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Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals1. These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample.

Resilience – the ability of a dynamic system to withstand, or adapt to, threats or risk to its stability, viability, or development – is an important component of environmental, economic, and social systems. While resilience has been studied extensively from individual-, family-, and community-level perspectives, substantially less work has been devoted to understanding resilience through a lens that crosscuts system levels so that an integrated model of resilience can be developed. This research aims to address this gap by identifying a link between family and community resilience as reported by 593 emerging adults. Results support the hypothesis that family resilience predicts community resilience during the transition to adulthood. The results support the proposed framework presented by Houston (2018) in which community resilience is positioned well for both top-down and bottom-up comparisons. The results are also consistent with the dynamic systems perspective which posits that resilience occurs as a result of interactions between and within the levels of complex systems to include the individual, family, and community. These results assist in understanding mechanisms by which resilience emerges from internal and external interactions between and within levels of each system and across developmental transitions.

Bile acids (BAs) mediate the crosstalk between human and microbial cells and influence diseases including Clostridioides difficile infection (CDI). While bile salt hydrolases (BSHs) shape the BA pool by deconjugating conjugated BAs, the basis for their substrate selectivity and impact on C. difficile remain elusive. Here we survey the diversity of BSHs in the gut commensals Lactobacillaceae, which are commonly used as probiotics, and other members of the human gut microbiome. We structurally pinpoint a loop that predicts BSH preferences for either glycine or taurine substrates. BSHs with varying specificities were shown to restrict C. difficile spore germination and growth in vitro and colonization in pre-clinical in vivo models of CDI. Furthermore, BSHs reshape the pool of microbial conjugated bile acids (MCBAs) in the murine gut, and these MCBAs can further restrict C. difficile virulence in vitro. The recognition of conjugated BAs by BSHs defines the resulting BA pool, including the expansive MCBAs. This work provides insights into the structural basis of BSH mechanisms that shape the BA landscape and promote colonization resistance against C. difficile.

Healthy individuals exhibit blood pressure variation over a 24-hour period with higher blood pressure during wakefulness and lower blood pressure during sleep. Loss or disruption of the blood pressure circadian rhythm has been linked to adverse health outcomes, for example, cardiovascular disease, dementia, and chronic kidney disease. However, the current diagnostic and therapeutic approaches lack sufficient attention to the circadian rhythmicity of blood pressure. Sleep patterns, hormone release, eating habits, digestion, body temperature, renal and cardiovascular function, and other important host functions as well as gut microbiota exhibit circadian rhythms, and influence circadian rhythms of blood pressure. Potential benefits of nonpharmacologic interventions such as meal timing, and pharmacologic chronotherapeutic interventions, such as the bedtime administration of antihypertensive medications, have recently been suggested in some studies. However, the mechanisms underlying circadian rhythm-mediated blood pressure regulation and the efficacy of chronotherapy in hypertension remain unclear. This review summarizes the results of the National Heart, Lung, and Blood Institute workshop convened on October 27 to 29, 2021 to assess knowledge gaps and research opportunities in the study of circadian rhythm of blood pressure and chronotherapy for hypertension.

Conventional cost-effectiveness analysis (CEA) for the value-based pricing of new medicines largely ignores the implications of limited market exclusivity (ie, patent-protection periods plus any exclusivity granted by regulators). This paper explores the implications of this methodological shortcoming, which produces several pricing anomalies with potentially unintended effects on research and development (RD) incentives.We illustrate these implications by comparing 4 stylized examples of increasing complexity, from short-term cures for acute conditions to long-term cures for rare, health-catastrophic conditions.(1) Conventional-CEA will project a different result than an adjusted CEA that considers generic or biosimilar entry; (2) free and flexible pricing of long-term treatments (eg, statins for hypercholesterolemia) or repeated-dose cures (eg, insulin for type 1 diabetes) for chronic conditions will likely result in predictable price increases at the end of the exclusivity period that may be perceived as unjustified or unsupported; and (3) one-time administration "cures" (eg, gene therapy for spinal muscular atrophy) have the potential to allocate a large share of the social surplus to the manufacturer over the product lifetime, which may or may not be dynamically efficient per se, but may also inadvertently disadvantage the development of valuable long-term treatments or repeated-dose cures for chronic conditions.We highlight the need for additional research on long-term solutions to these issues that would aim to promote dynamically efficient global RD. More work is needed on the following: (1) relationships between social surplus allocation and the amount and composition of global RD, as we may be as likely to be encouraging excessive RD in some areas as to be undersupplying it in others; and (2) relating the size of the surplus reward to RD cost and, thus, the return on investment.

