bluuebunny/crossref_metadata_2025 huggingface dataset:
AWOT and CWOT for genotype and genotype-by-treatment interaction joint analysis in pharmacogenetics GWAS
Authors: Zhang Hong , Mehrotra Devan V , Shen Judong
Published: January 2023

Motivation

Pharmacogenomics (PGx) research holds the promise for detecting association between genetic variants and drug responses in randomized clinical trials, but it is limited by small populations and thus has low power to detect signals. It is critical to increase the power of PGx genome-wide association studies (GWAS) with small sample sizes so that variant–drug-response association discoveries are not limited to common variants with extremely large effect.

Results

In this article, we first discuss the challenges of PGx GWAS studies and then propose the adaptively weighted joint test (AWOT) and Cauchy Weighted jOint Test (CWOT), which are two flexible and robust joint tests of the single nucleotide polymorphism main effect and genotype-by-treatment interaction effect for continuous and binary endpoints. Two analytic procedures are proposed to accurately calculate the joint test P-value. We evaluate AWOT and CWOT through extensive simulations under various scenarios. The results show that the proposed AWOT and CWOT control type I error well and outperform existing methods in detecting the most interesting signal patterns in PGx settings (i.e. with strong genotype-by-treatment interaction effects, but weak genotype main effects). We demonstrate the value of AWOT and CWOT by applying them to the PGx GWAS from the Bezlotoxumab Clostridium difficile MODIFY I/II Phase 3 trials.

Availability and implementation

The R package COWT is publicly available on CRAN https://cran.r-project.org/web/packages/cwot/index.html.

Supplementary information

Supplementary data are available at Bioinformatics online.
Hierarchical modelling of microbial communities
Authors: Glöckler Manuel , Dräger Andreas , Mostolizadeh Reihaneh
Published: January 2023

The human body harbours a plethora of microbes that play a fundamental role in the well-being of the host. Still, the contribution of many microorganisms to human health remains undiscovered. To understand the composition of their communities, the accurate genome-scale metabolic network models of participating microorganisms are integrated to construct a community that mimics the normal bacterial flora of humans. So far, tools for modelling the communities have transformed the community into various optimization problems and model compositions. Therefore, any knockout or modification of each submodel (each species) necessitates the up-to-date creation of the community to incorporate rebuildings. To solve this complexity, we refer to the context of SBML in a hierarchical model composition, wherein each species’s genome-scale metabolic model is imported as a submodel in another model. Hence, the community is a model composed of submodels defined in separate files. We combine all these files upon parsing to a so-called ‘flattened’ model, i.e., a comprehensive and valid SBML file of the entire community that COBRApy can parse for further processing. The hierarchical model facilitates the analysis of the whole community irrespective of any changes in the individual submodels.

Availability and implementation

The module is freely available at https://github.com/manuelgloeckler/ncmw.
NGSNGS: next-generation simulator for next-generation sequencing data
Authors: Henriksen Rasmus Amund , Zhao Lei , Korneliussen Thorfinn Sand
Published: January 2023

With the rapid expansion of the capabilities of the DNA sequencers throughout the different sequencing generations, the quantity of generated data has likewise increased. This evolution has also led to new bioinformatical methods, for which in silico data have become crucial when verifying the accuracy of a model or the robustness of a genomic analysis pipeline. Here, we present a multithreaded next-generation simulator for next-generation sequencing data (NGSNGS), which simulates reads faster than currently available methods and programs. NGSNGS can simulate reads with platform-specific characteristics based on nucleotide quality score profiles as well as including a post-mortem damage model which is relevant for simulating ancient DNA. The simulated sequences are sampled (with replacement) from a reference DNA genome, which can represent a haploid genome, polyploid assemblies or even population haplotypes and allows the user to simulate known variable sites directly. The program is implemented in a multithreading framework and is factors faster than currently available tools while extending their feature set and possible output formats.

Availability and implementation

The method and associated programs are released as open-source software, code and user manual are available at https://github.com/RAHenriksen/NGSNGS.

Supplementary information

Supplementary data are available at Bioinformatics online.
The influence ofTorulaspora delbrueckiion beer fermentation
Authors: Kayadelen Firuze , Agirman Bilal , Jolly Neil P , Erten Huseyin
Published: January 2023

