM, for 48 h for induction and suppression of HDAC2, respectively. Results: At baseline, expression of P-gp (4.79 ± 0.10 vs. 2.13 ± 0.12, p < 0.0001) and MRP-1 (3.99 ± 0.08 vs. 1.99 ±0.11, p < 0.0001) on PBMCs were increased whereas, HDAC2 mRNA levels (2.97 ± 0.15 vs. 6.02 ± 0.13, p < 0.0001) were significantly decreased in SRNS as compared to that of SSNS patients. Compared to baseline, theophylline reduced mRNA expression of P-gp and MRP-1 (fold change 2.65 and 2.21, * p < 0.0001 in SRNS) (fold change 1.25, 1.24, * p < 0.0001 in SSNS), respectively. However, it increased the expression of HDAC2 (fold change 5.67, * p < 0.0001 in SRNS) (fold change 6.93, * p < 0.0001 in SSNS). Compared to baseline, TSA treatment increased mRNA levels of P-gp and MRP-1 (fold change 7.51, 7.31, * p < 0.0001 in SRNS) and (fold change 3.49, 3.35, * p < 0.0001 in SSNS), respectively. It significantly decreased the level of HDAC2 (fold change 1.50, * p < 0.0001 in SRNS) (fold change 2.53, * p < 0.0001 in SSNS) patients. Conclusion: Reduced HDAC2 and increased P-gp/MRP-1 activity may play a role in response to steroids in childhood NS. HDAC2 and P-gp/MRP-1 are in reciprocal relationship with each other.

In-situ, In-Memory Stateful Vector Logic Operations based on Voltage Controlled Magnetic Anisotropy.

Recently, the exponential increase in compute requirements demanded by emerging applications like artificial intelligence, Internet of things, etc. have rendered the state-of-art von-Neumann machines inefficient in terms of energy and throughput owing to the well-known von-Neumann bottleneck. A promising approach to mitigate the bottleneck is to do computations as close to the memory units as possible. One extreme possibility is to do in-situ Boolean logic computations by using stateful devices. Stateful devices are those that can act both as a compute engine and storage device, simultaneously. We propose such stateful, vector, in-memory operations using voltage controlled magnetic anisotropy (VCMA) effect in magnetic tunnel junctions (MTJ). Our proposal is based on the well known manufacturable 1-transistor - 1-MTJ bit-cell and does not require any modifications in the bit-cell circuit or the magnetic device. Instead, we leverage the very physics of the VCMA effect to enable stateful computations. Specifically, we exploit the voltage asymmetry of the VCMA effect to construct stateful IMP (implication) gate and use the precessional switching dynamics of the VCMA devices to propose a massively parallel NOT operation. Further, we show that other gates like AND, OR, NAND, NOR, NIMP (complement of implication) can be implemented using multi-cycle operations.

MESL: Proposal for a Non-volatile Cascadable Magneto-Electric Spin Logic.

In the quest for novel, scalable and energy-efficient computing technologies, many non-charge based logic devices are being explored. Recent advances in multi-ferroic materials have paved the way for electric field induced low energy and fast switching of nano-magnets using the magneto-electric (ME) effect. In this paper, we propose a voltage driven logic-device based on the ME induced switching of nano-magnets. We further demonstrate that the proposed logic-device, which exhibits decoupled read and write paths, can be used to construct a complete logic family including XNOR, NAND and NOR gates. The proposed logic family shows good scalability with a quadratic dependence of switching energy with respect to the switching voltage. Further, the proposed logic-device has better robustness against the effect of thermal noise as compared to the conventional current driven switching of nano-magnets. A device-to-circuit level coupled simulation framework, including magnetization dynamics and electron transport model, has been developed for analyzing the present proposal. Using our simulation framework, we present energy and delay results for the proposed Magneto-Electric Spin Logic (MESL) gates.

FGF23 is associated with early post-transplant hypophosphataemia and normalizes faster than iPTH in living donor renal transplant recipients: a longitudinal follow-up study.