Engineered Toxin Bodies Specific for TROP2 Positive Cancers Authors: Garrett L. Cornelison, Ileana Pedraza, Kendra Garrison, Elizabeth M. Kapeel, Channing Pletka, Abdul Khan, Jessica Momb, Rebecca Martin, Adam Bartos, Joseph D. Dekker, Jay Zhao, John Majercak, Garrett L. Robinson Molecular Templates, Austin, TX Lanier Biotherapeutics, Bogart, GA Molecular Templates produces next generation immunotoxins called Engineered toxin bodies (ETBs). ETBs are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit (SLT-A) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forced internalization, undergoing retrograde translocation to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes resulting in the inhibition of protein synthesis and induction of apoptosis. In addition, Molecular Templates has expanded the ETB platform to include Antigen Seeding Technology (AST) to generate ETBs with the ability to deliver foreign protein antigen to targeted populations of tumor cells. This mechanism of action allows for the intracellular processing of antigen and subsequent surface MHC-I presentation required for activation of a re-directed T lymphocyte response and the capacity to restore a functional immune clearance program against the tumor. Three ETBs are in clinical development (MT-5111 targeting HER2, MT-0169 targeting CD38, and AST enabled MT-6402 targeting PD-L1). The novel mechanisms of action have potential benefit in different indications including in the relapsed setting, when disease has progressed after chemotherapies and other targeted therapies, and additionally may be able to combine with standard of care. ETBs are being developed that target other cell surface receptors expressed on solid tumors including tumor-associated calcium signal transducer 2 (TROP2). TROP2 is a clinically validated target in metastatic triple-negative breast cancer (mTNBC) and other cancers such as metastatic urothelial carcinoma (mUC) using antibody drug conjugate (ADC) therapies such as sacituzumab govitecan (Trodelvy®). In vitro, ETBs targeting TROP2 specifically and directly kill tumor cells expressing TROP2 with picomolar activity. ETBs can bind to TROP2 in the presence of the Trodelvy parent monoclonal antibody, sacituzumab, and ETBs retain potency on TROP2 positive cell lines in the presence of clinically relevant concentrations of sacituzumab. AST enabled Trop2 targeted ETBs retain direct cell killing activity and can deliver multiple viral antigens to induce cytokine secretion and T-cell mediated killing in a co-culture assay of TROP2 target cells with antigen matched HLA type and antigen specific T-cells. In vivo, TROP2 targeted ETBs demonstrate good tolerability in a murine HCC1806 triple-negative breast cancer xenograft model and significantly reduce tumor burden relative to vehicle control. These pre-clinical in vitro and in vivo data suggest AST enabled Trop2 targeted ETBs have the potential to deplete Trop2 positive malignancies through multiple unique mechanisms of action. Citation Format: Garrett L. Cornelison, Ileana Pedraza, Kendra Garrison, Elizabeth M. Kapeel, Channing Pletka, Abdul Khan, Jessica Momb, Rebecca Martin, Adam Bartos, Joseph D. Dekker, Jay Zhao, John Majercak, Garrett L. Robinson. Engineered Toxin Bodies Specific for TROP2 Positive Cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-18.

Background It has been theorized that hallucinations, a common symptom of schizophrenia, are caused by failures in reality monitoring. The paracingulate sulcus (PCS) has been implicated as a brain structure supporting reality monitoring with the absence or shorter length of PCS associated with an occurrence of hallucinations in schizophrenia. The absence or shorter length of PCS has been associated with an occurrence of hallucinations. There are inconsistent findings in the literature regarding the role of the asymmetry of this structure for hallucinations. Here, we investigated the length of the PCS and cortical thickness of surrounding structures in patients with a lifetime history of auditory verbal hallucinations (AVH). Design Seventy-seven patients and twenty-eight healthy controls (HC) underwent an anatomical MRI scan. PCS length and cortical thickness were estimated using Mango brain visualization and FreeSurfer, respectively. Patients with AVH (n = 45) and patients without AVH were compared (n = 32) to the controls. Results PCS length significantly differed between HC and patient groups (F(2,102) = 3.57, P = .032) in the left but not in the right sulcus. We found significantly longer PCS between HC and AVH group but no difference between patient groups. Similarly, we found significant thinning of cortical structures including structures surrounding anterior parts of PCS between HC and patients either in general or per group, but no significant differences were observed between patient groups. Conclusions PCS length in the left hemisphere is shorter in schizophrenia patients with hallucinations as compared to HC subjects. The patient group without hallucinations was in between those 2 groups. Cortical thickness of neighboring areas of PCS is diminished in patient groups relative to the healthy comparison subjects. The role of lateralization and functional involvement of the PCS region in processes underlying hallucinations, such as reality monitoring, needs further clarification.

