Category: Nevin Manimala

PLoS One. 2021 Jun 8;16(6):e0252533. doi: 10.1371/journal.pone.0252533. eCollection 2021.

ABSTRACT

Recent technological advances in the field of big data have increased our capabilities to query large databases and combine information from different domains and disciplines. In the area of preclinical studies, initiatives like SEND (Standard for Exchange of Nonclinical Data) will also contribute to collect and present nonclinical data in a consistent manner and increase analytical possibilities. With facilitated access to preclinical data and improvements in analytical algorithms there will surely be an expectation for organisations to ensure all the historical data available to them is leveraged to build new hypotheses. These kinds of analyses may soon become as important as the animal studies themselves, in addition to being critical components to achieve objectives aligned with 3Rs. This article proposes the application of meta-analyses at large scale in corporate databases as a tool to exploit data from both preclinical studies and in vitro pharmacological activity assays to identify associations between targets and tissues that can be used as seeds for the development of causal hypotheses to characterise of targets. A total of 833 in-house preclinical toxicity studies relating to 416 compounds reported to be active (pXC50 ≥ 5.5) against a panel of 96 selected targets of interest for potential off-target non desired effects were meta-analysed, aggregating the data in tissue-target pairs. The primary outcome was the odds ratio (OR) of the number of animals with observed events (any morphology, any severity) in treated and control groups in the tissue analysed. This led to a total of 2139 meta-analyses producing a total of 364 statistically significant associations (random effects model), 121 after adjusting by multiple comparison bias. The results show the utility of the proposed approach to leverage historical corporate data and may offer a vehicle for researchers to share, aggregate and analyse their preclinical toxicological data in precompetitive environments.

PMID:34101743 | DOI:10.1371/journal.pone.0252533

PLoS One. 2021 Jun 8;16(6):e0252140. doi: 10.1371/journal.pone.0252140. eCollection 2021.

ABSTRACT

BACKGROUND: The widely-used estimates of completeness of birth registration collected by Demographic and Health Surveys (DHS) and Multiple Indicator Cluster Surveys (MICS) and published by UNICEF primarily rely on registration status of children as reported by respondents. However, these self-reported estimates may be inaccurate when compared with completeness as assessed from nationally-reported official birth registration statistics, for several reasons, including over-reporting of registration due to concern about penalties for non-registration. This study assesses the concordance of self-reported birth registration and certification completeness with completeness calculated from civil registration and vital statistics (CRVS) systems data for 57 countries.

METHODS: Self-reported estimates of birth registration and certification completeness, at ages less than five years and 12-23 months, were compiled and calculated from the UNICEF birth registration database, DHS and MICS. CRVS birth registration completeness was calculated as birth registrations reported by a national authority divided by estimates of live births published in the United Nations (UN) World Population Prospects or the Global Burden of Disease (GBD) Study. Summary measures of concordance were used to compare completeness estimates.

FINDINGS: Birth registration completeness (based on ages less than five years) calculated from self-reported data is higher than that estimated from CRVS data in most of the 57 countries (31 countries according to UN estimated births, average six percentage points (p.p.) higher; 43 countries according to GBD, average eight p.p. higher). For countries with CRVS completeness less than 95%, self-reported completeness was higher in 26 of 28 countries, an average 13 p.p. and median 9-10 p.p. higher. Self-reported completeness is at least 30 p.p. higher than CRVS completeness in three countries. Self-reported birth certification completeness exhibits closer concordance with CRVS completeness. Similar results are found for self-reported completeness at 12-23 months.

CONCLUSIONS: These findings suggest that self-reported completeness figures over-estimate completeness when compared with CRVS data, especially at lower levels of completeness, partly due to over-reporting of registration by respondents. Estimates published by UNICEF should be viewed cautiously, especially given their wide usage.

PMID:34101745 | DOI:10.1371/journal.pone.0252140

PLoS One. 2021 Jun 8;16(6):e0252004. doi: 10.1371/journal.pone.0252004. eCollection 2021.

ABSTRACT

OBJECTIVE: To characterize the microbial communities of the anterior nares (nose) and posterior pharynx (throat) of adults dwelling in the community and in nursing homes before and after treatment with intranasal mupirocin.

METHODS: Staphylococcus aureus-colonized adults were recruited from the community (n = 25) and from nursing homes (n = 7). S. aureus colonization was confirmed using cultures. Participants had specimens taken from nose and throat for S. aureus quantitation using quantitative PCR for the nuc gene and bacterial profiling using 16S rRNA gene sequencing over 12 weeks. After two baseline study visits 4 weeks apart, participants received intranasal mupirocin for 5 days with 3 further visits over a 8 week follow-up period.

