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Although prior reviews have documented the effectiveness of engaging male caregivers in early childhood interventions, little is known about how these interventions have been designed and implemented to reach, engage, and support male caregivers in low-resource global settings. We searched five bibliographic databases for intervention studies that engaged male caregivers to improve nurturing care for children under 5 years of age in low- and middle-income countries. Forty-four articles met the inclusion criteria, which represented 33 interventions. Fathers specifically were the most common type of male caregivers targeted in these interventions. The majority of interventions invited fathers to participate alongside their female partners. Community-based peer-groups were the most common delivery model. Most interventions used the same program structure for fathers as applied to mothers, with few considering whether implementation adaptations were needed for men. Intervention curricula were multicomponent and largely targeted child nutrition, health, and couples' relationships. A minority of programs addressed parenting, psychosocial wellbeing, violence prevention, gender attitudes, or economic support. Behavior change techniques were limited to interactive counseling and peer learning. Male caregivers remain missing from caregiving interventions for young children. A greater focus on implementation research can inform better inclusion, engagement, and support for male caregivers in nurturing care interventions.

STUDY QUESTION Are chromosome abnormalities detected at Day 3 post-fertilization predominantly retained in structures of the blastocyst other than the inner cell mass (ICM), where chromosomally normal cells are preferentially retained? SUMMARY ANSWER In human embryos, aneuploid cells are sequestered away from the ICM, partly to the trophectoderm (TE) but more significantly to the blastocoel fluid within the blastocoel cavity (Bc) and to peripheral cells (PCs) surrounding the blastocyst during Day 3 to Day 5 progression. WHAT IS KNOWN ALREADY A commonly held dogma in all diploid eukaryotes is that two gametes, each with ‘n’ chromosomes (23 in humans), fuse to form a ‘2n’ zygote (46 in humans); a state that remains in perpetuity for all somatic cell divisions. Human embryos, however, display high levels of chromosomal aneuploidy in early stages that reportedly declines from Day 3 (cleavage stage) to Day 5 (blastocyst) post-fertilization. While this observation may be partly because of aneuploid embryonic arrest before blastulation, it could also be due to embryo ‘normalization’ to a euploid state during blastulation. If and how this normalization occurs requires further investigation. STUDY DESIGN, SIZE, DURATION A total of 964 cleavage-stage (Day 3) embryos underwent single-cell biopsy and diagnosis for chromosome constitution. All were maintained in culture, assessing blastulation rate, both for those assessed euploid and aneuploid. Pregnancy rate was assessed for those determined euploid, blastulated and subsequently transferred. For those determined aneuploid and blastulated (174 embryos), ICM (all 174 embryos), TE (all 174), Bc (47 embryos) and PC (38 embryos) were analyzed for chromosome constitution. Specifically, concordance with the original Day 3 diagnosis and determination if any ‘normalized’ to euploid karyotypes within all four structures was assessed. PARTICIPANTS/MATERIALS, SETTING, METHODS All patients (144 couples) were undergoing routine preimplantation genetic testing for aneuploidy in three IVF clinical settings. Cleavage-stage biopsy preceded chromosome analysis by next-generation sequencing. All patients provided informed consent. Additional molecular testing was carried out on blastocyst embryos and was analyzed for up to four embryonic structures (ICM, TE, Bc and PC). MAIN RESULTS AND THE ROLE OF CHANCE Of 463/964 embryos (48%) diagnosed as euploid at Day 3, 70% blastulated (leading to a 59% pregnancy rate) and 30% degenerated. Conversely, of the 501 (52%) diagnosed as aneuploid, 65% degenerated and 35% (174) blastulated, a highly significant difference (P < 0.0001). Of the 174 that blastulated, the ratio of ‘(semi)concordant-aneuploid’ versus ‘normalized-euploid’ versus ‘other-aneuploid’ embryos was, respectively, 39%/57%/3% in the ICM; 49%/48%/3% in the TE; 78%/21%/0% in the PC; and 83%/10%/5% in the Bc. The TE karyotype therefore has a positive predictive value of 86.7% in determining that of the ICM, albeit with marginally higher aneuploid rates of abnormalities (P = .071). Levels of abnormality in Bc/PC were significantly higher (P < 0.0001) versus the ploidy of the ICM and TE and nearly all chromosome abnormalities were (at least partially) concordant with Day 3 diagnoses. LIMITATIONS, REASONS FOR CAUTION The results only pertain to human IVF embryos so extrapolation to the in vivo situation and to other species is not certain. We acknowledge (rather than lineage-specific survival, as we suggest here) the possibility of other mechanisms, such as lineage-specific movement of cells, during blastulation. Ethical considerations, however, make investigating this mechanism difficult on human embryos. WIDER IMPLICATIONS OF THE FINDINGS Mosaic human cleavage-stage embryos can differentiate into a euploid ICM where euploid cell populations predominate. Sequestering of aneuploid cells/nuclei to structures no longer involved in fetal development has important implications for preimplantation and prenatal genetic testing. These results also challenge previous fundamental understandings of mitotic fidelity in early human development and indicate a complex and fluid nature of the human embryonic genome. STUDY FUNDING/COMPETING INTEREST(S) This research was funded by Organon Pharmaceuticals and Merck Serono by grants to W.G.K. W.G.K. is also an employee of AdvaGenix, who could, potentially, indirectly benefit financially from publication of this manuscript. R.C.M. is supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R35GM133747. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. D.K.G. provides paid consultancy services for Care Fertility. TRIAL REGISTRATION NUMBER N/A.