This paper is a further reflection on my dialogue with Larry Hickman, director emeritus of the Center for Dewey Studies, and Daisaku Ikeda, president of the lay Buddhist organization Soka Gakkai International (sgi). One surprising outcome of this dialogue is how similar Deweyan pragmatism is to many forms of Mahayana Buddhism such as sgi. Here I survey some similarities between Hickman’s philosophy of technology and Buddhism by emphasizing value creation and criticism. (Soka Gakkai means value creating society.) I then explore Peter D. Herschock’s, Buddhism and Intelligent Technology relying on Hickman to rectify Herschock’s philosophy of technology before discussing how Herschock’s insightful application of Buddhist ethics to ai and the internet accord with Hickman.

BackgroundThe evaluation of febrile infants ≤60 days of age is often guided by established protocols. However, structural racism and physicians’ implicit bias may affect how such clinical guidelines are applied.ObjectiveTo determine the association between self-identified race, insurance type, ZIP code–based median household income (MHI) and receiving a guideline-concordant lumbar puncture (GCLP) in febrile infants.MethodsThis was a 3-year retrospective cross-sectional study of all febrile infants ≤60 days old presenting to a children’s hospital from 2015 to 2017. GCLP was defined as obtaining or appropriately not obtaining a lumbar puncture as defined by the hospital’s clinical practice guideline, which recommended performing a lumbar puncture for all febrile infants ≤60 days of age unless an infant was >28 days of age and had respiratory syncytial virus-positive bronchiolitis. Univariate analyses were used to identify variables associated with receiving a GCLP. Variables with a P < .1 were included in a multivariate logistic regression with race, MHI, and insurance type.ResultsWe included 965 infants. Age (adjusted odds ratio, 0.95; 95% confidence interval, 0.94–0.97) and temperature on arrival (adjusted odds ratio, 1.36; 95% confidence interval, 1.04–1.78) were significantly associated with receipt of a GCLP. Self-identified race, insurance type, and MHI were not associated with receiving a GCLP.ConclusionReceipt of a GCLP was not associated with race, MHI, or insurance type. As recent national guidelines change to increase shared decision-making, physician awareness and ongoing assessment of the role of factors such as race and socioeconomic status in the clinical evaluation and outcomes of febrile infants will be critical.

This study quantifies the abundance and spatial distribution of the cetacean community occupying continental shelf edge and inner continental slope waters along the US southeast Atlantic coast. A shipboard visual line-transect survey was conducted between June and August of 2004 that included effort in waters >50m deep encompassing the shelf break and inner continental slope off the US east coast between 28°N and 38°N latitude. The abundance of nine cetacean taxa was estimated using line-transect distance analysis and an independent observer approach to correct for visibility bias. Canonical correspondence analysis was used to examine the spatial distribution of the cetaceans encountered during the survey as a function of surface temperature, surface salinity, surface fluorescence, bottom depth, and bottom slope. The abundance estimates for most species were much higher than those from a study of the area conducted in 1998. This is primarily due to increased coverage of the shelf-break region and correction for visibility bias. The multivariate analysis indicated four distinct groups of cetaceans that partitioned habitat as a function of salinity, depth, and a latitudinal gradient. These groups were associated with specific water masses and hydrographic features including mid-Atlantic shelf waters (Group I), the shelf break (Group II), mid-Atlantic slope waters (Group III), and south Atlantic slope water (Group IV). Areas where water masses converge such as the continental shelf break along the mid-Atlantic and near Cape Hatteras, North Carolina are therefore areas of both high diversity and density of cetaceans.