In this study, the effect of five different Torulaspora delbrueckii strains in combination with an ale type Saccharomyces cerevisiae on physical, chemical, microbiological, aroma composition, and sensory profiles of beer were examined. The ethyl alcohol content of produced beers ranged from 5.46% (v/v) to 5.93% (v/v), while the highest alcohol amount was obtained using a pure culture of S. cerevisiae. The major volatiles among beer aroma compounds was acetaldehyde, n-propanol, 3-methyl-butanol, 2-methyl-butanol, ethyl acetate, isoamyl acetate, 2,3-butanedione, and 2,3-pentanedione. It was ascertained that the total amount of higher alcohols was higher in the S. cerevisiae control beer compared to all mixed fermentations. Total ester levels were higher in all the mixed culture beers than the control beer. Sensory evaluation showed that all the mixed cultures of S. cerevisiae and T. delbrueckii positively influenced the sensory profile of the beers. Strain Y1031 was the most preferred and was characterized as rich in hop aroma and full bodied. It is therefore a suitable strategy to use T. delbrueckii in mixed fermentations with S. cerevisiae to produce beer with a distinctive flavor. The results demonstrate that, T. delbrueckii strains isolated or commercialized for winemaking can be equally employed as well in brewing.
Artificial intelligence empowers the second-observer strategy for colonoscopy: a randomized clinical trial
Authors: Wang Pu , Liu Xiao-Gang , Kang Min , Peng Xue , Shu Mei-Ling , Zhou Guan-Yu , Liu Pei-Xi , Xiong Fei , Deng Ming-Ming , Xia Hong-Fen , Li Jian-Jun , Long Xiao-Qi , Song Yan , Li Liang-Ping
Published: January 2023

Background

In colonoscopy screening for colorectal cancer, human vision limitations may lead to higher miss rate of lesions; artificial intelligence (AI) assistance has been demonstrated to improve polyp detection. However, there still lacks direct evidence to demonstrate whether AI is superior to trainees or experienced nurses as a second observer to increase adenoma detection during colonoscopy. In this study, we aimed to compare the effectiveness of assistance from AI and human observer during colonoscopy.

Methods

A prospective multicenter randomized study was conducted from 2 September 2019 to 29 May 2020 at four endoscopy centers in China. Eligible patients were randomized to either computer-aided detection (CADe)-assisted group or observer-assisted group. The primary outcome was adenoma per colonoscopy (APC). Secondary outcomes included polyp per colonoscopy (PPC), adenoma detection rate (ADR), and polyp detection rate (PDR). We compared continuous variables and categorical variables by using R studio (version 3.4.4).

Results

A total of 1,261 (636 in the CADe-assisted group and 625 in the observer-assisted group) eligible patients were analysed. APC (0.42 vs 0.35, P = 0.034), PPC (1.13 vs 0.81, P < 0.001), PDR (47.5% vs 37.4%, P < 0.001), ADR (25.8% vs 24.0%, P = 0.464), the number of detected sessile polyps (683 vs 464, P < 0.001), and sessile adenomas (244 vs 182, P = 0.005) were significantly higher in the CADe-assisted group than in the observer-assisted group. False detections of the CADe system were lower than those of the human observer (122 vs 191, P < 0.001).

Conclusions

Compared with the human observer, the CADe system may improve the clinical outcome of colonoscopy and reduce disturbance to routine practice (Chictr.org.cn No.: ChiCTR1900025235).
Association of Subjective and Objective Measures of Sleep With Gut Microbiota Composition and Diversity in Older Men: The Osteoporotic Fractures in Men Study
Authors: Estaki Mehrbod , Langsetmo Lisa , Shardell Michelle , Mischel Anna , Jiang Lingjing , Zhong Yuan , Kaufmann Christopher , Knight Rob , Stone Katie , Kado Deborah
Published: January 2023

Background

Growing evidence suggests bidirectional links between gut microbiota and sleep quality as shared contributors to health. Little is known about the relationship between microbiota and sleep among older persons.

Methods

We used 16S rRNA sequencing to characterize stool microbiota among men (n = 606, mean [standard deviation] age = 83.9 [3.8]) enrolled in the Osteoporotic Fractures in Men (MrOS) study from 2014 to 2016. Sleep was assessed concurrently by a questionnaire (Pittsburgh Sleep Quality index [PSQI]), and activity monitor to examine timing (acrophase) and regularity of patterns (F-statistic). Alpha diversity was measured using Faith’s phylogenetic diversity (PD). Beta diversity was calculated with robust Aitchison distance with matrix completion (RPCA) and phylogenetic-RPCA (PRPCA). Their association with sleep variables was tested with partial distance-based redundancy analysis (dbRDA). Predictive-ratio biomarkers associated with sleep measurements were identified with CoDaCoRe.

Results

In unadjusted analyses, men with poor sleep (PSQI >5) tended to have lower alpha diversity compared to men with normal sleep (Faith’s PD, beta = −0.15; 95% confidence interval [CI]: −0.30 to 0.01, p = .06). Sleep regularity was significantly associated with RPCA and PRPCA, even after adjusting for site, batch, age, ethnicity, body mass index, diabetes, antidepressant and sleep medication use, and health behaviors (RPCA/PRPCA dbRDA; p = .033/.002). In taxonomic analysis, ratios of 7:6 bacteria for better regularity (p = .0004) and 4:7 for worse self-reported sleep (p = .005) were differentially abundant: some butyrate-producing bacteria were associated with better sleep characteristics.