Compared to most mammals, human pregnancy is unusual in that it involves chromosomally diverse embryos, cyclical breakdown and regeneration of the uterine mucosa, and intimate integration of fetal and maternal cells at the uteroplacental interface. Not surprisingly, pregnancy often falters in early gestation. Whether these losses result in clinical miscarriages depends on the origins and impacts of chromosomal errors on fetal development and the ability of the decidualizing endometrium to engage in embryo biosensing and selection. Aneuploidy originating in oocytes during meiosis drives the age-related risk of miscarriage. By contrast, the frequency of endometrial cycles with an impaired decidual response may account for the stepwise increase in miscarriage rates with each pregnancy loss independently of maternal age. Additional physiological mechanisms operate in early gestation to ensure that most failing pregnancies are lost before vascular maternal-fetal connections are established by the end of the first trimester. Here, we summarise how investigations into the mechanisms that cause miscarriage led to new insights into the processes that govern maternal selection of human embryos in early gestation.

Embryo implantation in humans is interstitial, meaning the entire conceptus embeds in the endometrium before the placental trophoblast invades beyond the uterine mucosa into the underlying inner myometrium. Once implanted, embryo survival pivots on the transformation of the endometrium into an anti-inflammatory placental bed, termed decidua, under homeostatic control of uterine natural killer cells. Here, we examine the evolutionary context of embryo implantation and elaborate on uterine remodelling before and after conception in humans. We also discuss the interactions between the embryo and the decidualising endometrium that regulate interstitial implantation and determine embryo fitness. Together, this Review highlights the precarious but adaptable nature of the implantation process.

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.

Criegee intermediates are important atmospheric oxidants, formed via the reaction of ozone with volatile alkenes emitted into the troposphere. Small Criegee intermediates (e.g., CH