BACKGROUND: We aimed to longitudinally analyse changes in the levels of serum fibroblast growth factor 23 (FGF23), intact parathyroid hormone (iPTH) and associated minerals in patients undergoing renal transplantation. METHODS: Sixty-three patients with end-stage renal disease (ESRD) who underwent living donor transplantation were recruited. Serum FGF23, iPTH, uric acid, inorganic phosphorous (iP), blood urea nitrogen and serum creatinine were measured pre-transplant and at 1 (M1), 3 (M3) and 12 months (M12) post-transplantation. RESULTS: FGF23 levels were decreased at M1, M3 and M12 by 93.81, 96.74 and 97.53%, respectively. iPTH levels were decreased by 67.95, 74.95 and 84.9%, respectively. The prevalence of hyperparathyroidism at M1, M3 and M12 post-transplantation was 63.5, 42.9 and 11.1%, respectively. FGF23 and iP levels remained above the normal range in 23 (36.5%) and 17 (27%) patients at M1, 10 (15.9%) and 5 (8%) at M3 and in none at M12 post-transplantation, respectively. A multivariate regression model revealed that, pre-transplant, iP was positively associated with iPTH (P = 0.016) but not with FGF 23; however, post-transplant, iP level was negatively associated with FGF23 (P < 0.001) but not with iPTH. CONCLUSIONS: Post-transplant FGF23 levels settle faster than those of iPTH. However, 11% of patients continued to have hyperparathyroidism even after 12 months.

T-bet-positive mononuclear cell infiltration is associated with transplant glomerulopathy and interstitial fibrosis and tubular atrophy in renal allograft recipients.

OBJECTIVES: We aimed to study the role of T-bet-positive mononuclear cell infiltration in different compartments of kidney graft tissues in patients with chronic transplant glomerulopathy, interstitial fibrosis and tubular atrophy, and stable graft function. MATERIALS AND METHODS: There were 80 living-related renal transplant recipients included (chronic transplant glomerulopathy, n = 28; interstitial fibrosis and tubular atrophy, n = 28; stable graft function, n = 24). Histologic characteristics and scoring for peritubular capillaritis, glomerulitis, interstitial fibrosis and tubular atrophy, and intimal arteritis were performed according to Banff 2007 classification and compared between the groups. Immunohistologic staining was performed for transcription factor T-bet, T-bet mononuclear cells were counted, and T-bet infiltration score was compared between groups. RESULTS: Patients in different groups had similar clinical profiles and human leukocyte antigen mismatches, except the groups differed in serum creatinine and proteinuria. The prevalence and scoring of peritubular capillaritis and glomerulitis were significantly higher in chronic transplant glomerulopathy than interstitial fibrosis and tubular atrophy (P = .001) and stable graft function (P < .001). Tubulitis was observed in 6 patients (21.4%) with chronic transplant glomerulopathy but no patients with interstitial fibrosis and tubular atrophy. The C4d/donor-specific antibody was positive in 100% patients with chronic transplant glomerulopathy, 0% patients with interstitial fibrosis and tubular atrophy, and 4.1 % patients with stable graft function. Interstitial fibrosis and tubular atrophy was seen in 100% patients who had interstitial fibrosis and tubular atrophy; in patients who had chronic transplant glomerulopathy, 24 patients (85.7%) had interstitial fibrosis and 78.5% patients had tubular atrophy. The degree and severity of T-bet-positive cell infiltration were significantly higher in chronic transplant glomerulopathy than interstitial fibrosis and tubular atrophy or stable graft function; however, 85% patients with interstitial fibrosis and tubular atrophy also had T-bet-positive infiltration, suggesting a role of T-bet-positive cells in interstitial fibrosis and tubular atrophy. CONCLUSIONS: Chronic transplant glomerulopathy is a consequence of chronic active immune-mediated injury. Interstitial fibrosis and tubular atrophy may be associated with T-bet-positive mononuclear cell infiltration in the peritubular region. The T-bet infiltration should be evaluated in patients with chronic allograft injury.