Conclusions

Subjective and objective indicators of sleep quality suggest that older men with better sleep patterns are more likely to harbor butyrate-producing bacteria associated with better health.
Aorto-aortic bypass in an infant with middle aortic syndrome and Marfan syndrome: a 15-year follow-up
Authors: Heck Roland , Fischer-Zirnsak Björn , Photiadis Joachim , Horn Denise , Gehle Petra
Published: January 2023

We present a 15-year follow-up after aorto-aortic bypass surgery in a 7-month-old infant with middle aortic syndrome and confirmed Marfan syndrome. In anticipation of her growth, the length of the graft was adjusted to the anticipated length of the narrowed aorta in her adolescence. In addition, her height was controlled by oestrogen, and her growth was stopped at 178 cm. To date, the patient is free from aortic reoperation and lower limb malperfusion.
The impact of socio-demographic factors on health-related quality of life after coronary artery bypass surgery
Authors: Assmann Anna Kathrin , Assmann Alexander , Waßenberg Sebastian , Kojcici Besnik , Schaal Nora K , Lichtenberg Artur , Ennker Jürgen , Albert Alexander
Published: January 2023

OBJECTIVES

To achieve a beneficial impact on long-term outcome after coronary artery bypass grafting (CABG), the goal of the present study was the early identification of patients at risk of impaired postoperative health-related quality of life (HRQoL), particularly evaluating the significance of socio-demographic variables.

METHODS

In this prospective, single-centre cohort study of patients having an isolated CABG (January 2004–December 2014), preoperative socio-demographic (preSOC) and preoperative medical variables as well as 6-month follow-up data including the Nottingham Health Profile were analysed in 3,237 patients.

RESULTS

All preSOC (gender, age, marriage and employment) and follow-up (chest pain, dyspnoea) variables proved to have significant influence on HRQoL (P < 0.001), male patients below 60 years being particularly impaired. The effects of marriage and employment on HRQoL are modulated by age and gender. The significance of the predictors of reduced HRQoL differs between the 6 Nottingham Health Profile domains. Multivariable regression analyses revealed explained proportions of variance amounting to 7% for preSOC and 4% for preoperative medical variables.

CONCLUSIONS

The identification of patients at risk of impaired postoperative HRQoL is decisive for providing additional support. This study reveals that the assessment of 4 preoperative socio-demographic characteristics (age, gender, marriage, employment) is more predictive of HRQoL after CABG than are multiple medical variables.
O02 Improving antimicrobial use in HSE older persons residential care facilities
Authors: Shah M , Clancy A , Regan M , Maher A M , Armitage S , Ryan C , Mannion C , Sheehan P , Gallagher O , Foran R , Fagan S , Donnelly M , Love B
Published: January 2023

Background

Antimicrobial use in Irish older persons residential care facilities (OP RCFs) is higher than in other European countries. In 2020/21, for the first time, an antimicrobial pharmacist (AMP) was appointed to each community healthcare organization (CHO) to monitor, develop and promote antimicrobial stewardship in community settings.

Objectives

To establish baseline antibiotic use, develop antimicrobial stewardship tools for OP RCFs, promote best practice in relation to antimicrobial stewardship (AMS) and monitor trends in antimicrobial use in HSE (state-run) OP RCFs.

Methods

A baseline point prevalence survey (PPS) of antimicrobial use was conducted across all HSE OP RCFs between October 2020 and August 2021. Following the survey, key national recommendations and AMS resources were developed in collaboration with the national Antimicrobial Resistance and Infection Control Programme. Feedback was provided to participating facilities by CHO AMPs with antimicrobial stewardship support and education for nursing and medical staff. In September 2021, monthly monitoring of antibiotic use was established in HSE OP RCFs in collaboration with local managers, to capture the proportion of antibiotics used for prophylaxis or treatment each month.

Results

A baseline PPS of antimicrobial use in 2020/21 showed that 11.9% (528/4446) of residents were on a systemic antibiotic, with 6.3% on antibiotic prophylaxis. Urinary tract infection accounted for 51% of antibiotic prescriptions. Following the baseline PPS, CHO AMPs developed an AMS toolkit for OP RCFs, engaged with nursing and medical staff to communicate PPS results, AMS resources and support implementation of AMS recommendations. Subsequently, monthly self-reporting of antimicrobial use in HSE OP RCFs was commenced in September 2021 and showed a sustained decrease in antimicrobial use with 7.9% residents on an antibiotic in Quarter 2 2022, with 2.7% on antibiotic prophylaxis.

Conclusions

Newly appointed CHO AMPs have successfully promoted AMS across HSE OP RCFs. Following audit, feedback, education, development and promotion of antimicrobial stewardship resources, there was a sustained decrease in the proportion of residents on antibiotics used for treatment and prophylaxis of infection.
P10 Phage-encoded lysins as promising antibacterials against uropathogenic Escherichia coli
Authors: Hanif Sarmad , Das Ritam , Chavan Bhakti , Shah Sanket , Bajpai Urmi , Ahmed Syed
Published: January 2023

Background

Urinary tract infections (UTIs) represent a major public health issue. Uropathogenic Escherichia coli (UPEC) is a pathogen implicated in the vast majority of UTIs. Although treatable, the rampant and indiscriminate use of antibiotics has led to an alarming emergence of MDR strains. This can lead to complications, treatment failure, and increased rates of mortality and morbidity. Given the prevalence of these strains, we are exploring phage encoded-lysins as potential alternatives to antibiotics.

