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The medical response to monkeypox(mpox) is a key demonstration of how COVID-19 remodeled the global response to viruses in the medical field. As a result of the 2019 pandemic, the 2022 mpox outbreak was met with mass production of vaccines, widely available PCR testing, and increased public health and research efforts. Easy access to vaccines such as the ACAM2000 and the JYNNEOS vaccines bolstered prevention while antivirals alleviated symptoms and shortened viral duration in at-risk patients. Various methods of detection have been developed for mpox over a short period with PCR currently being used in an attempt to isolate specific strains of the virus. In this brief review, we discuss its classical presentation, and detection and treatment strategies adapted to mitigate this public health risk.

This paper examines the health tradeoffs associated with the historical expansion in coalfired electricity generation in the United States. We combine newly digitized data on all major coal-fired power plants for the period 1938-1962 with two complementary difference-indifferences strategies. Coal-fired plants imposed large negative health externalities that were partially offset by the benefits from local electricity generation. The health impacts varied widely according to initial electricity access and evolved as the stock of generating capacity expanded over the sample period. These findings highlight the importance of accounting for both current and future payoffs when designing environmental regulation.

This chapter critically analyses what we label the Reconciliation Thesis, which holds that cultural heritage should be protected during armed conflict because of its instrumental use in promoting peace and reconciliation between warring groups. We begin by arguing that combatants and military decision makers have strong reasons to fight in ways that uphold the prospects of future peace. We then identify several ways in which the safeguarding of cultural heritage might plausibly contribute to post-war peacebuilding. Nevertheless, we ultimately argue that there are reasons to be sceptical of the Reconciliation Thesis, especially when it is evoked as a justification for imposing serious risks or costs on persons, or sacrificing other significant military objectives.

Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

When estimating unknown quantities, people insufficiently adjust from values they have previously considered, a phenomenon known as anchoring. We suggest that anchoring is at least partially caused by a desire to avoid making extreme adjustments. In seven studies ( N = 5,279), we found that transparently irrelevant cues of extremeness influenced people’s adjustments from anchors. In Studies 1–6, participants were less likely to adjust beyond a particular amount when that amount was closer to the maximum allowable adjustment. For example, in Study 5, participants were less likely to adjust by at least 6 units when they were allowed to adjust by a maximum of 6 units than by a maximum of 15 units. In Study 7, participants adjusted less after considering whether an outcome would be within a smaller distance of the anchor. These results suggest that anchoring effects may reflect a desire to avoid adjustments that feel too extreme.

Successful outcomes of in vitro fertilization (IVF) rely on both the formation of a chromosomally normal embryo and its implantation in a receptive endometrium. Pre-implantation genetic testing for aneuploidy (PGT-A) has been widely accepted as a tool to assess the viability of an embryo. In 2011, the endometrial receptivity array (ERA) was first published as a tool to determine when the endometrium is most receptive to an embryo, commonly referred to as the “window of implantation” (WOI). The ERA uses molecular arrays to assess proliferation and differentiation in the endometrium and screens for inflammatory markers. Unlike PGT-A, there has been dissent within the field concerning the efficacy of the ERA. Many studies that contest the success of the ERA found that it did not improve pregnancy outcomes in patients with an already-good prognosis. Alternatively, studies that utilized the ERA in patients with repeated implantation failure (RIF) and transfer of known euploid embryos demonstrated improved outcomes. This review aims to describe the ERA as a novel technique, review the various settings that the ERA may be used in, such as natural frozen embryo transfer (nFET) and hormone replacement therapy frozen embryo transfer (HRT-FET), and provide a summary of the recent clinical data for embryo transfers in patients with RIF utilizing the ERA.