IntroductionChildren’s early development is affected by caregiving experiences, with lifelong health and well-being implications. Governments and civil societies need population-based measures to monitor children’s early development and ensure that children receive the care needed to thrive. To this end, the WHO developed the Global Scales for Early Development (GSED) to measure children’s early development up to 3 years of age. The GSED includes three measures for population and programmatic level measurement: (1) short form (SF) (caregiver report), (2) long form (LF) (direct administration) and (3) psychosocial form (PF) (caregiver report). The primary aim of this protocol is to validate the GSED SF and LF. Secondary aims are to create preliminary reference scores for the GSED SF and LF, validate an adaptive testing algorithm and assess the feasibility and preliminary validity of the GSED PF.Methods and analysisWe will conduct the validation in seven countries (Bangladesh, Brazil, Côte d’Ivoire, Pakistan, The Netherlands, People's Republic of China, United Republic of Tanzania), varying in geography, language, culture and income through a 1-year prospective design, combining cross-sectional and longitudinal methods with 1248 children per site, stratified by age and sex. The GSED generates an innovative common metric (Developmental Score: D-score) using the Rasch model and a Development for Age Z-score (DAZ). We will evaluate six psychometric properties of the GSED SF and LF: concurrent validity, predictive validity at 6 months, convergent and discriminant validity, and test–retest and inter-rater reliability. We will evaluate measurement invariance by comparing differential item functioning and differential test functioning across sites.Ethics and disseminationThis study has received ethical approval from the WHO (protocol GSED validation 004583 20.04.2020) and approval in each site. Study results will be disseminated through webinars and publications from WHO, international organisations, academic journals and conference proceedings.Registration detailsOpen Science Frameworkhttps://osf.io/on 19 November 2021 (DOI 10.17605/OSF.IO/KX5T7; identifier: osf-registrations-kx5t7-v1).

Recently published single-cell sequencing data from individual human sperm (n=41,189; 969–3377 cells from each of 25 donors) offer an opportunity to investigate questions of inheritance with improved statistical power, but require new methods tailored to these extremely low-coverage data (∼0.01× per cell). To this end, we developed a method, named rhapsodi, that leverages sparse gamete genotype data to phase the diploid genomes of the donor individuals, impute missing gamete genotypes, and discover meiotic recombination breakpoints, benchmarking its performance across a wide range of study designs. We then applied rhapsodi to the sperm sequencing data to investigate adherence to Mendel’s Law of Segregation, which states that the offspring of a diploid, heterozygous parent will inherit either allele with equal probability. While the vast majority of loci adhere to this rule, research in model and non-model organisms has uncovered numerous exceptions whereby ‘selfish’ alleles are disproportionately transmitted to the next generation. Evidence of such ‘transmission distortion’ (TD) in humans remains equivocal in part because scans of human pedigrees have been under-powered to detect small effects. After applying rhapsodi to the sperm data and scanning for evidence of TD, our results exhibited close concordance with binomial expectations under balanced transmission. Together, our work demonstrates that rhapsodi can facilitate novel uses of inferred genotype data and meiotic recombination events, while offering a powerful quantitative framework for testing for TD in other cohorts and study systems.

Chromosomal mosaicism, or the co-existence of cells with different chromosomal content, is a phenomenon that has been documented in human embryos for three decades. Early versions of preimplantation genetic testing (PGT-A) did not measure mosaicism, either because typically only a single cell was assessed, or because the technique could not accurately identify it. While this led to a straightforward diagnosis (an embryo was considered either normal or abnormal), it simply avoided the matter and in hindsight may have led to numerous misdiagnoses with negative clinical consequences. Modern PGT-A evaluates a multicellular biopsy with technologies capable of recognizing intermediate copy number signals for chromosomes or sub-chromosomal regions. We are therefore inevitably confronted with the issue of mosaicism and the challenge of managing embryos producing such results in the clinic. Here we discuss recent data showing that not only mosaicism in general, but specific features of mosaicism detected with PGT-A are associated with variable clinical outcomes. The conclusion is evident: mosaicism should be considered for more informed and improved embryo selection in the clinic.