Objectives

Our study involved the development of an in silico strategy for the discovery and characterization of prophage-derived lysin sequences targeting the E. coli cell wall and evaluating the antibacterial activity of the recombinant lysins using in vitro assays.

Methods

Novel lysin sequences were searched by BLAST homology and by screening E. coli prophages in the database (using PHASTER). They were computationally characterized and their domain architecture was examined. Based on the desired physicochemical properties of the 16 lysins, 7 were selected for cloning, expression, and purification as recombinant proteins for the in vitro antibacterial activity.

Results

In silico analysis showed lysozyme-like domain in 9 out of 16 lysins and the predicted structure was either modular or globular. Cationic and hydrophobic residues at the C-terminal end and cationic residues in the catalytic domains indicate intrinsic bactericidal activity. Lysins (7) were cloned in pET28 vector and purified as His-tagged recombinant proteins by Ni-NTA chromatography. Using spot assay, 3 out of 7 lysins (9–12 μg) showed lysis of E. coli cells (BL21 DE3). The most promising was lysin sequence 5, which showed lysis of E. coli cells, both at stationary as well as mid-log phase cells. Turbidity reduction assay showed a 74.94% drop in OD600 in lysin (15 μM) treated cells after 3 h of incubation, at 37°C. Log killing assay showed 4 log10 reduction in the treated cells. Lysozyme assay demonstrates higher than / comparable lysozyme activity of lysin sequence 5 with the positive control.

Conclusions

Sixteen novel prophage-encoded lysin sequences have been identified to create a lysin bank (to screen against E. coli), and 7 of them have been purified. Screening shows three lysins having intrinsic bactericidal activity and hence did not require the addition of an Outer Membrane Permeabilizer (OMP). Lysin sequence 5 has exhibited the highest activity against E. coli cells. Enzyme stability and kinetics studies and screening of clinical isolates of E. coli from UTI patients is underway. Investigating this bank of lysins is aimed at the identification and development of a lead ‘enzybiotic’ with desired PK/PD characteristics against UTI-causing E. coli.
P16 Overuse of antibiotics during the first year of the COVID-19 pandemic in Poland
Authors: Owsianka Izabella , Gajda Mateusz , Krzyściak Paweł , Gryglewska Barbara , Różańska Anna , Wójkowska-Mach Jadwiga
Published: January 2023

Background

It was a retrospective study conducted at the University Hospital in Kraków in Poland (UHC). The objectives of the study identify the trends of the antimicrobial consumption profile from February 2020 to February 2021, the first year of the COVID-19 pandemic in Poland. The hospital records data have been analysed to identify factors that were associated with antimicrobial consumption and illustrate how the situation evolved over time. The secondary objective is to identify the determinants of antimicrobial use.

Methods

The analysis was carried out on data based on electronically registered health care data from the UHC and hospital pharmacy. We included 250 adult patients, divided into 5 groups, and hospitalized with confirmed SARS-CoV-2 infection. The study began on 13 February 2020, when the patient with a confirmed hospital-acquired (HA)-COVID-19 in March was admitted to UHC. Next, we enrolled 49 consecutive patients and then, consecutive 50 patients admitted to the UHK on 13 May 2020, 13 August 2020, 13 November 2020 and 13 February 2021. Patients with HA-COVID-19 were eligible for inclusion in this study.

Results

In total, 178 patients received antimicrobials (ABX), 71.2% of all and the incidence rate of laboratory confirmed healthcare-associated infection (LC-HAI) was 20%. No patients had laboratory-confirmed bacterial co-infection at admission. The severity of COVID-19 was mild in 102 (40.8%), moderate in 92 (36.8%), and severe in 56 (22.4%) patients. Forty-three (17.2%) patients were hospitalized in an ICU, and 97.7% of them were treated with antimicrobials. The length of stay was greater among patients receiving ABX. The percentage of patients receiving antibiotic therapy changed throughout the covered time periods. The lowest proportion was recorded in May 2020 (48.0%), whereas the highest was observed in November 2021 and February 2021 (84.0% both). Systemic glucocorticoids (GCS) were used in 117 patients, 46.8% of all, significantly more frequently in patients with ABXs P<0.001. Patients with severe COVID-19 had the highest antimicrobial consumption values, the median DDD in this group was 20.92, P<0.001. Patients admitted at the beginning of the pandemic (February, May 2020) had significantly higher median DDD values, respectively 25.3 and 16.0 compared with those admitted in later months of the pandemic (August, November 2020; February 2021), 11.0, 11.0 and 11.2.