Introduction Craving is considered a central process to addictive behavior including cigarette smoking, although the clinical utility of craving relies on how it is defined and measured. Network analysis enables examining the network structure of craving symptoms, identifying the most central symptoms of cigarette craving, and improving our understanding of craving and its measurement. Aims and Methods This study used network analysis to identify the central symptoms of self-reported cigarette craving as measured by the Craving Experience Questionnaire, which assesses both craving strength and craving frequency. Data were obtained from baseline of a randomized controlled trial of mindfulness training for smoking cessation. Results The most central symptoms in an overall cigarette craving network were the frequency of imagining its smell, imagining its taste, and intrusive thoughts. The most central symptoms of both craving frequency and craving strength sub-networks were imagining its taste, the urge to have it, and intrusive thoughts. Conclusions The most central craving symptoms reported by individuals in treatment for cigarette smoking were from the frequency domain, demonstrating the value of assessing craving frequency along with craving strength. Central craving symptoms included multisensory imagery (taste, smell), intrusive thoughts, and urge, providing additional evidence that these symptoms may be important to consider in craving measurement and intervention. Findings provide insight into the symptoms that are central to craving, contributing to a better understanding of cigarette cravings, and suggesting potential targets for clinical interventions. Implications This study used network analysis to identify central symptoms of cigarette craving. Both craving frequency and strength were assessed. The most central symptoms of cigarette craving were related to craving frequency. Central symptoms included multisensory imagery, intrusive thoughts, and urge. Central symptoms might be targeted by smoking cessation treatment.

Coastal common bottlenose dolphins show a variety of migration and residency patterns adding to the difficulty of defining stocks for management purposes. Genetic structure plays an important role in identifying population stocks of dolphins. This study examines genetic differentiation in common bottlenose dolphins both between two social groups occurring in Biscayne Bay, Florida and between Biscayne Bay and an adjacent group of dolphins in Florida Bay. Skin biopsy samples were sequenced at the mitochondrial DNA (mtDNA) control region and genotyped at microsatellite loci. Significant genetic differentiation was found between bottlenose dolphins in Biscayne Bay and Florida Bay (mtDNA FST = 0.139, p ≤ 0.001; microsatellite FST = 0.042, p ≤ 0.001) supporting independent management stock status for these two populations. Within Biscayne Bay, evidence of weak but significant population differentiation was found between the two social groups using microsatellite markers (FST = 0.0149, p ≤ 0.009); however, differentiation was not evident from the mtDNA-based estimates of FST and φST. The lack of differentiation at mtDNA coupled with field observations indicating overlapping home ranges for these two groups suggests ongoing, though perhaps low, levels of interbreeding. These data are insufficient to warrant splitting the Biscayne Bay management stock at this time.

High-quality, well-annotated, healthy tissue specimens are crucial to the success of basic and translational research, but often difficult to procure. Postmortem (PM) tissue collections provide the opportunity to collect these healthy biospecimens. PM procurement programs led by biobanks can further contribute by providing researchers with rare biospecimens collected with short postmortem intervals (PMI) in controlled environments. To support biomedical and translational research, the Cornell Veterinary Biobank (CVB), an ISO 20387 accredited core resource at the Cornell University College of Veterinary Medicine, has performed PM tissue collections from research and privately owned animals since 2013. The CVB PM collection team, consisting of a board-certified veterinary pathologist, a licensed veterinary technician collection specialist, and a data capture specialist, performs rapid tissue collections during controlled warm necropsies, with an accepted PMI of ≤2 hours and a target PMI of ≤1 hour. A retrospective analysis of PM collections between 2013 and 2020 was completed, consisting of 4077 aliquots of 1582 biospecimens from 69 donors (48 canine, 16 feline, and 5 equine). An average of 22.93 biospecimens per donor were collected (range: 1-49). The average PMI for standard collections was 43.48 ± 2.30 minutes, starting on average 20.81 ± 1.61 minutes after time of death. Thus far, the CVB has a favorable utilization rate, with 414 aliquots (10.15%) from 350 specimens (20.12%) and 45 animals (65.22%) distributed to researchers. The success of the CVB PM tissue biobanking program, collecting high-quality biospecimens with short PMIs, was due to support from veterinary pathologists, the competence of CVB personnel, and the continuous evolution of methods within a quality management system. Improvement of PM tissue collection programs in biobanks, with standardized practices for all processes and specialized personnel, can enhance the quality and increase utilization of its biospecimens and associated data.