Growth differentiation factor 8 (GDF8), a.k.a. myostatin, is a member of the larger TGFβ superfamily of signaling ligands. GDF8 has been well characterized as a negative regulator of muscle mass. After synthesis, GDF8 is held latent by a noncovalent complex between the N-terminal prodomain and the signaling ligand. Activation of latent GDF8 requires proteolytic cleavage of the prodomain at residue D99 by a member of the tolloid family of metalloproteases. While tolloid proteases cleave multiple substrates, they lack a conserved consensus sequence. Here, we investigate the tolloid cleavage site of the GDF8 prodomain to determine what residues contribute to tolloid recognition and subsequent proteolysis. Using sequential alanine mutations, we identified several residues adjacent to the scissile bond, including Y94, that when mutated, abolish tolloid-mediated activation of latent GDF8. Using the astacin domain of Tll1 (Tolloid Like 1) we determined that prodomain mutants were more resistant to proteolysis. Purified latent complexes harboring the prodomain mutations, D92A and Y94A, impeded activation by tolloid but could be fully activated under acidic conditions. Finally, we show that co-expression of GDF8 WT with prodomain mutants that were tolloid resistant, suppressed GDF8 activity. Taken together our data demonstrate that residues towards the N-terminus of the scissile bond are important for tolloid-mediated activation of GDF8 and that the tolloid-resistant version of the GDF8 prodomain can function dominant negative to WT GDF8.

Criegee intermediates (CIs) play a vital role in the atmosphere-known most prominently for enhancing the oxidizing capacity of the troposphere. Knowledge of their electronic absorption spectra is of vital importance for two reasons: (1) to aid experimentalists in detecting CIs and (2) in deciding if their removal is affected by solar photolysis. In this article we report a simple and efficient method based on the nuclear ensemble method that may be effectively used to compute the electronic absorption spectra of Criegee intermediates without the need for extensive computation of preparing the initial configurations of the starting geometry. We use this method to benchmark several excited-state electronic structure methods and their efficacy in reproducing the electronic absorption spectra of two well-known cases of CI: CH2OO and CH3CHOO. The success and computational feasibility of the methodology are crucial for its applicability to CIs of increasing molecular complexity, which have no known experimentally measured electronic absorption spectra, allowing a guide for experimentalists. Application of the methodology to more complex CIs (e.g., those with extended conjugation or those derived from endocyclic alkenes) will also reveal if solar photolysis becomes a competitive removal process when compared to unimolecular decay or bimolecular chemistry.

Compared to its predecessors, the Telomere-to-Telomere CHM13 genome adds nearly 200 million base pairs of sequence, corrects thousands of structural errors, and unlocks the most complex regions of the human genome for clinical and functional study. We show how this reference universally improves read mapping and variant calling for 3202 and 17 globally diverse samples sequenced with short and long reads, respectively. We identify hundreds of thousands of variants per sample in previously unresolved regions, showcasing the promise of the T2T-CHM13 reference for evolutionary and biomedical discovery. Simultaneously, this reference eliminates tens of thousands of spurious variants per sample, including reduction of false positives in 269 medically relevant genes by up to a factor of 12. Because of these improvements in variant discovery coupled with population and functional genomic resources, T2T-CHM13 is positioned to replace GRCh38 as the prevailing reference for human genetics.

Emergence from anesthesia can be associated with a wide spectrum of cognitive and behavioral dysregulation in children, including delirium or acute brain dysfunction. This period of neurobehavioral recovery can be further confounded by pain, anxiety, and fear. The implementation of monitoring for level of consciousness, pain, and delirium using valid pediatric tools is necessary to avoid misdiagnosis due to overlapping symptomatology and support appropriate management. Understanding the epidemiology of delirium in the postoperative setting will require consistent use of accurate terminology in the medical literature. The current interchangeable use of the terms "emergence agitation" and "emergence delirium" needs to be highlighted and awareness of differences in patient conditions and assessment tools is essential. We discuss epidemiology of emergence agitation and delirium in the pediatric population, and the challenges for future delineation of monitoring and management. Furthermore, we describe the possible impact of long-term consequences of emergence delirium among infants and children, and the necessary areas of future research.