RESULTS: We found a decrease in the absolute abundance of S. aureus in the nose for 8 weeks after mupirocin (1693 vs 141 fg/ul, p = 0.047). Mupirocin caused a statistically significant disruption in bacterial communities of the nose and throat after 1 week, which was no longer detected after 8 weeks. Bacterial community profiling demonstrated that there was a decrease in the relative abundance of S. aureus (8% vs 0.3%, p<0.01) 8 weeks after mupirocin and a transient decrease in the relative abundance of Staphylococcus epidermidis in the nose (21% vs 5%, p<0.01) 1 week after mupirocin.

CONCLUSIONS: Decolonization with mupirocin leads to a sustained effect on absolute and relative abundance of S. aureus but not for other bacteria in the nose. This demonstrates that a short course of mupirocin selectively decreases S. aureus in the nose for up to 8 weeks.

PMID:34101737 | DOI:10.1371/journal.pone.0252004

Nat Commun. 2021 Jun 7;12(1):3411. doi: 10.1038/s41467-021-23627-6.

ABSTRACT

Tree-ring chronologies underpin the majority of annually-resolved reconstructions of Common Era climate. However, they are derived using different datasets and techniques, the ramifications of which have hitherto been little explored. Here, we report the results of a double-blind experiment that yielded 15 Northern Hemisphere summer temperature reconstructions from a common network of regional tree-ring width datasets. Taken together as an ensemble, the Common Era reconstruction mean correlates with instrumental temperatures from 1794-2016 CE at 0.79 (p < 0.001), reveals summer cooling in the years following large volcanic eruptions, and exhibits strong warming since the 1980s. Differing in their mean, variance, amplitude, sensitivity, and persistence, the ensemble members demonstrate the influence of subjectivity in the reconstruction process. We therefore recommend the routine use of ensemble reconstruction approaches to provide a more consensual picture of past climate variability.

PMID:34099683 | DOI:10.1038/s41467-021-23627-6

Nat Commun. 2021 Jun 7;12(1):3417. doi: 10.1038/s41467-021-22491-8.

ABSTRACT

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease.

PMID:34099642 | DOI:10.1038/s41467-021-22491-8

Nat Commun. 2021 Jun 7;12(1):3394. doi: 10.1038/s41467-021-23134-8.

ABSTRACT

The large majority of variants identified by GWAS are non-coding, motivating detailed characterization of the function of non-coding variants. Experimental methods to assess variants’ effect on gene expressions in native chromatin context via direct perturbation are low-throughput. Existing high-throughput computational predictors thus have lacked large gold standard sets of regulatory variants for training and validation. Here, we leverage a set of 14,807 putative causal eQTLs in humans obtained through statistical fine-mapping, and we use 6121 features to directly train a predictor of whether a variant modifies nearby gene expression. We call the resulting prediction the expression modifier score (EMS). We validate EMS by comparing its ability to prioritize functional variants with other major scores. We then use EMS as a prior for statistical fine-mapping of eQTLs to identify an additional 20,913 putatively causal eQTLs, and we incorporate EMS into co-localization analysis to identify 310 additional candidate genes across UK Biobank phenotypes.

PMID:34099641 | DOI:10.1038/s41467-021-23134-8

Proc Natl Acad Sci U S A. 2021 Jun 15;118(24):e2020620118. doi: 10.1073/pnas.2020620118.

ABSTRACT

Despite their great promise, artificial intelligence (AI) systems have yet to become ubiquitous in the daily practice of medicine largely due to several crucial unmet needs of healthcare practitioners. These include lack of explanations in clinically meaningful terms, handling the presence of unknown medical conditions, and transparency regarding the system’s limitations, both in terms of statistical performance as well as recognizing situations for which the system’s predictions are irrelevant. We articulate these unmet clinical needs as machine-learning (ML) problems and systematically address them with cutting-edge ML techniques. We focus on electrocardiogram (ECG) analysis as an example domain in which AI has great potential and tackle two challenging tasks: the detection of a heterogeneous mix of known and unknown arrhythmias from ECG and the identification of underlying cardio-pathology from segments annotated as normal sinus rhythm recorded in patients with an intermittent arrhythmia. We validate our methods by simulating a screening for arrhythmias in a large-scale population while adhering to statistical significance requirements. Specifically, our system 1) visualizes the relative importance of each part of an ECG segment for the final model decision; 2) upholds specified statistical constraints on its out-of-sample performance and provides uncertainty estimation for its predictions; 3) handles inputs containing unknown rhythm types; and 4) handles data from unseen patients while also flagging cases in which the model’s outputs are not usable for a specific patient. This work represents a significant step toward overcoming the limitations currently impeding the integration of AI into clinical practice in cardiology and medicine in general.

