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Supplementary Figures PDF file - 114K, Includes sequence information on KSP and VEGF siRNAs, murine Hep3B tumor model data with ALN-VSP, ALN-VSP Phase I study design, KSP and VEGF mRNA levels in tumor cell lines and normal liver, and comparison of ALN-VSP PK data in cancer patients and non-human primates

Supplementary Methods and Legends PDF file - 72K, Includes detailed methods for 5' RACE assay and DCE-MRI scans, as well as figure legends for the six supplementary figures

Supplementary Tables PDF file - 67K, Includes data showing effect of ALN-VSP on spleen in non-human primates, tumor response data from the Phase I trial, and safety data (including adverse events and dose-limiting toxicities) from the Phase I trial

In this article, Fifth generation mobile technology is termed 5G. It is basically a standard notation, used for a major phase of mobile telecommunication other than 4G standards. After the overall success of fourth generation (4G) mobile communications which was based on the platform named “Long Term Evolution (LTE)-Advanced standard” developed by the Third Generation Partnership Project (3GPP), the industry along with the research department such as International Telecommunication Union — Radio communications Standardization Sector (ITU-R), 3GPP, has been continuously working on the 5G mobile communication standards through some projects, such as the EU FP7 METIS and independently. In the year 2015, a paper has published in which it was reported that ITU-R developed a vision for 5G mobile communications. This vision supports the accommodation of explosive growth of data traffic through enhanced mobile broadband (eMBB). It also supports massive machine-type communications (MTC), along with ultra-reliable and low-latency communications (URLLC). This paper presents a review of the innovation, updates, and advancements from the first generation (1G) to the fifth generation (5G). Also, the network capabilities providing reasonable broadband wireless connectivity for all generations of telecommunication are discussed here.

Conjugation of oligonucleotide therapeutics, including small interfering ribonucleic acids (siRNAs) or antisense oligonucleotides (ASOs) to N-acetylgalactosamine (GalNAc) ligands has become the primary strategy for hepatocyte-targeted delivery, and with the recent approvals of GIVLAARI® (givosiran) for the treatment of acute hepatic porphyria, OXLUMOTM (lumasiran) for the treatment of primary hyperoxaluria, and Leqvio® (inclisiran) for the treatment of hypercholesterolemia, the technology has been well-validated clinically. While much knowledge has been gained over decades of development there is a paucity of published literature on the DMPK properties of GalNAc-siRNA. With this in mind the goals of this mini-review are to provide an aggregate analysis of these nonclinical ADME data to build confidence on the translation of these properties to human. Upon subcutaneous administration, GalNAc-conjugated siRNAs are quickly distributed to the liver, resulting in plasma pharmacokinetic (PK) properties that reflect rapid elimination through ASGPR-mediated uptake from circulation into hepatocytes. These studies confirm that liver PK, including half-life and, most importantly, siRNA levels in RNA-induced silencing complex (RISC) in hepatocytes are better predictors of pharmacodynamics (PD) than plasma PK. Several in vitro and in vivo nonclinical studies were conducted to characterize the absorption, distribution, metabolism and excretion (ADME) properties of GalNAc-conjugated siRNAs. These studies demonstrate that the PK/PD and ADME properties of GalNAc-conjugated siRNAs are highly conserved across species, largely predictable, and can be accurately scaled to human, allowing us to identify efficacious and safe clinical dosing regimens in the absence of human liver PK profiles. Significance Statement Several nonclinical ADME studies have been conducted in order to provide a comprehensive overview of the disposition and elimination of GalNAc-conjugated siRNAs and the PK/PD translation between species. These studies demonstrate that the ADME properties of GalNAc-conjugated siRNAs are well correlated and predictable across species building confidence in the ability to extrapolate to human.

The secret to tumor growth and survival is proliferation. Therefore, to plan and formulate a required therapy process, the study of the propagation rate is very important. The objective of the immune system is to protect against disease or other potentially harmful foreign bodies, a set of processes and mechanisms within the body. In regulating the growth of a tumor, different cells of our immune system perform their assigned function. Natural Killer cells, Dendritic cells, and CD8+ cells are among the many cells. In our scientific literature, in the presence of numerous family components of the human immune system, we have developed a mathematical model to evaluate the dynamics involved in tumor formation. We separated the population of tumor cells into proliferating and inactive subsets and felt that the cells of the immune system had little effect on the dormant cells. This partition of the universal tumor set into the subsets as mentioned has never been made in any of the previous research works. Also, to the best of authors’ knowledge, the compartment combination considered for the present work adds novelty to the article.