This study examined whether child diet and mother-child interactions mediated the effects of a responsive stimulation and nutrition intervention delivered from 2009 to 2012 to 1324 children aged 0-24 months living in rural Pakistan. Results showed that the intervention improved children's cognitive, language and motor development through child diet and mother-child interactions. Although the intervention did not improve child growth or socio-emotional development, we observed positive indirect effects on child growth via child diet and on socio-emotional development via both child diet and mother-child interactions. In addition, child diet emerged as a shared mechanism to improve both child growth and development, whereas mother-child interactions emerged as a distinct mechanism to improve child development. Nevertheless, our results suggest the two mechanisms were mutually reinforcing and that interventions leveraging both mechanisms are likely to be more effective at improving child outcomes than interventions leveraging only one of these mechanisms.

Self-regulation is crucial for children’s development and learning. Almost by convention, it is assumed that self-regulation is a relatively stable skill, and little is known about its dynamic nature and context dependency. Traditional measurement approaches such as single direct assessments and adult reports are not well suited to address questions around variations of self-regulation within individuals and influences from social-contextual factors. Measures relying on child observations are uniquely positioned to address these questions and to advance the field by shedding light on self-regulatory variability and incremental growth. In this paper, we review traditional measurement approaches (direct assessments and adult reports) and recently developed observational measures. We discuss which questions observational measures are best suited to address and why traditional measurement approaches fall short. Finally, we share lessons learned based on our experiences using child observations in educational settings and discuss how measurement approaches should be carefully aligned to the research questions.

Mendel’s Law of Segregation states that the offspring of a diploid, heterozygous parent will inherit either allele with equal probability. While the vast majority of loci adhere to this rule, research in model and non-model organisms has uncovered numerous exceptions whereby “selfish” alleles are disproportionately transmitted to the next generation. Evidence of such “transmission distortion” (TD) in humans remains equivocal in part because scans of human pedigrees have been under-powered to detect small effects. Recently published single-cell sequencing data from individual human sperm (n = 41,189; 969-3,377 cells from each of 25 donors) offer an opportunity to revisit this question with unprecedented statistical power, but require new methods tailored to extremely low-coverage data (∼0.01 × per cell). To this end, we developed a method, named rhapsodi, that leverages sparse gamete genotype data to phase the diploid genomes of the donor individuals, impute missing gamete genotypes, and discover meiotic recombination breakpoints, benchmarking its performance across a wide range of study designs. After applying rhapsodi to the sperm sequencing data, we then scanned the gametes for evidence of TD. Our results exhibited close concordance with binomial expectations under balanced transmission, in contrast to tenuous signals of TD that were previously reported in pedigree-based studies. Together, our work excludes the existence of even weak TD in this sample, while offering a powerful quantitative framework for testing this and related hypotheses in other cohorts and study systems.