Mosaic mutations in blood are common with increasing age and are prognostic markers for cancer, cardiovascular dysfunction and other diseases. This group of acquired mutations include megabase-scale mosaic chromosomal alterations (mCAs). These large mutations have mainly been surveyed using SNP array data from individuals of European (EA) or Japanese genetic ancestry. To gain a better understanding of mCA rates and associated risk factors in genetically diverse populations, we surveyed whole genome sequencing data from 67,390 individuals, including 20,132 individuals of African ancestry (AA), and 7,608 of Hispanic ancestry (HA) with deep (30X) whole genome sequencing data from the NHLBI Trans Omics for Precision Medicine (TOPMed) program. We adapted an existing mCA calling algorithm for application to WGS data, and observed higher sensitivity with WGS data, compared with array-based data, in uncovering mCAs at low mutant cell fractions. As in previous reports, we observed a strong association with age and a non-uniform distribution of mCAs across the genome. The presence of autosomal (but not chromosome X) mCAs was associated with an increased risk of both lymphoid and myeloid malignancies. After adjusting for age, we found that individuals of European ancestry have the highest rates of autosomal mCAs, mirroring the higher rate of leukemia in this group. Our analysis also uncovered higher rates of chromosome X mCAs in AA and HA compared to EA, again after adjusting for age. Germline variants in ATM and MPL showed strong associations with mCAs in cis, including ancestry specific variants. And rare variant gene-burden analysis confirmed the association of putatively protein altering variants in ATM and MPL with mCAs in cis. Individual rare variants in DCPS, ADM17, PPP1R16B, and TET2 were all associated with autosomal mCAs and rare variants in OR4C16 were associated with chromosome X mCAs in females. There was significant enrichment of co-occurrence of CHIP mutations and mCAs both altering cancer associated genes TET2, DNMT3A, JAK2, CUX1, and TP53. Overall, our study demonstrates that rates of mCAs differ across populations and that rare inherited germline variants are strongly associated with mCAs across genetically diverse populations. These results strongly motivate further studies of mCAs in under-represented populations to better understand the causes and consequences of this class of somatic variation. Citation Format: Yasminka A. Jakubek, Ying Zhou, Adrienne Stilp, Jason Bacon, Justin Wong, Zuhal Ozcan, Donna Arnett, Kathleen Barnes, Josh Bis, Eric Boerwinkle, April Carson, Daniel Chasman, Michael Cho, Matthew Conomos, Nancy Cox, Margaret Doyle, Myriam Fornage, Xiuqing Guo, Sharon Kardia, Joshua Lewis, Ruth Loos, Xiaolong Ma, Mitchell Machiela, Taralynn Mack, Rasika Mathias, Braxton Mitchell, Kari North, Nathan Pankratz, Patricia Peyser, Michael Preuss, Bruce Psaty, Laura Raffield, Ramachandran Vasan, Susan Redline, Stephen Rich, Jerome Rotter, Edwin Silverman, Jennifer Smith, Margaret Taub, Jeong Yun, Yun Li, Pinkal Desai, Alexander Bick, Alexander Reiner, Paul Scheet, Paul Auer. Mosaic chromosomal alterations in blood across ancestries via whole-genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3507.

BACKGROUND: Vitamin D supplements may only be beneficial for the prevention of osteoporotic fractures when administered with calcium and in individuals with low blood levels of 25(OH)D, but possible hazards of calcium supplements on CVD cannot be excluded. OBJECTIVES: We conducted a meta-analysis of all placebo-controlled randomized trials assessing the effects of calcium supplements alone or with vitamin D on CHD, stroke, and all-cause mortality. METHODS: A meta-analysis of 11 trials included 7 comparisons of calcium alone compared with control (n = 8634) and 6 comparisons of calcium plus vitamin D compared with control (n = 46,804). Aggregated study-level data were obtained from individual trials and combined using a fixed-effects meta-analysis. The main outcomes included MI, CHD death, any CHD, stroke, and all-cause mortality. RESULTS: Among trials of calcium alone (mean daily dose 1 g), calcium was not significantly associated with any excess risk of MI (RR, 1.15; 95% CI: 0.88, 1.51; n = 219 events), CHD death (RR, 1.24; 95% CI: 0.89, 1.73; n = 142), any CHD (RR, 1.01; 95% CI: 0.75, 1.37; n = 177), or stroke (RR, 1.15; 95% CI, 0.90, 1.46, n = 275). Among 6 trials of combined treatment, supplementation with calcium plus vitamin D was not significantly associated with any excess risk of MI (RR, 1.09; 95% CI: 0.95, 1.25; n = 854), CHD death (RR, 1.04; 95% CI: 0.85, 1.27; n = 391), any CHD (RR, 1.05; 95% CI: 0.93, 1.19; n = 1061), or stroke (RR, 1.02; 95% CI: 0.89, 1.17; n = 885). Likewise, calcium alone, or with vitamin D had no significant associations with all-cause mortality. CONCLUSIONS: This meta-analysis demonstrated that calcium supplements were not associated with any significant hazard for CHD, stroke, or all-cause mortality and excluded excess risks above 0.3%–0.5% per year for CHD or stroke. Further trials of calcium and vitamin D are required in individuals with low blood levels of 25(OH)D for the prevention of fracture and other disease outcomes.