Purpose The Phase 3 ENDEAVOUR study evaluated revusiran, an investigational RNA interference therapeutic targeting hepatic transthyretin (TTR) production, for treating cardiomyopathy caused by hereditary transthyretin-mediated (hATTR) amyloidosis. Methods Patients with hATTR amyloidosis with cardiomyopathy were randomized 2:1 to receive subcutaneous daily revusiran 500 mg (n = 140) or placebo (n = 66) for 5 days over a week followed by weekly doses. Co-primary endpoints were 6-min walk test distance and serum TTR reduction. Results Revusiran treatment was stopped after a median of 6.71 months; the study Sponsor prematurely discontinued dosing due to an observed mortality imbalance between treatment arms. Eighteen (12.9%) patients on revusiran and 2 (3.0%) on placebo died during the on-treatment period. Most deaths in both treatment arms were adjudicated as cardiovascular due to heart failure (HF), consistent with the natural history of the disease. A post hoc safety investigation of patients treated with revusiran found that, at baseline, a greater proportion of those who died were ≥ 75 years and showed clinical evidence of more advanced HF compared with those who were alive throughout treatment. Revusiran pharmacokinetic exposures and TTR lowering did not show meaningful differences between patients who died and who were alive. Revusiran did not deleteriously affect echocardiographic parameters, cardiac biomarkers, or frequency of cardiovascular and HF hospitalization events. Conclusions Causes for the observed mortality imbalance associated with revusiran were thoroughly investigated and no clear causative mechanism could be identified. Although the results suggest similar progression of cardiac parameters in both treatment arms, a role for revusiran cannot be excluded. Clinical Trial Registration NCT02319005.

Identifying genetic variants associated with lower waist-to-hip ratio can reveal new therapeutic targets for abdominal obesity. We use exome sequences from 362,679 individuals to identify genes associated with waist-to-hip ratio adjusted for BMI (WHRadjBMI), a surrogate for abdominal fat that is causally linked to type 2 diabetes and coronary heart disease. Predicted loss of function (pLOF) variants inINHBEassociate with lower WHRadjBMI and this association replicates in data from AMP-T2D-GENES.INHBEencodes a secreted protein, the hepatokine activin E. In vitro characterization of the most commonINHBEpLOF variant in our study, indicates an in-frame deletion resulting in a 90% reduction in secreted protein levels. We detect associations with lower WHRadjBMI for variants inACVR1C, encoding an activin receptor, further highlighting the involvement of activins in regulating fat distribution. These findings highlight activin E as a potential therapeutic target for abdominal obesity, a phenotype linked to cardiometabolic disease.

Previous research findings have shown that an unhealthy diet can trigger the progression of tumors leading to a high mortality rate. Also, it has been noted that the hormonal changes caused in the human body support the proliferation rate in several kinds of cancer. In the present research, the light is thrown on breast cancer. Estrogens are a class of hormones that play an essential function in women’s proper sexual and reproductive advancement. Moreover, studies have revealed that a woman’s risk of breast cancer is proportional to the Estrogen and testosterone produced by the. Long-term and/or high-level exposure to these hormones has been associated with an increased risk of breast cancer. A novel mathematical model is framed to analyze the effect of estrogen levels on cancer advancement in females integrated with the effect of the unhealthy diet model. The levels of Estrogen are fixed to explore the other cell densities. The research concluded that the level of estrogen produced has a remarkable effect on the immune system in the case of a patient with breast cancer consuming an unhealthy diet.