Extra or missing chromosomes—a phenomenon termed aneuploidy—frequently arises during human meiosis and embryonic mitosis and is the leading cause of pregnancy loss, including in the context of in vitro fertilization (IVF). While meiotic aneuploidies affect all cells and are deleterious, mitotic errors generate mosaicism, which may be compatible with healthy live birth. Large-scale abnormalities such as triploidy and haploidy also contribute to adverse pregnancy outcomes, but remain hidden from standard sequencing-based approaches to preimplantation genetic testing (PGT-A). The ability to reliably distinguish meiotic and mitotic aneuploidies, as well as abnormalities in genome-wide ploidy may thus prove valuable for enhancing IVF outcomes. Here, we describe a statistical method for distinguishing these forms of aneuploidy based on analysis of low-coverage whole-genome sequencing data, which is the current standard in the field. Our approach overcomes the sparse nature of the data by leveraging allele frequencies and linkage disequilibrium (LD) measured in a population reference panel. The method, which we term LD-informed PGT-A (LD-PGTA), retains high accuracy down to coverage as low as 0.05× and at higher coverage can also distinguish between meiosis I and meiosis II errors based on signatures spanning the centromeres. LD-PGTA provides fundamental insight into the origins of human chromosome abnormalities, as well as a practical tool with the potential to improve genetic testing during IVF.Significance StatementWhole chromosome gains and losses—termed aneuploidies—are the leading cause of human pregnancy loss and congenital disorders. Recent work has demonstrated that in addition to harmful meiotic aneuploidies, mitotic aneuploidies (which lead to mosaic embryos harboring cells with different numbers of chromosomes) may also be common in preimplantation embryos but potentially compatible with healthy birth. Here we developed and tested a method for distinguishing these forms of aneuploidy using genetic testing data from 8154 IVF embryos. We re-classified embryos based on signatures of meiotic and mitotic error, while also revealing lethal forms of chromosome abnormality that were hidden to existing approaches. Our method complements standard protocols for preimplantation and prenatal genetic testing, while offering insight into the biology of early development.

Large genomic insertions, deletions, and inversions are a potent source of functional and fitness-altering variation, but are challenging to resolve with short-read DNA sequencing alone. While recent long-read sequencing technologies have greatly expanded the catalog of structural variants (SVs), their costs have so far precluded their application at population scales. Given these limitations, the role of SVs in human adaptation remains poorly characterized. Here, we used a graph-based approach to genotype 107,866 long-read-discovered SVs in short-read sequencing data from diverse human populations. We then applied an admixture-aware method to scan these SVs for patterns of population-specific frequency differentiation—a signature of local adaptation. We identified 220 SVs exhibiting extreme frequency differentiation, including several SVs that were among the lead variants at their corresponding loci. The top two signatures traced to separate insertion and deletion polymorphisms at the immunoglobulin heavy chain locus, together tagging a 325 Kbp haplotype that swept to high frequency and was subsequently fragmented by recombination. Alleles defining this haplotype are nearly fixed (60-95%) in certain Southeast Asian populations, but are rare or absent from other global populations composing the 1000 Genomes Project. Further investigation revealed that the haplotype closely matches with sequences observed in two of three high-coverage Neanderthal genomes, providing strong evidence of a Neanderthal-introgressed origin. This extraordinary episode of positive selection, which we infer to have occurred between 1700 and 8400 years ago, corroborates the role of immune-related genes as prominent targets of adaptive archaic introgression. Our study demonstrates how combining recent advances in genome sequencing, genotyping algorithms, and population genetic methods can reveal signatures of key evolutionary events that remained hidden within poorly resolved regions of the genome.

Compared to its predecessors, the Telomere-to-Telomere CHM13 genome adds nearly 200 Mbp of sequence, corrects thousands of structural errors, and unlocks the most complex regions of the human genome to clinical and functional study. Here we demonstrate how the new reference universally improves read mapping and variant calling for 3,202 and 17 globally diverse samples sequenced with short and long reads, respectively. We identify hundreds of thousands of novel variants per sample—a new frontier for evolutionary and biomedical discovery. Simultaneously, the new reference eliminates tens of thousands of spurious variants per sample, including up to 12-fold reduction of false positives in 269 medically relevant genes. The vast improvement in variant discovery coupled with population and functional genomic resources position T2T-CHM13 to replace GRCh38 as the prevailing reference for human genetics.One Sentence SummaryThe T2T-CHM13 reference genome universally improves the analysis of human genetic variation.