Conclusions

The results show that despite COVID-19 being a viral disease, the use of antimicrobials has been common in infected patients, especially at the beginning of the pandemic. The observed incidence of LC-HAI did not change during 12 months of follow-up and was very high, despite the fact that only 1/5 of the patients were hospitalized in the ICU.
Upper age limits for US male human papillomavirus vaccination for oropharyngeal cancer prevention: a microsimulation-based modeling study
Authors: Landy Rebecca , Haber Gregory , Graubard Barry I , Campos Nicole G , Sy Stephen , Kim Jane J , Burger Emily A , Cheung Li C , Katki Hormuzd A , Gillison Maura L , Chaturvedi Anil K
Published: January 2023

Background

Human papillomavirus (HVP)–positive oropharyngeal cancer is the most common HPV-associated cancer in the United States. The age at acquisition of oral HPV infections that cause oropharyngeal cancer (causal infections) is unknown; consequently, the benefit of vaccination of US men aged 27-45 years remains uncertain.

Methods

We developed a microsimulation-based, individual-level, state-transition model of oral HPV16 and HPV16-positive oropharyngeal cancer among heterosexual US men aged 15-84 years, calibrated to population-level data. We estimated the benefit of vaccination of men aged 27-45 years for prevention of oropharyngeal cancer, accounting for direct- and indirect effects (ie, herd effects) of male and female vaccination.

Results

In the absence of vaccination, most (70%) causal oral HPV16 infections are acquired by age 26 years, and 29% are acquired between ages 27 and 45 years. Among men aged 15-45 years in 2021 (1976-2006 birth cohorts), status quo vaccination of men through age 26 years is estimated to prevent 95% of 153 450 vaccine-preventable cancers. Assuming 100% vaccination in 2021, extending the upper age limit to 30, 35, 40, or 45 years for men aged 27-45 years (1976-1994 cohorts) is estimated to yield small benefits (3.0%, 4.2%, 5.1%, and 5.6% additional cancers prevented, respectively). Importantly, status quo vaccination of men through age 26 years is predicted to result in notable declines in HPV16-positive oropharyngeal cancer incidence in young men by 2035 (51% and 24% declines at ages 40-44 years and 45-49 years, respectively) and noticeable declines (12%) overall by 2045.

Conclusion

Most causal oral HPV16 infections in US men are acquired by age 26 years, underscoring limited benefit from vaccination of men aged 27-45 years for prevention of HPV16-positive oropharyngeal cancers.
Beyond law and politics: an empirical study of judicial mediation in China
Authors: Fan Kun
Published: January 2023

Beyond law and politics, how will other factors influence individual judicial behaviour in China? How do the gains of efficiency and substantive justice compare with the potential losses of procedural protections? Do judges see their role as to resolve the disputes between the parties by the most appropriate means, or is it only an attempt to render and enforce an authoritative binding decision? Through a series of interviews with Chinese judges, the research provides an empirical narrative on how judicial mediation is actually practiced in China and analyses values and limitations of judicial mediation. The article empirically illustrates the multiplicity of influences on judicial behaviour in China, and the perception of the role of judges in China. Conceptually, the article aspires to contribute to the field of comparative judicial behaviour. It attempts to expand our inquiry beyond the focus on the role of politics and law when analysing judicial behaviour.
Facilitating transcriptional transitions: an overview of chromatin bivalency in plants
Authors: Faivre Léa , Schubert Daniel
Published: January 2023

Chromatin is an essential contributor to the regulation of transcription. The two histone post-translational modifications H3K4me3 and H3K27me3 act as an activator and repressor of gene expression, respectively, and are usually described as being mutually exclusive. However, recent work revealed that both marks might co-exist at several loci, forming a distinctive chromatin state called bivalency. While this state has been detected on a handful of genes involved in plant development and stress responses, its role in the regulation of transcription remains unclear. In an effort to shed more light on the putative function(s) of bivalency in plants, this review details the potential players involved in its setting and reading, and explores how this chromatin state might contribute to the control of gene expression. We propose that bivalency maintains transcriptional plasticity by facilitating transitions between a repressed and an active state and/or by preventing irreversible silencing of its targets. We also highlight recently developed techniques that could be used for further investigating bivalency.
Valid Arguments as True Conditionals
Authors: Iacona Andrea
Published: January 2023

This paper explores an idea of Stoic descent that is largely neglected nowadays, the idea that an argument is valid when the conditional formed by the conjunction of its premises as antecedent and its conclusion as consequent is true. As will be argued, once some basic features of our naïve understanding of validity are properly spelled out, and a suitable account of conditionals is adopted, the equivalence between valid arguments and true conditionals makes perfect sense. The account of validity outlined here, which displays one coherent way to articulate the Stoic intuition, accords with standard formal treatments of deductive validity and encompasses an independently grounded characterization of inductive validity.
A foreground model-independent Bayesian CMB temperature and polarization signal reconstruction and cosmological parameter estimation over large angular scales
Authors: Joseph Albin , Purkayastha Ujjal , Saha Rajib
Published: January 2023