Hereditary transthyretin-mediated (hATTR) amyloidosis is an underdiagnosed, progressively debilitating disease caused by mutations in the transthyretin (TTR) gene. V122I, a common pathogenic TTR mutation, is found in 3–4% of individuals of African ancestry in the United States and has been associated with cardiomyopathy and heart failure. To better understand the phenotypic consequences of carrying V122I, we conducted a phenome-wide association study scanning 427 ICD diagnosis codes in UK Biobank participants of African ancestry (n = 6062). Significant associations were tested for replication in the Penn Medicine Biobank (n = 5737) and the Million Veteran Program (n = 82,382). V122I was significantly associated with polyneuropathy in the UK Biobank (odds ratio [OR] = 6.4, 95% confidence interval [CI] 2.6–15.6, p = 4.2 × 10−5), which was replicated in the Penn Medicine Biobank (OR = 1.6, 95% CI 1.2–2.4, p = 6.0 × 10–3) and Million Veteran Program (OR = 1.5, 95% CI 1.2–1.8, p = 1.8 × 10−4). Polyneuropathy prevalence among V122I carriers was 2.1%, 9.0%, and 4.8% in the UK Biobank, Penn Medicine Biobank, and Million Veteran Program, respectively. The cumulative incidence of common hATTR amyloidosis manifestations (carpal tunnel syndrome, polyneuropathy, cardiomyopathy, heart failure) was significantly enriched in V122I carriers compared with non-carriers (HR = 2.8, 95% CI 1.7–4.5, p = 2.6 × 10−5) in the UK Biobank, with 37.4% of V122I carriers having at least one of these manifestations by age 75. Our findings show that V122I carriers are at increased risk of polyneuropathy. These results also emphasize the underdiagnosis of disease in V122I carriers with a significant proportion of subjects showing phenotypic changes consistent with hATTR amyloidosis. Greater understanding of the manifestations associated with V122I is critical for earlier diagnosis and treatment.

For oligonucleotide therapeutics, chemical modifications of the sugar-phosphate backbone are frequently used to confer drug-like properties. Because 2′-deoxy-2′-fluoro (2′-F) nucleotides are not known to occur naturally, their safety profile was assessed when used in revusiran and ALN-TTRSC02, two short interfering RNAs (siRNAs), of the same sequence but different chemical modification pattern and metabolic stability, conjugated to an N-acetylgalactosamine (GalNAc) ligand for targeted delivery to hepatocytes. Exposure to 2′-F-monomer metabolites was low and transient in rats and humans. In vitro, 2′-F-nucleoside 5′-triphosphates were neither inhibitors nor preferred substrates for human polymerases, and no obligate or non-obligate chain termination was observed. Modest effects on cell viability and mitochondrial DNA were observed in vitro in a subset of cell types at high concentrations of 2′-F-nucleosides, typically not attained in vivo. No apparent functional impact on mitochondria and no significant accumulation of 2′-F-monomers were observed after weekly administration of two GalNAc–siRNA conjugates in rats for ∼2 years. Taken together, the results support the conclusion that 2′-F nucleotides can be safely applied for the design of metabolically stabilized therapeutic GalNAc–siRNAs with favorable potency and prolonged duration of activity allowing for low dose and infrequent dosing.

Background: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, multisystem disease that presents with cardiomyopathy or polyneuropathy. The APOLLO study assessed the efficacy and tolerability of patisiran in patients with hATTR amyloidosis. The effects of patisiran on cardiac structure and function in a prespecified subpopulation of patients with evidence of cardiac amyloid involvement at baseline were assessed. Methods: APOLLO was an international, randomized, double-blind, placebo-controlled phase 3 trial in patients with hATTR amyloidosis. Patients were randomized 2:1 to receive 0.3 mg/kg patisiran or placebo via intravenous infusion once every 3 weeks for 18 months. The prespecified cardiac subpopulation comprised patients with a baseline left ventricular wall thickness ≥13 mm and no history of hypertension or aortic valve disease. Prespecified exploratory cardiac end points included mean left ventricular wall thickness, global longitudinal strain, and N -terminal prohormone of brain natriuretic peptide. Cardiac parameters in the overall APOLLO patient population were also evaluated. A composite end point of cardiac hospitalizations and all-cause mortality was assessed in a post hoc analysis. Results: In the cardiac subpopulation (n=126; 56% of total population), patisiran reduced mean left ventricular wall thickness (least-squares mean difference ± SEM: –0.9±0.4 mm, P =0.017), interventricular septal wall thickness, posterior wall thickness, and relative wall thickness at month 18 compared with placebo. Patisiran also led to increased end-diastolic volume (8.3±3.9 mL, P =0.036), decreased global longitudinal strain (–1.4±0.6%, P =0.015), and increased cardiac output (0.38±0.19 L/min, P =0.044) compared with placebo at month 18. Patisiran lowered N -terminal prohormone of brain natriuretic peptide at 9 and 18 months (at 18 months, ratio of fold-change patisiran/placebo 0.45, P N -terminal prohormone of brain natriuretic peptide at 18 months was observed in the overall APOLLO patient population (n=225). Median follow-up duration was 18.7 months. The exposure-adjusted rates of cardiac hospitalizations and all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups, respectively (Andersen–Gill hazard ratio, 0.54; 95% CI, 0.28–1.01). Conclusions: Patisiran decreased mean left ventricular wall thickness, global longitudinal strain, N -terminal prohormone of brain natriuretic peptide, and adverse cardiac outcomes compared with placebo at month 18, suggesting that patisiran may halt or reverse the progression of the cardiac manifestations of hATTR amyloidosis. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01960348.