Growth differentiation factor 8 (GDF8; also known as myostatin) and GDF11 are closely related members of the transforming growth factor β (TGF-β) family. GDF8 strongly and negatively regulates skeletal muscle growth, and GDF11 has been implicated in various age-related pathologies such as cardiac hypertrophy. GDF8 and GDF11 signaling activities are controlled by the extracellular protein antagonists follistatin; follistatin-like 3 (FSTL3); and WAP, follistatin/kazal, immunoglobulin, Kunitz, and netrin domain–containing (WFIKKN). All of these proteins contain a follistatin domain (FSD) important for ligand binding and antagonism. Here, we investigated the structure and function of the FSD from murine WFIKKN2 and compared it with the FSDs of follistatin and FSTL3. Using native gel shift and surface plasmon resonance analyses, we determined that the WFIKKN2 FSD can interact with both GDF8 and GDF11 and block their interactions with the type II receptor activin A receptor type 2B (ActRIIB). Further, we solved the crystal structure of the WFIKKN2 FSD to 1.39 Å resolution and identified surface-exposed residues that, when substituted with alanine, reduce antagonism of GDF8 in full-length WFIKKN2. Comparison of the WFIKKN2 FSD with those of follistatin and FSTL3 revealed differences in both the FSD structure and position of residues within the domain that are important for ligand antagonism. Taken together, our results indicate that both WFIKKN and follistatin utilize their FSDs to block the type II receptor but do so via different binding interactions.

Dependable flow rate measurements are necessary to calculate flow volumes and resulting nutrient loads from subsurface drainage systems and associated conservation practices. The objectives of this study were (1) to develop appropriate weir equations for a new stainless steel-edged 45° V-notch weir developed for AgriDrain inline water level control structures and (2) to determine if the equation was independent of flow depth in the structure. Weirs for 15 cm (6 in.) and 25 cm (10 in.) inline water level control structures were placed at three heights in each structure: at the base, 48 cm from the base, or 97 cm from the base, and the height of the nappe above the weir crest was recorded over a range of flow rates. The resulting data were fitted to equations of the form Q = aHb where Q is the flow rate, H is the height of the nappe above the weir crest, and a and b are fitted parameters. There were no significant differences in the fitted parameters across the two structure sizes or across the three weir placements. The fitted equation for these new stainless steel-edged V-notch weirs was Q = 0.011H2.28 with Q in liters per second and H in centimeters, and Q = 1.44H2.28, with Q in gallons per minute and H in inches. These equations can be used for measuring flow through AgriDrain in-line structures, although in-house weir calibration is highly recommended for specific applications, when possible. Keywords: Drainage, Flow monitoring, Subsurface drainage, V-notch weir, Weir calibration.

In 2001, Celera Genomics and the International Human Genome Sequencing Consortium published their initial drafts of the human genome, which revolutionized the field of genomics. While these drafts and the updates that followed effectively covered the euchromatic fraction of the genome, the heterochromatin and many other complex regions were left unfinished or erroneous. Addressing this remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium has finished the first truly complete 3.055 billion base pair (bp) sequence of a human genome, representing the largest improvement to the human reference genome since its initial release. The new T2T-CHM13 reference includes gapless assemblies for all 22 autosomes plus Chromosome X, corrects numerous errors, and introduces nearly 200 million bp of novel sequence containing 2,226 paralogous gene copies, 115 of which are predicted to be protein coding. The newly completed regions include all centromeric satellite arrays and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies for the first time.

Criegee intermediates (CIs) play a vital role in the atmosphere-known most prominently for enhancing the oxidizing capacity of the troposphere. Knowledge of their electronic absorption spectra is of vital importance for two reasons: (1) to aid experimentalists in detecting CIs and (2) in deciding if their removal is affected by solar photolysis. In this article we report a simple and efficient method based on the nuclear ensemble method that may be effectively used to compute the electronic absorption spectra of Criegee intermediates without the need for extensive computation of preparing the initial configurations of the starting geometry. We use this method to benchmark several excited-state electronic structure methods and their efficacy in reproducing the electronic absorption spectra of two well-known cases of CI: CH