Background Improvement in clinical outcomes and normalisation of objective markers of inflammation, high-sensitivity C-reactive protein (hs-CRP) and faecal calprotectin (FCP), are considered treatment targets per STRIDE-II guidelines.1 We evaluated the effect of the oral selective Janus kinase inhibitor upadacitinib (UPA) on changes in hs-CRP, FCP, and clinical outcomes in patients with Crohn’s disease (CD). Methods In 2 phase 3, randomized, double-blind, placebo-controlled induction studies (U-EXCEL, NCT03345849; U-EXCEED, NCT03345836), patients with moderate-to-severe CD received 12-week treatment with UPA 45 mg (UPA45) once daily (QD) or placebo (PBO). Patients with clinical response to UPA45 were rerandomised in U-ENDURE (NCT03345823) to receive 52-week maintenance treatment with UPA 30 mg QD (UPA30), UPA 15 mg QD (UPA15), or PBO. Endpoints included marker normalisation (hs-CRP ≤ 5 mg/L, FCP ≤ 250 µg/g) in patients with elevated baseline marker levels, normal marker and clinical remission by Crohn’s Disease Activity Index (CDAI < 150) or very soft/liquid stool frequency (SF)/abdominal pain score (APS) (average daily SF ≤ 2.8 and average daily APS ≤ 1, neither greater than baseline), and ≥ 50% reduction from baseline in marker values with a decrease of at least 100 points in CDAI from baseline. Median changes from baseline in marker levels were also evaluated. Non-responder imputation with no special data handling for missing data due to COVID-19 was used. Results Of 1021 enrolled patients, 645 (63.2%) had elevated hs-CRP (> 5 mg/L) and 750 (73.5%) had elevated FCP (> 250 µg/g) levels at baseline. Significantly greater proportions of patients with elevated baseline marker levels achieved normalisation with UPA compared with PBO at week 12 (Fig 1A/B) and week 52 (Fig 2A/B; nominal P < .001 for all). Decreases in marker levels from baseline with UPA were observed as early as week 2 and were significantly greater than with PBO through week 12 (Fig 1C) and week 52 (Fig 2C; nominal P < .001 for all). Patients achieved clinical endpoints and improvements in markers at significantly higher rates with UPA45 vs PBO at week 12 (Fig 1D–F) and with UPA15 and UPA30 vs PBO at week 52 (Fig 2D–F; P < .001 for all). The safety profile of UPA in CD was previously reported and no new safety concerns were identified. Conclusion Improvements in clinical endpoints and normalisation of objective markers of inflammation were achieved as early as week 2 with UPA45 induction and sustained with UPA15 and UPA30 maintenance therapy in patients with CD. Median changes in hs-CRP and FCP with UPA support continued improvement of inflammation up to week 52. 1. Turner D., et al. Gastroenterology. 2021;160(5):1570–1583.

Genetic programming (GP) is an evolutionary algorithm used to produce high-quality solutions to various problems. It has seen few claims in circuitry and the development of antenna designs. The application of GP in the model of embedded digital systems on multi-channel antenna arrays of subsurface imaging equipment has not yet been investigated. This study focuses on designing and developing a digital multimeter embedded with a multigene genetic programming (MGGP) model for multi-array transmitter antenna used for subsurface imaging operating at a low frequency of 3.5 kHz to 18.5 kHz using Arduino microcontroller for prototyping. The electrical outputs of a transmitter antenna system employed in a subsurface imaging device require live measurement and monitoring during operation for data logging purposes. The amount of transmitted voltage, produced current, and operating frequency are significant parameters for mapping the underground resistivity, thus the produced GP models are functions of the three parameters. GP fitness function was determined through MATLAB software. The output current signal from the transmitter were imitated in Proteus simulation software using a current source in the designed current measuring circuit. This produced linear and nonlinear relationships of the electrical outputs where GP modeling was beneficially applied. The application of GP in with the microcontroller provided an accurate reading of frequency, current and voltage produced by the multi-array transmitter antenna. These measurements were displayed using LM016L LCD display. Moreover, this embedded digital multimeter on transmitter antenna avoids utilizing costly high voltage measuring devices.