International audience; BACKGROUND AND OBJECTIVES: In the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an RNA interference therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production. The objective of this first-in-human, randomized, placebo-controlled trial was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of lumasiran in healthy participants and patients with primary hyperoxaluria type 1. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This phase 1/2 study was conducted in two parts. In part A, healthy adults randomized 3:1 received a single subcutaneous dose of lumasiran or placebo in ascending dose groups (0.3-6 mg/kg). In part B, patients with primary hyperoxaluria type 1 randomized 3:1 received up to three doses of lumasiran or placebo in cohorts of 1 or 3 mg/kg monthly or 3 mg/kg quarterly. Patients initially assigned to placebo crossed over to lumasiran on day 85. The primary outcome was incidence of adverse events. Secondary outcomes included pharmacokinetic and pharmacodynamic parameters, including measures of oxalate in patients with primary hyperoxaluria type 1. Data were analyzed using descriptive statistics. RESULTS: Thirty-two healthy participants and 20 adult and pediatric patients with primary hyperoxaluria type 1 were enrolled. Lumasiran had an acceptable safety profile, with no serious adverse events or study discontinuations attributed to treatment. In part A, increases in mean plasma glycolate concentration, a measure of target engagement, were observed in healthy participants. In part B, patients with primary hyperoxaluria type 1 had a mean maximal reduction from baseline of 75% across dosing cohorts in 24-hour urinary oxalate excretion. All patients achieved urinary oxalate levels ≤1.5 times the upper limit of normal. CONCLUSIONS: Lumasiran had an acceptable safety profile and reduced urinary oxalate excretion in all patients with primary hyperoxaluria type 1 to near-normal levels. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Study of Lumasiran in Healthy Adults and Patients with Primary Hyperoxaluria Type 1, NCT02706886.

Conjugation of oligonucleotide therapeutics, including small interfering RNAs (siRNAs) or antisense oligonucleotides, to

Introduction: Patisiran is approved for the treatment of hATTR amyloidosis with polyneuropathy and its long-term efficacy/safety is being studied in a Global OLE. Plasma biomarkers are being investigated for utility in facilitating earlier diagnosis and monitoring disease /treatment response. Objective: Evaluate long-term change in neurofilament light chain (NfL) levels in response to patisiran in patients enrolled in the Global Open-Label Extension (OLE) study. Methods: NfL plasma levels were measured in duplicate in healthy controls and patients with ATTRv amyloidosis with polyneuropathy using the Quanterix Simoa platform. Patient samples were analyzed from the APOLLO study at baseline and 18 months, and also measured at 12 and 24 months following APOLLO in patients who rolled into the Global OLE. Results: NfL levels at APOLLO baseline were 63.2 (placebo) and 72.1 pg/ mL (patisiran). NfL increased during APOLLO in the placebo group (99.5 pg/mL), whereas a significant decrease was observed at 18 months following patisiran (48.8 pg/mL). Reduced NfL levels were maintained in the APOLLO-patisiran group through 24 months of additional patisiran treatment in the Global OLE (44.0 pg/mL), consistent with maintained improvement in mNIS+7. Upon initiation of patisiran in the Global OLE, the APOLLO-placebo group experienced a reduction in NfL levels through 24 months (44.2 pg/mL), reaching a similar level to the APOLLO-patisiran group. Conclusions: NfL may serve as a biomarker of active nerve damage and polyneuropathy, making it useful as a potential biomarker of disease progression, treatment response and for earlier diagnosis of polyneuropathy in patients with ATTRv amyloidosis and monitoring disease.