Trichromacy is unique to primates among mammals, enabled by blue (short/S), green (medium/M), and red (long/L) cones. In humans and Old World monkeys, cones make a poorly understood choice between M and L cone subtype fates. To determine mechanisms specifying M and L cones, we developed an approach to visualize expression of the highly similarM- andL-opsinmRNAs.M-opsin, but notL-opsin, was observed during early human eye development, suggesting that M cones are generated before L cones. In adult human tissue, the early-developing central retina contained a mix of M and L cones compared to the late-developing peripheral region, which contained a high proportion of L cones. Retinoic acid (RA)-synthesizing enzymes are highly expressed early in retinal development. High RA signaling early was sufficient to promote M cone fate and suppress L cone fate in retinal organoids. Across a human population sample, natural variation in the ratios of M and L cone subtypes was associated with a noncoding polymorphism in theNR2F2gene, a mediator of RA signaling. Our data suggest that RA promotes M cone fate early in development to generate the pattern of M and L cones across the human retina.

Miscarriage is generally defined as the loss of a pregnancy before viability. An estimated 23 million miscarriages occur every year worldwide, translating to 44 pregnancy losses each minute. The pooled risk of miscarriage is 15·3% (95% CI 12·5–18·7%) of all recognised pregnancies. The population prevalence of women who have had one miscarriage is 10·8% (10·3–11·4%), two miscarriages is 1·9% (1·8–2·1%), and three or more miscarriages is 0·7% (0·5–0·8%). Risk factors for miscarriage include very young or older female age (younger than 20 years and older than 35 years), older male age (older than 40 years), very low or very high body-mass index, Black ethnicity, previous miscarriages, smoking, alcohol, stress, working night shifts, air pollution, and exposure to pesticides. The consequences of miscarriage are both physical, such as bleeding or infection, and psychological. Psychological consequences include increases in the risk of anxiety, depression, post-traumatic stress disorder, and suicide. Miscarriage, and especially recurrent miscarriage, is also a sentinel risk marker for obstetric complications, including preterm birth, fetal growth restriction, placental abruption, and stillbirth in future pregnancies, and a predictor of longer-term health problems, such as cardiovascular disease and venous thromboembolism. The costs of miscarriage affect individuals, health-care systems, and society. The short-term national economic cost of miscarriage is estimated to be £471 million per year in the UK. As recurrent miscarriage is a sentinel marker for various obstetric risks in future pregnancies, women should receive care in preconception and obstetric clinics specialising in patients at high risk. As psychological morbidity is common after pregnancy loss, effective screening instruments and treatment options for mental health consequences of miscarriage need to be available. We recommend that miscarriage data are gathered and reported to facilitate comparison of rates among countries, to accelerate research, and to improve patient care and policy development.

This paper presents design and installation details and full-scale test results for a prestressed mechanically fastened fiber-reinforced polymer (MF-FRP) retrofit solution that restores the...

Facet injections and other pain management interventions are commonly performed in combination with conservative therapy to address spinal pain. Joint mobilizations are a highly utilized intervention for manual practitioners to treat patients with spinal pain. Clinical reasoning and decision making models have not been well described in the literature assessing if and when joint mobilizations are appropriate interventions immediately or shortly following facet injection procedures. It has not been well studied if joint mobilizations immediately following facet injections negatively impact the injected solution at the respective joint and thus influence therapeutic effect. More specifically, there is a paucity of evidence assessing this at the thoracic spine. The purpose of this study was to assess if thoracic joint high-velocity low amplitude thrust manipulations caused extravasation of injected radiolucent material at respective thoracic facet joints on a cadaver. This study included an expert physician performing ultrasound-guided facet injections, an experienced manual physical therapist performing joint mobilization techniques, and fluoroscopic assessment of radiolucent material pre- and post-manipulation by a board-certified radiologist with experience in this field of study. Imaging interpretation confirmed that extravasation at respective joints did not occur following manipulation. This basic research can help guide clinical reasoning for practitioners considering implementing manual therapy techniques following facet injections and help guide further research.