Recent CMB observations have resulted in very precise observational data. A robust and reliable CMB reconstruction technique can lead to efficient estimation of the cosmological parameters. We demonstrate the performance of our methodology using simulated temperature and polarization observations using cosmic variance-limited future-generation PRISM satellite mission. We generate samples from the joint distribution by implementing the CMB inverse covariance weighted internal-linear-combination (ILC) with the Gibbs sampling technique. We use the Python Sky Model (PySM), d4f1s1 to generate the realistic foreground templates. The synchrotron emission is parametrized by a spatially varying spectral index, whereas the thermal dust emission is described as a two-component dust model. We estimate the marginalized densities of CMB signal and theoretical angular power spectrum utilizing the samples from the entire posterior distribution. The best-fitting cleaned CMB map and the corresponding angular power spectrum are consistent with the CMB realization and the sky angular power spectrum, implying an efficient foreground-minimized reconstruction. The likelihood function estimated by making use of the Blackwell–Rao estimator is used for the estimation of cosmological parameters. Our methodology can estimate the tensor-to-scalar ratio r ≥ 0.0075 for the chosen foreground models and the instrumental noise levels. Our current work demonstrates an analysis pipeline starting from the reliable estimation of CMB signal and its angular power spectrum to the case of cosmological parameter estimation using the foreground model-independent Gibbs–ILC method.
Introduction
Authors: Gray Elizabeth Kelly
Published: January 2023

Americans learned more and more about drug dependency from 1776 to 1914, and those who commented on the topic—predominantly members of the white middle class—defended nonmedical drug use by members of the white middle class while criticizing such use by others. Opiate use in America increased extensively in the nineteenth century, and it is important to place this subject in an international context, because news of overseas use both enhanced Americans’ understanding of addiction and ultimately led the government to begin regulating drugs nationally. Understanding of the issue, however, was incomplete. People did not recognize addiction as a brain disease. Also, observers advocated protecting only the white middle class from negative consequences of their own drug use or that of others. For example, they falsely suggested that only members of the white middle class could use drugs without posing a threat to others. This notion would endure.
Habitual Opiate Use in Great Britain, 1821–1877
Authors: Gray Elizabeth Kelly
Published: January 2023

In the 1820s, accounts of habitual opiate use in England shocked middle-class Americans who had assumed that educated white Westerners could avoid addiction. Thomas De Quincey published Confessions of an English Opium-Eater in 1821, and accounts of poet Samuel Taylor Coleridge’s longtime dependency became public. Americans found these accounts interesting because they provided new information, especially as domestic habituation was not publicly discussed. Readers learned that Coleridge never ended his use and that he lied to those around him to get money for laudanum. De Quincey wrote the earliest extant first-person account of addiction, and he maintained that there were many English habitués. He described opium’s “pleasures” and “pains” and denied blame for his condition. Some criticized him for publishing his account because many Americans, after reading Confessions, tried the drug out of curiosity. Others, however, dismissed the possibility that drug addiction could become widespread in America.
American Opium Dens, 1850–1910
Authors: Gray Elizabeth Kelly
Published: January 2023

Many Chinese men emigrated to the United States in the mid-nineteenth century and Americans criticized their opium smoking, though the practice later caught on among native-born Americans. Xenophobia flourished as Chinese immigrants successfully competed with native-born Americans for jobs. Smoking opium provided solace for Chinese immigrants as they endured prejudice and homesickness. Some Americans suggested that smoking opium was a sinister pastime. Opium dens were typically dark, hidden, underground spaces, and reporters visited Chinatowns and described the dens to their readers. Some suggested that den owners enticed and corrupted white youth—which would become an anti-drug trope—and most of these accusations were revealed to be lies. Opium smoking did spread eastward and catch on with a white clientele, first members of urban underworlds and then more “respectable” people. The earliest law against drugs other than alcohol was a San Francisco ordinance barring opium smoking.
For-Profit Philanthropy
Authors: Brakman Reiser Dana , Dean Steven A.
Published: January 2023

For-Profit Philanthropy reimagines the history of philanthropy law, revealing it not to be a tool to subsidize private efforts to benefit the public but a strategic arrangement binding ordinary Americans and elites together in a common purpose. Rather than providing for pure private (no tax or regulation) or public (highly progressive taxes or tight regulation) control over the vast resources amassed by the wealthiest Americans, in 1969 Congress struck a Grand Bargain with both sides. That Grand Bargain preserved private autonomy by imposing a regulatory framework that elevated the public’s voice through detailed timing, targeting, and transparency requirements. Philanthropy law uses the private foundation form to ensure that elites must each year spend a small but meaningful portion of their assets pledged to the public. The foundation also imposes prophylactic targeting restrictions on transactions separating a funder’s business and political interests from their philanthropy. Foundations must also disclose to the public more about the sources and uses of their assets than any other business or charity. Far more assertive regulation would have been possible in the absence of the Grand Bargain’s minimum standards of accountability. Today, innovations from commercially affiliated donor-advised funds to strategic corporate philanthropy to philanthropy limited liability companies set that Grand Bargain aside to provide elites with greater autonomy and privacy. Private ordering, targeted regulation, or a new strategic bargain could strike a modern balance, preserving the benefits of this long-standing partnership. For-Profit Philanthropy offers a detailed roadmap to show how it could be accomplished.
Commercially Affiliated Donor-Advised Fund Sponsors
Authors: Brakman Reiser Dana , Dean Steven A.
Published: January 2023