PMID:34099565 | DOI:10.1073/pnas.2020620118

Light Sci Appl. 2021 Jun 7;10(1):120. doi: 10.1038/s41377-021-00558-x.

ABSTRACT

Mode-locked lasers have been widely used to explore interactions between optical solitons, including bound-soliton states that may be regarded as “photonic molecules”. Conventional mode-locked lasers normally, however, host at most only a few solitons, which means that stochastic behaviours involving large numbers of solitons cannot easily be studied under controlled experimental conditions. Here we report the use of an optoacoustically mode-locked fibre laser to create hundreds of temporal traps or “reactors” in parallel, within each of which multiple solitons can be isolated and controlled both globally and individually using all-optical methods. We achieve on-demand synthesis and dissociation of soliton molecules within these reactors, in this way unfolding a novel panorama of diverse dynamics in which the statistics of multi-soliton interactions can be studied. The results are of crucial importance in understanding dynamical soliton interactions and may motivate potential applications for all-optical control of ultrafast light fields in optical resonators.

PMID:34099618 | DOI:10.1038/s41377-021-00558-x

J Investig Med. 2021 Jun 7:jim-2021-001816. doi: 10.1136/jim-2021-001816. Online ahead of print.

ABSTRACT

The role of thrombolysis in submassive pulmonary embolism (PE) is controversial due to the high risk of hemorrhage. This study aimed to evaluate the role of half-dose tissue-type plasminogen activator (rt-PA) in preventing death/hemodynamic decompensation in submassive (intermediate-risk) PE without increasing the risk of bleeding. In a prospective, non-randomized, open-label, single-center trial, we compared 50 mg rt-PA plus low molecular weight heparin (LMWH) with LMWH in submassive (intermediate-risk) PE. Eligible cases had confirmed pulmonary hypertension on echocardiography, and/or right ventricular cavity expansion and/or interventricular septal deviation on echocardiography, and/or right to left ventricular ratio equal to or greater than 0.9 mm on CT angiography. The primary outcome was death or hemodynamic decompensation within 7 and 30 days after treatment was given. The primary safety outcome was major extracranial bleeding or hemorrhagic stroke within 7 days. Seventy-six patients were included in the study. Total death/hemodynamic decompensation in the first 7 and 30 days was significantly less in the half-dose rt-PA group than in the LMWH group (p=0.028 and p=0.009, respectively). No significant differences were found between the two groups in terms of recurrent embolism and pulmonary hypertension at 6-month follow-up (p=1.000 and p=0.778). There was no intracranial hemorrhage in any of the patients. There were no statistically significant differences between the two groups in terms of major or minor bleeding complications. This trial showed half-dose rt-PA treatment in submassive (intermediate-risk) PE prevented death/hemodynamic decompensation in the first 7-day and 30-day period compared with LMWH treatment without increasing the risk of bleeding.

PMID:34099544 | DOI:10.1136/jim-2021-001816

Cancer Discov. 2021 Jun 7:candisc.1500.2020. doi: 10.1158/2159-8290.CD-20-1500. Online ahead of print.

ABSTRACT

Immune checkpoint blockade (ICB) has revolutionized cancer therapy. However, the response of patients to ICB is difficult to predict. Here, we examined 81 lung cancer patients under ICB treatment and found that patients with MET amplification were resistant to ICB and had a poor progress-free survival. Tumors with MET amplifications had significantly decreased STING levels and antitumor T cell infiltration. Furthermore, we performed deep single-cell RNA sequencing on more than 20000 single immune cells and identified an immunosuppressive signature with increased subsets of XIST- and CD96-positive exhausted NK cells and decreased CD8+ T cell and NK cell populations in patients with MET-amplification. Mechanistically, we found that oncogenic MET signaling induces phosphorylation of UPF1 and downregulates tumor cell STING expression via modulation of the 3′-UTR length of STING by UPF1. Decreased efficiency of ICB by MET amplification can be overcome by inhibiting MET.

PMID:34099454 | DOI:10.1158/2159-8290.CD-20-1500