Nevin Manimala

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

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

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

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

Neurology. 2021 Jun 7:10.1212/WNL.0000000000012343. doi: 10.1212/WNL.0000000000012343. Online ahead of print.

ABSTRACT

OBJECTIVE: To investigate the relationship between late-life duration of poverty exposure and cognitive function and decline among older adults in China.

METHODS: Data were from 3,209 participants aged ≥64 in the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Duration of poverty, defined according to urban and rural regional standards from the China Statistical Yearbook, was assessed based on annual household income from 2005-2011 (never in poverty; 1/3 of the period in poverty; ≥2/3 of the period in poverty). Cognitive function was measured by the Chinese Mini Mental State Exam (CMMSE) from 2011-2018. We used attrition-weighted, multivariable mixed-effects Tobit regression to examine the association of duration of poverty with cognitive function and rate of decline.

RESULTS: A total of 1,162 individuals (36.21%) were never in poverty over the period from 2005-2011, 1,172 (36.52%) were in poverty 1/3 of the period, and 875 (27.27%) were in poverty ≥2/3 of the period. A longer poverty duration was associated with lower subsequent CMMSE scores with a dose-response relationship (1/3 vs. never in poverty: β = -0.98; 95% CI: -1.61 to -0.35; ≥2/3 vs. never in poverty: β = -1.55; 95% CI: -2.29 to -0.81). However, a longer duration of poverty was associated with a slower rate of CMMSE score decline over time from 2011-2018.

CONCLUSION: These findings provide valuable evidence on the role of cumulative late-life poverty in relation to cognitive health among older adults in a rapidly urbanizing and aging middle-income country. Our findings may support a compensation hypothesis for cognitive reserve in this setting.

PMID:34099525 | DOI:10.1212/WNL.0000000000012343

BMJ Glob Health. 2021 Jun;6(6):e005238. doi: 10.1136/bmjgh-2021-005238.

ABSTRACT

BACKGROUND: Little is known about the contribution of community health posts and community health workers (CHWs) to geographical accessibility of primary healthcare (PHC) services at community level and strategies for optimising geographical accessibility to these services.

METHODS: Using a complete georeferenced census of community health posts and CHWs in Niger and other high-resolution spatial datasets, we modelled travel times to community health posts and CHWs between 2000 and 2013, accounting for training, commodities and maximum population capacity. We estimated additional CHWs needed to optimise geographical accessibility of the population beyond the reach of the existing community health post network. We assessed the efficiency of geographical targeting of the existing community health post network compared with networks designed to optimise geographical targeting of the estimated population, under-5 deaths and Plasmodium falciparum malaria cases.

RESULTS: The per cent of the population within 60-minute walking to the nearest community health post with a CHW increased from 0.0% to 17.5% between 2000 and 2013. An estimated 10.4 million people (58.5%) remained beyond a 60-minute catchment of community health posts. Optimal deployment of 7741 additional CHWs could increase geographical coverage from 41.5% to 82.9%. Geographical targeting of the existing community health post network was inefficient but optimised networks could improve efficiency by 32.3%-47.1%, depending on targeting metric.

INTERPRETATIONS: We provide the first estimates of geographical accessibility to community health posts and CHWs at national scale in Niger, highlighting improvements between 2000 and 2013, geographies where gaps remained and approaches for optimising geographical accessibility to PHC services at community level.

PMID:34099482 | DOI:10.1136/bmjgh-2021-005238

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

J Am Soc Cytopathol. 2021 May 19:S2213-2945(21)00050-8. doi: 10.1016/j.jasc.2021.05.003. Online ahead of print.

ABSTRACT

INTRODUCTION: Cytopathology fellowships need measures to assess performance of fellows. We sought to compare several internal quantitative assessment metrics in our fellowship with external metrics, such as performance on the American Society of Cytopathology (ASC) Progressive Evaluation of Competency (PEC) examination and United States Medical Licensing Examination (USMLE).

METHODS: Quantitative parameters generated from our laboratory information system (LIS) on cytopathology fellows were evaluated over 6 years, including case volume and diagnostic discrepancies, in addition to ASC PEC and USMLE scores. For discrepancy reports, interpretations made by the fellow were compared with that of the cytopathologist, and classified as none (concordant), minor (<2-levels) or major (≥2-levels).

RESULTS: We evaluated internal and external metrics on 13 fellows over 6 years. The program average diagnostic concordance rate was 89.9%, with an average major discrepancy rate of 1.5%, and an average monthly case volume of 260 cases. More fellows with above-average ASC PEC performance showed above-average concordant diagnoses and lower case volume, while below-average PEC scores were seen more often with higher major discrepancy rates. More fellows with above-average USMLE scores had higher case volumes, while low USMLE scores showed a trend towards higher major discrepancy rates.

CONCLUSION: Our fellowship program has used a variety of internal and external measures of performance for cytopathology fellows. Although the findings show no statistically significant finding correlating performance, these quantitative parameters generated from our LIS were helpful to identify areas of improvement, facilitate comparison to peers, and provide case volume documentation.

PMID:34099427 | DOI:10.1016/j.jasc.2021.05.003