Cultural appropriation can be understood as involving members of one culture taking or adopting objects or practices which ‘belong’ to another culture in the sense of being affiliated or connected to that other culture in a unique or special way. But what constitutes this ‘belonging’ precisely? This paper proposes that belonging, in the targeted sense, is determined by meaningful connections between an object or practice and the relevant culture—in other words, connections that could be described as the thing’s ‘meanings’. Such meanings primarily include relations of causality, teleology, and symbolic representation. After expounding this account, the paper closes with a word of caution. The term ‘belongs’ is sometimes ambiguous, indicating both affiliation and legal or moral property rights. Despite this, belonging as affiliation or meaningful connectedness is not equivalent to rightful ownership. Nor does the former, by itself, entail the latter.

This article estimates population infection rates from coronavirus disease 2019 (COVID-19) across four Canadian provinces from late March to early May 2020. The analysis combines daily data on the number of conducted tests and diagnosed cases with a methodology that corrects for non-random testing. We estimate the relationship between daily changes in the number of conducted tests and the fraction of positive cases in the non-random sample (typically less than 1 percent of the population) and apply this gradient to extrapolate the predicted fraction of positive cases if testing were expanded to the entire population. Over the sample period, the estimated population infection rates were 1.7–2.6 percent in Quebec, 0.7–1.4 percent in Ontario, 0.5–1.2 percent in Alberta, and 0.2–0.4 percent in British Columbia. In each province, these estimates are substantially below the average positive case rate, consistent with non-random testing of higher-risk populations. The results also imply widespread undiagnosed COVID-19 infection. For each identified case by mid-April, we estimate there were roughly 12 population infections.

BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician’s diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV(1)/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10(−8) in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10(−6)). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV(1) (P = 3.3 × 10(−3)), postbronchodilator (PB) FEV(1) (7.3 × 10(−3)), and PB FEV(1)/FVC ratio (P = 2.7 × 10(−3)). The identified baseline FEV(1)/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.

Current pathologic diagnosis of benign and neoplastic bone marrow disorders relies in part on the microscopic analysis of bone marrow aspirate (BMA) smears and manual counting of nucleated cell populations to obtain a cell differential. This manual process has significant limitations, including the limited sample of cells analyzed by a conventional 500-cell differential compared to the thousands of nucleated cells present, as well as the inter-observer variability seen between differentials on single samples due to differences in cell selection and classification. To address these shortcomings, we developed an automated computational platform for obtaining cell differentials from scanned whole-slide BMAs at 40x magnification. This pipeline utilizes a sequential process of identifying BMA regions with high proportions of marrow nucleated cells that are ideal for cell counting, detecting individual cells within these optimal regions, and classifying cells into one of 11 types within the differential. Training of convolutional neural network models for region and cell classification, as well as a region-based convolutional neural network for cell detection, involved the generation of an annotated training data set containing 10,948 BMA regions, 28,914 cell boundaries, and 23,609 cell classifications from 73 BMA slides. Among 44 testing BMA slides, an average of 19,209 viable cells per slide were identified and used in automated cell differentials, with a range of 237 to 126,483 cells. In comparing these automated cell differential percentages with corresponding manual differentials, cell type-specific correlation coefficients ranged from 0.913 for blast cells to 0.365 for myelocytes, with an average coefficient of 0.654 among all 11 cell types. A statistically significant concordance was observed among slides with blast percentages less or greater than 20% (p=1.0x10-5) and with plasma cell percentages less or greater than 10% (p=5.9x10-6) between automated and manual differentials, suggesting potential diagnostic utility of this automated pipeline for malignancies such as acute myeloid leukemia and multiple myeloma. Additionally, by simulating the manual counting of 500 cells within localized areas of a BMA slide and iterating over all optimal slide locations, we quantified the inter-observer variability associated with limited sample size in traditional BMA cell counting. Localized differentials exemplify an average variance ranging from 24.1% for erythroid precursors to 1.8% for basophils. Variance in localized differentials of up to 44.8% for blast cells and 36.9% for plasma cells was observed, demonstrating that sample classification based on diagnostic thresholds of cell populations is variable even between different areas within a single slide. Finally, pipeline outputs of region classification, cell detection, cell classification, and localized cell differentials can be visualized using whole-slide image analysis software. By improving cell sampling and reducing inter-observer variability, this automated pipeline has potential to improve the current standard of practice for utilizing BMA smears in the diagnosis of hematologic disorders.