We designed a prospective, observational study enrolling patients presenting for treatment of acute myeloid leukemia (AML) at 13 institutions to analyze associations between hematopoietic cell transplantation (HCT) and survival, quality of life (QOL), and function in: the entire cohort, those aged ≥65 years, those with high comorbidity burden, intermediate cytogenetic risk, adverse cytogenetic risk, and first complete remission with or without measurable residual disease. Patient were assessed 8 times over 2 years. Time-dependent regression models were used. Among 692 patients that were evaluable, 46% received HCT with a 2-year survival of 58%. In unadjusted models, HCT was associated with reduced risks of mortality most of the subgroups. However, after accounting for covariates associated with increased mortality (age, comorbidity burden, disease risks, frailty, impaired QOL, depression, and impaired function), the associations between HCT and longer survival disappeared in most subgroups. Although function, social life, performance status, and depressive symptoms were better for those selected for HCT, these health advantages were lost after receiving HCT. Recipients and nonrecipients of HCT similarly ranked and expected cure as main goal of therapy, whereas physicians had greater expectations for cure than the former. Accounting for health impairments negates survival benefits from HCT for AML, suggesting that the unadjusted observed benefit is mostly owing to selection of the healthier candidates. Considering patients’ overall expectations of cure but also the QOL burdens of HCT motivate the need for randomized trials to identify the best candidates for HCT. This trial was registered at www.clinicaltrials.gov as #NCT01929408.

Pangenomics is emerging as a powerful computational paradigm in bioinformatics. This field uses population-level genome reference structures, typically consisting of a sequence graph, to mitigate reference bias and facilitate analyses that were challenging with previous reference-based methods. In this work, we extend these methods into transcriptomics to analyze sequencing data using the pantranscriptome: a population-level transcriptomic reference. Our novel toolchain can construct spliced pangenome graphs, map RNA-seq data to these graphs, and perform haplotype-aware expression quantification of transcripts in a pantranscriptome. This workflow improves accuracy over state-of-the-art RNA-seq mapping methods, and it can efficiently quantify haplotype-specific transcript expression without needing to characterize a sample’s haplotypes beforehand.

Strained alkyne-containing cycloparaphenylenes unite curved carbon nanomaterials with tunable reactivity via physical organic chemistry. Herein we describe the rational design and synthesis of new derivatives with heightened SPAAC reactivity.

Repetitivity of 21-axis symmetry element in three polymorphic crystal structures of carboxamide compound with high Z′ packing problem.

Since its initial release in 2000, the human reference genome has covered only the euchromatic fraction of the genome, leaving important heterochromatic regions unfinished. Addressing the remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium presents a complete 3.055 billion–base pair sequence of a human genome, T2T-CHM13, that includes gapless assemblies for all chromosomes except Y, corrects errors in the prior references, and introduces nearly 200 million base pairs of sequence containing 1956 gene predictions, 99 of which are predicted to be protein coding. The completed regions include all centromeric satellite arrays, recent segmental duplications, and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies.

Genetic datasets lack diversity and include very few data from Indigenous populations. Research models based on equitable partnership have the potential to increase Indigenous participation and have led to successful collaborations. We report here on a meeting of participants in four Indigenous community-university partnerships pursuing research on precision medicine. The goal of the meeting was to define values and practices that strengthen opportunities for genetic research. The group accorded the highest priority to developing trusting relationships, ensuring respect for Indigenous community authority, and pursuing research that has the potential to lead to community benefit. Supporting priorities included incorporation of Indigenous expertise in research planning, transparent communication, and development of community capacity, including capacity to participate in formulating research questions, informing research methodology, and leading research projects. Participants also noted the importance of attention to social determinants of health so that genetic contributors to health are evaluated in the appropriate context.