The donor-advised fund (DAF) works like a debit card for charitable spending. Donors transfer assets to a sponsor entity, which holds the assets in an account until the donor advises the sponsor to contribute them to a charity. Sponsors were once community foundations providing guidance to donors on needs and organizations in their local regions. Today, sponsors affiliated with commercial investment firms dominate the field. DAF sponsors affiliated with commercial entities have come to account for four of the ten largest recipients of charitable funds in the United States: Fidelity Charitable, Goldman Sachs Philanthropy Fund, Schwab Charitable Fund, and the Vanguard Charitable Endowment Program. This chapter explores the potential impact of this dramatic shift on the future of philanthropy. The emergence of DAFs as platforms for giving could supercharge philanthropy. At the same time, they reduce accountability, concentrating control in the hands of society’s elites while obscuring their influence.
Positive Masculinity and Brooklyn Nine-Nine
Authors: Lawson Robert
Published: January 2023

Chapter 7 focuses on ‘positive masculinities’ and explores how men are encouraged to pursue healthier conceptualizations of masculinity. Since the media plays a key part in setting out cultural scripts and expectations of masculinity, this chapter then presents an analysis of the television comedy show Brooklyn Nine-Nine to examine how men use language to connect with others, build relationships, and demonstrate affiliation with friends and loved ones, subsequently subverting and destabilizing hegemonic forms of masculinity. Given that the intersection of language, masculinity, and television is a somewhat unexplored area, this chapter is important in improving our understanding of the role the media plays in promoting alternative constructions of masculinity.
A “Pious” History of the Earth? 1500–1650
Authors: Dal Prete Ivano
Published: January 2023

Chapter 4 details how the new natural, geographical, and ethnographical knowledge that Europe’s colonial expansion depended on shook the foundations of the medieval Earth. The radicalization of religious tensions, the Protestant and Catholic reformations, and the rise of biblical literalism shattered the barriers that for centuries guarded the autonomy of natural philosophy from theology, and vice versa. Restrictions to intellectual freedom all over Europe came with unprecedented calls for a Christianized science of nature. Yet, the new orientations often broadened the scope and breadth of traditional Earth history rather than outright replacing it. In Catholic Europe, authors were only required to state that the world had a beginning, not to uphold a recent one. A created world of undetermined age continued to inform much of the relevant literature.
Conclusion
Authors: Dal Prete Ivano
Published: January 2023

As the French Revolution engendered the socially conservative Napoleonic Empire rather than the dreaded democratic new order, milder versions of diluvialism and an ancient Earth became again more acceptable. During the nineteenth century, however, growing evidence against the Flood along with Darwinian natural selection kindled the revival of biblical literalism on the one hand, and on the other, of the “conflict thesis” that singled out Christianity as a major obstacle to the progress of humankind. Both strands built upon the belief, by then well established, of the historical opposition of Christianity to an ancient Earth. During the twentieth century this flawed yet almost universal historical narrative nurtured Flood Geology and the growth of Young Earth creationism, as conservative Christians (including prominent US politicians and state legislatures) have found it tempting to undermine evolution by casting doubt on the millions of years it requires.
“You Are Like My Only Friend, Idc If You Are 12”
Authors: Lorenzo-Dus Nuria
Published: January 2023

This chapter examines digital sexual groomers’ styling of self and others, aligning these to their ability to gain—and exploit—their target’s trust. The analysis shows that digital sexual groomers seek to lure targets by closely aligning self- and other (target) styles. To do so, they falsely present self and target as fully complementary in stances of sexual expertise, communicative openness, and victim-oriented avidity. The groomers display sexual expertise and are willing to share it with the target, who is willing to acquire it. The groomers also exploit cultural rhetoric that digital sharing is good: they perform emotional self-disclosure, especially concerning negative, vulnerability-triggering feelings, which ignite mutual reciprocity cycles from their target. And they display intense interest in the target, who is ascribed a stance of being worthy of their avidity. This requires complex facework toward the target that simultaneously resorts to politeness (positive and negative) and impoliteness strategies, with consequently variable levels of closeness- and non-imposition-based behavior, on the one hand, and encroachment-based behavior, on the other. Finally, the analysis also shows that digital sexual groomers place considerable emphasis on cultivating a sense of exclusivity with their target. Individuals who may already have an affective bond with her, typically parents and friends, thus become the groomers’ opponents—the main obstacle to their exclusivity and secrecy needs. Consequently, groomers style their opponents in negative and less favorable ways than those used to style themselves and their target.
Reasonableness and Risk
Authors: Keating Gregory C.
Published: January 2023