Background: Angiotensinogen (AGT) is the sole precursor of all angiotensin peptides and plays a key role in hypertension pathogenesis. We evaluated the effect of ALN-AGT01, a subcutaneous investigational RNAi therapeutic targeting hepatic AGT synthesis, on blood pressure in hypertensive patients. Methods: As part of a phase 1 program designed to assess the safety and tolerability of ALN-AGT01, we conducted a multicenter study randomizing patients aged 18-65 years with mild to moderate hypertension (mean seated systolic blood pressure [SBP] of >130 and ≤165 mmHg after washout of antihypertensive medication) 2:1 to ascending single doses of ALN-AGT01 or placebo. Change from baseline in BP at 8 weeks was measured by ambulatory BP monitoring (ABPM). We report interim results as of May 14, 2020. Results: Sixty patients (mean age 52 years, 45% female, mean baseline 24h SBP 139 +/- 7 mm Hg) were enrolled in ascending dose cohorts of 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg. Dose-related reductions in serum AGT levels were observed (figure), with reductions >90% in the 100 and 200 mg dose cohorts. AGT remained durably reduced through 12 weeks after single dose administration. Concomitant reductions in BP from baseline were observed with AGT knockdown, with an over 10 mm Hg reduction of mean 24-hour SBP observed at Week 8 after single doses of 100 mg or 200 mg. No symptomatic hypotension, treatment-related serious adverse events, or clinically significant elevations in blood creatinine or potassium were seen. Conclusions: Single dose administration of ALN-AGT01 to hypertensive patients resulted in dose-related reductions in serum AGT and BP over 8 weeks without hypotension or other related serious adverse events. Durable AGT knockdown to 12 weeks supports further evaluation of once quarterly or potentially less frequent dose administration.

IntroductionHereditary transthyretin-mediated (hATTR) amyloidosis is an underdiagnosed, progressively debilitating disease caused by mutations in the transthyretin (TTR) gene. The V122I variant, one of the most common pathogenic TTR mutations, is found in 3-4% of Black individuals, and has been associated with cardiomyopathy.MethodsTo better understand the phenotypic consequences of carrying V122I, we conducted a phenome-wide association study scanning 427 ICD diagnosis codes for association with this variant in Black participants of the UK Biobank (n= 6,062). Significant associations were tested for replication in the Penn Medicine Biobank (n= 5,737) and the Million Veteran Program (n= 82,382).ResultsOur analyses discovered a significant association between V122I and polyneuropathy diagnosis (odds ratio = 6.4, 95% confidence interval [CI] = 2.6 to 15.6, P = 4.2 × 10−5) in the UK Biobank,which was replicated in the Penn Medicine Biobank (p=6.0×10−3)) and Million Veteran Program (P= 1.8×10−4)). Polyneuropathy prevalence among V122I carriers was 2.1–9.0% across biobanks. The cumulative incidence of common hATTR amyloidosis manifestations (carpal tunnel syndrome, polyneuropathy, cardiomyopathy, heart failure) was significantly enriched in V122I carriers versus non-carriers (hazard ratio = 2.8, 95% CI = 1.7–4.5, P = 2.6 × 10−5) in the UK Biobank;37.4% of V122I carriers having a diagnosis of any one of these manifestations by age 75.ConclusionsOur findings show that, although the V122I variant is known to be associated with cardiomyopathy, carriers are also at significantly increased risk of developing polyneuropathy. These results also emphasize the underdiagnosis of disease in V122I carriers with a significant proportion of subjects showing phenotypic changes consistent with hATTR. Greater understanding of the manifestations associated with V122I is critical for earlier diagnosis and treatment.