Genome-wide association studies (GWAS) have identified hundreds of loci associated with Crohns disease (CD), however, as with all complex diseases, deriving pathogenic mechanisms from these non-coding GWAS discoveries has been challenging. To complement GWAS and better define actionable biological targets, we analysed sequenced data from more than 30,000 CD patients and 80,000 population controls. We observe rare coding variants in established CD susceptibility genes as well as ten genes where coding variation directly implicates the gene in disease risk for the first time.

The passage of landmark government regulation is often the culmination of evolving social pressure and incremental policy change. During this process, firms may preemptively adjust behavior in anticipation of impending regulation, making it difficult to quantify the overall economic impact of the legislation. This study leverages newly digitized data on the operation of virtually every fossil-fuel power plant in the United States from 1938-1994 to examine the impacts of the 1970 Clean Air Act (CAA) on the power sector. This unique long panel provides an extended pre-regulation benchmark, allowing us to account for both anticipatory behavior by electric utilities in the years leading up to the Act's passage and reallocative effects of the CAA across plant vintages. We find that the CAA led to large and persistent decreases in output and productivity, but only for plants that opened before 1963. This timing aligns with the passage of the original 1963 CAA, which provided the federal government with limited authority to “control” air pollution, but signaled impending federal regulation. We provide historical evidence of anticipatory responses by utilities in the design and siting of plants that opened after 1963. We also find that the aggregate productivity losses of the CAA borne by the power sector were substantially mitigated by the reallocation of output from older less efficient power plants to newer plants.

This paper studies the contribution of the workplace to the SES-health gradient. Our analysis is based on a unique dataset that tracks various health outcomes and workplace risks among healthcare workers during the first four months of the coronavirus 2019 (COVID-19) pandemic. The setting provides an exceptional opportunity to test for work-related disparities in health, while controlling for confounding determinants of the SES-health gradient. We find that low-SES nurses were systematically more likely to contract COVID-19 as a result of workplace exposure. These differentials existed in all healthcare institutions, but were particularly large in non-hospital settings. In contrast, we find no relationship between SES and non work-related infection rates. The differences in workplace infection rates are substantially larger than those implied by standard ‘task-based’ indices of transmission risk, and cannot be attributable to easily identifiable metrics of workplace risk. Together, our results show how subtle differences in work conditions or job duties can substantially contribute to the SES-health gradient.

This paper studies how school access affects men’s fertility decisions. To separately identify the male response, we adopt a regression discontinuity approach that exploits the timing of a major expansion in school access in Mali and the country’s large gender gap in the age of marriage. Increased school access for boys led to large subsequent decreases in fertility by age 25. The effects appear to be driven by delayed marriage entry and urbanization. The study shows how failing to account for the impact of male education on fertility may lead to an underestimate of the potential for expansions in school access to stimulate demographic transition.

Si certaines œuvres balzaciennes trahissent l’influence de l’esthétisme romantique, qu’il soit intime ou romanesque, ainsi dans Le Lys dans la vallée (1835), Balzac a aussi saisi les limites des romantiques et s’est tourné vers le roman réaliste. Devenant finalement le père du mouvement réaliste français, il a su créer une écriture renommée pour l’observation détaillée des milieux sociaux. Dans cet article, je me penche sur le roman moins connu de Balzac, Une fille d’Ève (1838), qui représente un angle du réalisme en abordant la problématique de la tension entre les femmes et les hommes. Mon analyse vise à faire ressortir le fait que cette tension qui a inspiré Balzac provient sans doute de la méthode Jacotot liée au roman Les Aventures de Télémaque de Fénelon. Le présent article propose d’explorer cette relation philosophique en partant des références et des pratiques intertextuelles du roman de Balzac, deux caractéristiques essentielles de l’écriture balzacienne.