The law of torts is fundamental. Any mature legal system must contain a body of law addressing what we owe in the way of obligations to respect each other’s physical and psychological integrity, property, privacy, freedom of action, reputation, and so on. If people were free to injure and interfere with one another in any way that they wished, we would still be in a state of nature. Yet if the law of torts is fundamental, it is also elusive. One hundred and fifty years ago, Oliver Wendell Holmes opined that tort law was not “a proper subject for a law book.” Holmes soon changed his mind, but to this day, leading torts scholars assert that the law of torts is so fundamentally fragmented that the only adequate way to describe the field is to say that it encompasses some civil wrongs that do not arise out of contract. This book argues that the law of torts is a fundamental legal institution because it establishes an essential form of justice among persons. Tort is about what it is that we owe to each other in the way of reciprocal responsibilities not to interfere with, or impair, essential interests that we possess simply because we are persons. Tort law’s rhetoric of reasonableness thus reveals its fundamental moral commitment. Tort law seeks to impose responsibilities not to impair or interfere with each other’s urgent interests on terms that are justifiable both to those protected, and to those burdened, by its terms.
The Importance of Interests
Authors: Keating Gregory C.
Published: January 2023

Contemporary tort theory is a contest between two moral outlooks. One outlook takes law and morality to be concerned with producing states of the world in which some value—usually well-being—is maximized. This outlook is consequentialist. The other takes law and morality to be concerned with relations among persons—with what it is that people owe to one another. This outlook is deontological. The deontological concern with relations among persons underlies an avowedly formalist account of tort law that rallies around the battle cry that tort is “private law.” Theorists of tort as “private law” understand tort as a law of equal freedom and insist that the substance of the law of torts can be extracted entirely from its form. This view goes wrong by both asking and making too much of form. It asks too much of form when it attempts to make sense of the private law of torts eschews all talk of interests. We cannot understand or justify the law of torts without attending to the fact that urgent individual interests—in physical integrity, in psychological well-being, in privacy, and more—play a fundamental role in the law of torts. Rightful relations among persons are a matter of substance as well as form. Tort law can only establish our equality and independence if it guards urgent interests against impairment and interference. The view of tort as “private law” makes too much of form when it presents tort as a private fiefdom walled off from surrounding legal fields. Tort is one member of a family of institutions responsible for protecting us against unwarranted impairment and interference.
Strict Responsibilities
Authors: Keating Gregory C.
Published: January 2023

Chapter Six explicates and defends tort law’s two major forms of strict liability. Strict liabilities hold actors accountable for inflicting harms that the law does not think they should have avoided. One form protects powers of control that the law assigns to people over their own persons and property. These liabilities are strict in the sense that they may be imposed on conduct that is excusable. People may be reasonably unaware that they are violating other people’s powers of control over their persons or property and yet do so. These strict liabilities rests on the defensible premise that predicating liability on fault would unacceptably compromise people’s sovereignty over their own persons and possessions. A second form of strict liability identifies a kind of conditional wrong. It expresses the judgment that—in the circumstance at hand—it is not wrong to inflict harm, but it is wrong to harm-without-repairing. Harm-based strict liabilities embody the same principle of fairness that underlies the takings clause in U.S. Constitution. In some cases, it is unfair to foist the burden of unavoidable physical harm inflicted by some activity on those whose misfortune it is to find themselves in the path of the activity. Reparation rights this unfairness and averts what would otherwise be a wrong. Absent reparation for harm done, those who engage in, and profit from, the infliction of injuries that should not be avoided exploit those who suffer serious injury. Both forms identify genuine tortious wrongs.
The Heterogeneity of Tort
Authors: Keating Gregory C.
Published: January 2023

Contemporary tort scholarship is torn between a nightmare that torts is merely a motley collection of heterogeneous wrongs and a noble dream that a single unifying value or idea lies latent beneath the field’s turbulent surface. Chapter Eight argues against both theses. Against the grab-bag view, Chapter Eight argues that the role of tort law is stable. By specifying interests important enough to warrant the law’s protection, tort law establishes an essential part of our security as members of civil society—an important part of what John Stuart Mill called “the groundwork of our existence.” Tort law’s diverse regimes of responsibility can be understood as matters of what we owe to each other with respect to coercively enforceable obligations not to interfere with and impair each other’s urgent interests. The stability of tort law’s role and the persistence of its core concerns over time coexist, however, with internal turbulence and incompleteness. Tort is torn between competing principles of fault and strict liability; between individualistic and collective conceptions of responsibility; and many of the interests that it takes to be urgent enough to warrant its protection change over time. Tort is incomplete because there are forms of interference and impairment to which it cannot adequately respond. Most vividly, tort cannot respond adequately to irreparable injury. Chapter Eight argues that we should accept the pluralism of the normative conceptions that inform tort law and welcome the arguments to which tort law’s heterogeneity gives rise as proof of the field’s intellectual vitality.
The Prehistory of English and the Other Indo-European Languages
Authors: Leben William R. , Kessler Brett , Denning Keith
Published: January 2023

English belongs to the Germanic branch of the Indo-European family, which goes back five to six thousand years. French, which earlier chapters have shown to be a rich source of English words, belongs to the Italic branch, as does Latin. Greek belongs to the Hellenic branch of Indo-European. In their descent from Indo-European, these languages all underwent their own sets of changes. Remarkably, thanks to the regularity of sound change and despite the passage of millennia, it’s possible to retrace the origin of many English words back to their Indo-European source. To demonstrate this, the present chapter presents one of the major sound changes, Grimm’s law, and shows the correspondences between a variety of English words and the original sounds in the ancestral language.