Background Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, life-threatening disease caused by mutations in the transthyretin (TTR) gene. hATTR amyloidosis phenotypes can vary by patient and mutation. The V122I (Val122Ile; p.V142I) variant is one of the most common pathogenic TTR mutations, is primarily found in people of West African descent and has historically been associated with cardiomyopathy (CM). Purpose To characterize the cumulative incidence of diagnoses frequently seen with hATTR amyloidosis in V122I carriers and non-carriers in the UK Biobank (UKBB) and the Penn Medicine BioBank (PMBB). Methods UKBB and PMBB are prospective studies with ∼500,000 and ∼60,000 subjects, respectively. Clinical presentations frequently seen with hATTR amyloidosis were assessed using ICD10 diagnosis codes: G62–polyneuropathy (PN), I50 or I098–heart failure (HF), G560–carpal tunnel syndrome (CTS), I42–CM, and E85–amyloidosis. The cumulative incidence of diagnoses was estimated using Kaplan-Meier curves. Time to first hATTR amyloidosis-related diagnosis was compared between V122I carriers and non-carriers using Cox proportional hazards regression, controlling for age, sex, smoking, and genetic ancestry. Results Of the 6,062 unrelated black participants in the UKBB, 243 were V122I carriers. Only 0.8% of V122I carriers had a formal diagnosis of hATTR amyloidosis. V122I carriers were significantly more likely to have a PN diagnosis than non-carriers (p=6.35x10–5), a finding which was replicated in the PMBB. Of the ICD10 codes assessed, Cox proportional hazards regression revealed a significant association between V122I genotype and time to first diagnosis (p=2.6x10–5), with 11.1% of V122I carriers having at least one diagnosis during follow-up versus 4.9% of non-carriers. The calculated population attributable risk showed an excess risk of 16.7% for a PN diagnosis, 6.5% for HF, 4.1% for CTS, and 2.4% for CM in V122I carriers. The cumulative incidence of any hATTR amyloidosis-related diagnosis among V122I carriers by age 65 was 11.9% (95% CI=3.1–19.8%). The incidence increased to 37.4% (95% CI=20.5–50.7%) by age 75, which was significantly higher than non-carriers (13.8%, 95% CI=11.6–16%). Additionally, an assessment of the cumulative incidence of each diagnosis separately revealed that PN became more prevalent at younger ages, while HF and CM became more prevalent at older ages. Conclusions V122I carriers were significantly more likely to receive diagnoses frequently seen with hATTR amyloidosis than non-carriers. Although these diagnoses may not all be attributed to amyloidosis, the small fraction of patients diagnosed with hATTR amyloidosis suggests a potential underdiagnosis of disease. The V122I mutation has historically been associated with a cardiac phenotype, yet these data also suggest an increased incidence of PN. Increased vigilance for the mixed phenotype may lead to earlier diagnoses and treatment of V122I carriers. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Alnylam Pharmaceuticals

ObjectiveTo identify changes in the proteome associated with onset and progression of hereditary transthyretin-mediated (hATTR) amyloidosis, also known as ATTRv amyloidosis, we performed an observational, case-controlled study that compared proteomes of patients with ATTRv amyloidosis and healthy controls.MethodsPlasma levels of >1,000 proteins were measured in patients with ATTRv amyloidosis with polyneuropathy who received either placebo or patisiran in a Phase 3 study of patisiran (APOLLO), and in healthy controls. The effect of patisiran on the time profile of each protein was determined by linear mixed model at 0, 9, and 18 months. Neurofilament light chain (NfL) was further assessed with an orthogonal quantitative approach.ResultsLevels of 66 proteins were significantly changed with patisiran vs placebo, with NfL change most significant (p< 10−20). Analysis of changes in protein levels demonstrated that the proteome of patients treated with patisiran trended toward that of healthy controls at 18 months. Healthy controls' NfL levels were 4-fold lower than in patients with ATTRv amyloidosis with polyneuropathy (16.3 pg/mL vs 69.4 pg/mL, effect −53.1 pg/mL [95% confidence interval –60.5 to −45.9]). NfL levels at 18 months increased with placebo (99.5 pg/mL vs 63.2 pg/mL, effect 36.3 pg/mL [16.5–56.1]) and decreased with patisiran treatment (48.8 pg/mL vs 72.1 pg/mL, effect −23.3 pg/mL [–33.4 to −13.1]) from baseline. At 18 months, improvement in modified Neuropathy Impairment Score +7 score after patisiran treatment significantly correlated with reduced NfL (R= 0.43 [0.29–0.55]).ConclusionsFindings suggest that NfL may serve as a biomarker of nerve damage and polyneuropathy in ATTRv amyloidosis, enable earlier diagnosis of patients with ATTRv amyloidosis, and facilitate monitoring of disease progression.Classification of EvidenceThis study provides Class III evidence that NfL levels may enable earlier diagnosis of polyneuropathy in patients with ATTRv amyloidosis and facilitate monitoring of disease progression.