50 Pág., In March 2022, following the annual International Committee on Taxonomy of Viruses (ICTV) ratifcation vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. The phylum was expanded by two new families (bunyaviral Discoviridae and Tulasviridae), 41 new genera, and 98 new species. Three hundred forty-nine species were renamed and/or moved. The accidentally misspelled names of seven species were corrected. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV, This work was supported in part through Laulima Govern ment Solutions, LLC prime contract with the US National Institute of Allergy and Infectious Diseases (NIAID) under Contract No. HHSN272201800013C. J.H.K. performed this work as an employee of Tunnell Government Services (TGS), a subcontractor of Laulima Gov ernment Solutions, LLC under Contract No. HHSN272201800013C. This work was also funded in part by Contract No. HSHQDC 15-C-00064 awarded by DHS S&T for the management and operation of The National Biodefense Analysis and Countermeasures Center, a federally funded research and development center operated by the Battelle National Biodefense Institute (V.W.); and NIH contract HHSN272201000040I/HHSN27200004/D04 and grant R24AI120942 (N.V., R.B.T.). S.S. acknowledges support from the Mississippi Agri cultural and Forestry Experiment Station (MAFES), USDA-ARS pro ject 58-6066-9-033 and the National Institute of Food and Agriculture, US Department of Agriculture, Hatch Project, under Accession Num ber 1021494.

It has been well over a decade since lidar-based research began in earnest in the Maya Lowlands of southern Mexico, Guatemala, Belize, and Honduras. Most investigations have an archaeological focus, with a few integrating studies of the ancient Maya with analyses of local ecology and land-use. A review of frequently cited publications reveals a lack of consistency in assessing the accuracy of archaeological feature classifications in lidar data with variables such as sensor type, class definitions, and ground-truthing methods differentially affecting assessment results across the Lowlands. In general, area-based ground-truthing approaches to classifications of full waveform lidar data present the most comprehensive accuracy assessments. New assessment data from the Buenavista Valley of north-central Guatemala are presented to compare against existing studies and to demonstrate how a geographic approach (a comprehensive, landscape-scale study of features over space and time) to classification error assessment can enhance understanding of classification accuracy. Results show that meaningful comparisons of archaeological features across lidar datasets cannot be considered reliable without more uniform and detailed presentations of accuracy assessment methods, analyses, and results. The article concludes with recommendations for how such collaborations might proceed.

A total of 73 species of Argia Rambur, 1842 are reported as present from Mexico, Central America and the Lesser Antilles, of which five are new to science and are described here: Argia annae n. sp. (holotype ♂: MEXICO, Veracruz, Puente Texolo, roadside seepages near bridge, 19.4028°N, 96.9867°W, 1065 m, 17 June 2009, Rosser W. Garrison & Natalia von Ellenrieder leg., in CSCA), Argia gonzalezi n. sp. (holotype ♂: MEXICO, Chiapas, 3.5 mi east of Rayón, stream, approximately 17.2058°N, 92.9700°W, 1676 m, 16 July 1965, Dennis R. Paulson leg., in CNIN), A. noveloi n. sp. (holotype ♂: MEXICO, Veracruz, Puente Texolo, 19.4028°N, 96.9867°W, 1065 m, 26 August 1988, Rosser W. Garrison leg., in INECOL), A. paludicola n. sp. (holotype ♂: U. S. A., Arizona, Apache County, Bog Tank, north of Highway 260, 34.0467°N, 109.683°W, 1400 m, 1 July 2016, Pierre Deviche leg., in CSCA) and A. paulsoni n. sp. (holotype ♂: COSTA RICA, San José, 7.5 km northeast of Londres, on road to Rancho Tinamú Lodge, 9.4856°N, 83.9911°W, 700 m, 5 July 2019, William A. Haber leg., in UNH). Redescriptions of male and female are provided for the following species: Argia calida (Hagen, 1861), A. chelata Calvert, 1902, A. deami Calvert, 1902, A. fulgida Navás, 1934, A. herberti Calvert, 1902, A. johannella Calvert, 1907, A. mayi González-Soriano, 2012, A. percellulata Calvert, 1902, A. pocomana Calvert, 1907, A. rogersi Calvert, 1902, A. talamanca Calvert, 1907, A. terira Calvert, 1907, A. underwoodi Calvert, 1907, and A. variabilis Selys, 1865. All 73 species are measured, illustrated, and distinguished from their congeners. The following synonymies are suggested based on examination of type material: A. wilsoni Calvert, 1902, a junior synonym of A. calida (Hagen, 1861), A. plana Calvert, 1902, a junior synonym of A. funebris (Hagen, 1861), and A. trifoliata Fraser, 1942 (Fig. 736), a junior synonym of A. variegata Förster, 1914. Lectotypes are designated for Agrion calidum Hagen, 1861, Agrion funebris Hagen, 1861, and Argia variabilis Selys, 1865. Keys to the 73 known Argia species from Mexico, Middle America and the Lesser Antilles are provided as well as distribution maps based on an examination of over 16,000 specimens.