Conjugated proteins and enzymes are often formed using N-hydroxysuccinimide (NHS) chemistry, which reacts with free primary amines resulting in a loss of charge and a reduction in isoelectric point (pI). Measurement of the extent of reaction of these conjugates is critical for biopharmaceutical developers. Due to this change in protein charge state, denaturing capillary isoelectric focussing (cIEF) offers a potentially straightforward and convenient approach for extent-of-reaction quantification. Here, we demonstrate the potential of this technique with poly(ethylene glycol) (PEG) conjugates of Erwinia chrysanthemil-asparaginase (ErA). Development of an appropriate sample preparation technique is critical to achieving reproducible cIEF electropherograms, particularly for denaturation-resistant proteins such as ErA, and an emphasis was placed on this during development of the PEG-ErA cIEF method. cIEF electropherograms demonstrating a distribution of PEGylation states in a bell-shaped curve were obtained, and assignment of PEGylation states to these peaks was critical to routine use of the method. The method is sensitive enough to resolve non-lysine adducts of PEG (such as those conjugated to histidine residues) and was shown to give reproducible results over a 2 year period. Biopharmaceutical developers should consider cIEF for extent of reaction monitoring and measurement for conjugates of free amine groups.

This paper studies how better access to public health insurance affects infant mortality during pandemics. Our analysis combines cross-state variation in mandated eligibility for Medicaid with two influenza pandemics — the 1957-58 "Asian Flu" pandemic and the 1968-69 "Hong Kong Flu" — that arrived shortly before and after the program's introduction. Exploiting heterogeneity in the underlying severity of these two shocks across counties, we find no relationship between Medicaid eligibility and pandemic infant mortality during the 1957-58 outbreak. After Medicaid implementation, we find that better access to insurance in high-eligibility states substantially reduced infant mortality during the 1968-69 pandemic. The reductions in pandemic infant mortality are too large to be attributable solely to new Medicaid recipients, suggesting that the expansion in health insurance coverage mitigated disease transmission among the broader population.

Overexpression and long terminal repeat (LTR) polymorphism of the HRES‑1/Rab4 human endogenous retrovirus locus have been associated with T cell activation and disease manifestations in systemic lupus erythematosus (SLE). Although genomic DNA methylation is diminished overall in SLE, its role in HRES-1/Rab4 expression is unknown. Therefore, we determined how lupus-associated polymorphic rs451401 alleles of the LTR regulate transcription from the HRES-1/Rab4 promoter and thus affect T cell activation. The results showed that cytosine(–119) is hypermethylated while cytosine(–51) of the promoter and the LTR enhancer are hypomethylated in SLE. Pharmacologic or genetic inactivation of DNA methyltransferase 1 augmented the expression of HRES-1/Rab4. The minimal promoter was selectively recognized by metabolic stress sensor NRF1 when cytosine(–119) but not cytosine(–51) was methylated, and NRF1 stimulated HRES-1/Rab4 expression in human T cells. In turn, IRF2 and PSIP1 bound to the LTR enhancer and exerted control over HRES-1/Rab4 expression in rs451401 genotype– and methylation-dependent manners. The LTR enhancer conferred markedly greater expression of HRES-1/Rab4 in subjects with rs451401CC over rs451401GG alleles that in turn promoted mechanistic target of rapamycin (mTOR) activation upon T cell receptor stimulation. HRES-1/Rab4 alone robustly activated mTOR in human T cells. These findings identify HRES-1/Rab4 as a methylation- and rs451401 allele–dependent transducer of environmental stress and controller of T cell activation.

Philosophers, archeologists, and other heritage professionals often take a rather negative view of heritage reconstruction, holding that it is inappropriate or even impermissible. In this essay, we argue that taking such hardline attitudes toward the reconstruction of heritage is unjustified. To the contrary, we believe that the reconstruction of heritage can be both permissible and beneficial, all things considered. In other words, sometimes we have good reasons, on balance, to pursue reconstructions, and doing so can be morally acceptable. In defending this claim, we discern a number of arguments made against heritage reconstruction and demonstrate that these arguments are either exaggerated or lack support.