Introduction: Nutritional deficiency may result in adverse health consequences. Socio-cultural practices, financial condition, awareness of parents and local factors influence the nutritional status. Malnutrition is one of the leading health issues in India. Aim: To assess the nutritional status of school age children and the influence of socioeconomic status on nutrition. Materials and Methods: A community based cross-sectional study was conducted among 208 numbers of school children (4-14 years) in Guntur and Vijayawada slum areas during July and August 2018. Semi-structured questionnaire was used to collect anthropometric and general data. Anthropometric measurements such as weight in Kg and height in cm were recorded. Chi-square test, unpaired t-test and Multivariate analysis were used to assess nutritional status at 5% level of significance. Results: The prevalence of stunted children (low height for age), Wasted children (low BMI for age) were 46.63% and 48.08%, respectively. The percentage of children with underweight (low weight for age), overweight (high BMI for age) were 68.27% and 4.80%, respectively. 53.85% underweight children belonged to lower socioeconomic status. No difference in prevalence was observed among boys and girls for stunting and underweight (p>0.05). The mean heights of normal and stunted children were significantly different (p

The entire world is engulfed in the fight against the COVID-19 pandemic, leading to a significant surge in research experiments, government policies, and social media discussions. A multi-modal information access and data visualization platform can play a critical role in supporting research aimed at understanding and developing preventive measures for the pandemic. In this paper, we present a multi-faceted AI-based search and visualization engine, CovidExplorer. Our system aims to help researchers understand current state-of-the-art COVID-19 research, identify research articles relevant to their domain, and visualize real-time trends and statistics of COVID-19 cases. In contrast to other existing systems, CovidExplorer also brings in India-specific topical discussions on social media to study different aspects of COVID-19. The system, demo video, and the datasets are available at http://covidexplorer.in., Comment: 4 pages, 7 figures, The associated system can be accessed at http://covidexplorer.in, To be published in the Proceedings of the 29th ACM International Conference on Information and Knowledge Management (CIKM '20) (October 19-23, 2020)(Virtual Event, Ireland)

Short interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) are the most clinically advanced oligonucleotide-based platforms. A number of N-acetylgalactosamine (GalNAc)-conjugated siRNAs (GalNAc-siRNAs), also referred to as RNA interference (RNAi) therapeutics, are currently in various stages of development, though none is yet approved. While the safety of ASOs has been the subject of extensive review, the nonclinical safety profiles of GalNAc-siRNAs have not been reported. With the exception of sequence differences that confer target RNA specificity, GalNAc-siRNAs are largely chemically uniform, containing limited number of phosphorothioate linkages, and 2’-O-methyl and 2’-deoxy-2’-fluoro ribose modifications. Here, we present the outcomes of short-term (3–5 week) rat and monkey weekly repeat-dose toxicology studies of six Enhanced Stabilization Chemistry GalNAc-siRNAs currently in clinical development. In nonclinical studies at supratherapeutic doses, these molecules share similar safety signals, with histologic findings in the organ of pharmacodynamic effect (liver), the organ of elimination (kidney), and the reticuloendothelial system (lymph nodes). The majority of these changes are nonadverse, partially to completely reversible, correlate well with pharmacokinetic parameters and tissue distribution, and often reflect drug accumulation. Furthermore, all GalNAc-siRNAs tested to date have been negative in genotoxicity and safety pharmacology studies.

In this paper, an Average Information based approach for lung cancer analysis and diagnosis has been proposed. Suggested methodology is established on average information parameters by utilizing image processing tools for lung cancer investigation. The real issue for the lung cancer diagnosis is the time constrictions for physical diagnosis that expands the death possibilities. Henceforth essentially proposed technique is an approach that would help the medical practitioners for precise and superior decision against the lung cancer discovery. Microscopic lung images are taken for analysis and investigation by using digital image processing with MATLAB. The statistical and mathematical parameters under statistical analysis are selected on the basis of the principle working of Average information technique. The input parameters like Entropy, Standard Deviation, Mean, Variance and MSE for average information method are implemented over a large microscopic lung image database. The individual statistical and mathematical parameter analysis with its impact on lung cancer images is successfully carried out and finally the accuracy, selectivity, and sensitivity of the proposed method is calculated by implementing the standard diagnostic test on the proposed method. This method also successfully rejects null hypothesis test by implementing one of the standard statistical methods.