This study aimed to provide recommendations for identifying and implementing real option value (ROV) calculations in value assessment.We identified the primary mechanisms through which ROV can be created based on a theoretical framework for ROV, assessed approaches for predicting future innovations and improvements in health, and described the steps for estimating ROV in a cost-effectiveness analysis framework.The 3 primary mechanisms by which ROV can be created are when a current treatment (1) prolongs survival to increase the proportion of patients who can receive future innovations, (2) slows disease progression to increase patients' eligibility for future innovations, and (3) directly affects the efficacy of future innovations. We provide 5 recommendations for implementing ROV in value assessment. First, the decision to quantify ROV should be based on a qualitative evaluation of whether the treatment can enable greater benefits from future innovations. Second, ROV should be quantified in the same value assessment framework (eg, cost-effectiveness analysis using quality-adjusted life-year) as the conventional value. Third, method for quantifying ROV should consider data availability, rate of innovation, and sources of future health improvements. Fourth, ROV estimate should be presented alongside the conventional value as a separate element due to its inherently large uncertainty. Finally, generalizability of ROV estimate should be evaluated, and local data should be used when available.ROV can arise from a variety of mechanisms that should be considered before investing in an ROV analysis. Calculating ROV includes exploring different approaches for forecasting future innovations and future improvements in health.

Introduction Count outcomes in tobacco research are often analyzed with the Poisson distribution. However, they often exhibit features such as overdispersion (variance larger than expected) and zero inflation (extra zeros) that violate model assumptions. Furthermore, longitudinal studies have repeated measures that generate correlated counts. Failure to account for overdispersion, zero inflation, and correlation can yield incorrect statistical inferences. Thus, it is important to familiarize researchers with proper models for such data. Aims and Methods Poisson and Negative Binomial models with correlated random effects with and without zero inflation are presented. The illustrative data comes from a study comparing a mindfulness training app (Craving to Quit [C2Q], n = 60) with a control app (experience sampling-only app, n = 66) on smoking frequency at 1, 3, and 6 months. Predictors include app, time, the app-by-time interaction, and baseline smoking. Each model is evaluated in terms of accounting for zero inflation, overdispersion, and correlation in the data. Emphasis is placed on evaluating model fit, subject-specific interpretation of effects, and choosing an appropriate model. Results The hurdle Poisson model provided the best fit to the data. Smoking abstinence rates were 33%, 32%, and 28% at 1, 3, and 6 months, respectively, with variance larger than expected by a factor >7 at each follow-up. Individuals on C2Q were less likely to achieve abstinence across time but likely to smoke fewer cigarettes if smoking. Conclusions The models presented are specifically suited for analyzing correlated count outcomes and account for zero inflation and overdispersion. We provide guidance to researchers on the use of these models to better inform nicotine and tobacco research. Implications In tobacco research, count outcomes are often measured repeatedly on the same subject and thus correlated. Such outcomes often have many zeros and exhibit large variances relative to the mean. Analyzing such data require models specifically suited for correlated counts. The presented models and guidelines could improve the rigor of the analysis of correlated count data and thus increase the impact of studies in nicotine and tobacco research using such outcomes.

Resolving the spatial distribution of RNA and protein in tissues at subcellular resolution is a challenge in the field of spatial biology. We describe spatial molecular imaging, a system that measures RNAs and proteins in intact biological samples at subcellular resolution by performing multiple cycles of nucleic acid hybridization of fluorescent molecular barcodes. We demonstrate that spatial molecular imaging has high sensitivity (one or two copies per cell) and very low error rate (0.0092 false calls per cell) and background (~0.04 counts per cell). The imaging system generates three-dimensional, super-resolution localization of analytes at ~2 million cells per sample. Cell segmentation is morphology based using antibodies, compatible with formalin-fixed, paraffin-embedded samples. We measured multiomic data (980 RNAs and 108 proteins) at subcellular resolution in formalin-fixed, paraffin-embedded tissues (nonsmall cell lung and breast cancer) and identified18 distinct cell types, ten unique tumor microenvironments and 100 pairwise ligand-receptor interactions. Data on800,000 single cells and ~260 million transcripts can be accessed at http://nanostring.com/CosMx-dataset .