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Background Intestinal and perianal fistulas and fissures are associated with significant morbidity and decreased quality of life in patients with Crohn’s disease (CD). We evaluated rates of fistula and fissure improvements with upadacitinib (UPA), an oral selective Janus kinase inhibitor, in patients with CD who had fistulas or fissures at baseline in phase 3 induction and maintenance trials. Methods In the U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836) phase 3 induction trials, patients with moderate-to-severe CD were randomized to UPA 45 mg once daily (QD) or placebo (PBO) for 12 weeks. Patients who achieved clinical response after 12 weeks of induction were eligible for U-ENDURE (NCT03345823) and rerandomized to UPA 30 mg QD, UPA 15 mg QD, or PBO for an additional 52 weeks of maintenance treatment. Fistula activity was assessed by presence of external openings and draining upon gentle compression. Presence of perianal fissures was also assessed. The proportion of patients with external closure of fistula openings, complete resolution of draining, and ≥ 50% reduction in draining was recorded at weeks 12 and 52. Endpoints were analyzed using non-responder imputation. Results Of 1021 enrolled patients, 143 patients had fistulas (124 [86.7%] perianal; 19 [13.3%] enterocutaneous) and 54 patients had perianal fissures at baseline. The proportion of patients who achieved external closure of fistula openings was higher with UPA vs PBO at week 12 (Fig 1A) and at week 52 (Fig 2A). The proportion of patients who achieved complete resolution of draining and ≥ 50% reduction in draining was higher with UPA vs PBO at week 12 (Fig 1B and 1C) and at week 52 (Fig 2B and 2C). A higher proportion of patients achieved complete resolution of fissures with UPA vs PBO at week 12 (Fig 1D) and at week 52 (Fig 2D). At weeks 12 and 52, a higher proportion of patients with fistulas treated with UPA vs PBO achieved clinical remission and endoscopic response (Fig 1E and 2E). Rates of adverse events (AEs), serious AEs, or AEs leading to study drug discontinuation were similar in UPA groups compared with PBO during the induction and maintenance periods. Rates of abscess formation were 1.8% with UPA 45 mg and 6.8% with PBO at week 12, and 3.0% with UPA 30 mg, 6.4% with UPA 15 mg, and 2.5% with PBO at week 52. Conclusion Among patients with CD complicated with fistulas and/or fissures at baseline, UPA treatment led to higher rates of external closure of fistula openings, resolution of draining, and healing of fissures, along with clinical remission and improvements in luminal disease compared with PBO. No new safety concerns were identified.

BACKGROUND: Despite evidence demonstrating limited benefit, many clinicians continue to perform routine laboratory testing of well-appearing children to medically clear them before psychiatric admission. METHODS: We conducted a quality improvement project to reduce routine laboratory testing among pediatric patients requiring admission to our psychiatric unit. We convened key stakeholders whose input informed the modification of an existing pathway and the development of a medical clearance algorithm. Our outcome was a reduction in routine laboratory testing for children requiring psychiatric admission. Our balancing measure was the number of patients requiring transfer from the inpatient psychiatry unit to a medical service. We used run charts to evaluate nonrandom variation and demonstrate sustained change. RESULTS: Before the introduction of the new medical clearance algorithm, 93% (n = 547/589) of children with psychiatric emergencies received laboratory testing. After implementing the medical clearance algorithm, 19.6% (n = 158/807) of children with psychiatric emergencies received laboratory testing. Despite a decreased rate of routine testing, there were no transfers to the medical service. CONCLUSIONS: Implementing a medical clearance algorithm can decrease routine laboratory testing without increasing transfers to the medical service among children requiring psychiatric admission.

Recommendations from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) for interpreting sequence variants specify the use of computational predictors as "supporting" level of evidence for pathogenicity or benignity using criteria PP3 and BP4, respectively. However, score intervals defined by tool developers, and ACMG/AMP recommendations that require the consensus of multiple predictors, lack quantitative support. Previously, we described a probabilistic framework that quantified the strengths of evidence (supporting, moderate, strong, very strong) within ACMG/AMP recommendations. We have extended this framework to computational predictors and introduce a new standard that converts a tool's scores to PP3 and BP4 evidence strengths. Our approach is based on estimating the local positive predictive value and can calibrate any computational tool or other continuous-scale evidence on any variant type. We estimate thresholds (score intervals) corresponding to each strength of evidence for pathogenicity and benignity for thirteen missense variant interpretation tools, using carefully assembled independent data sets. Most tools achieved supporting evidence level for both pathogenic and benign classification using newly established thresholds. Multiple tools reached score thresholds justifying moderate and several reached strong evidence levels. One tool reached very strong evidence level for benign classification on some variants. Based on these findings, we provide recommendations for evidence-based revisions of the PP3 and BP4 ACMG/AMP criteria using individual tools and future assessment of computational methods for clinical interpretation.

Anaerobic processes (e.g., methanogenesis and fermentation) largely contribute to element cycling and natural contaminant attenuation/mobilization, even in well-oxygenated porous environments, such as shallow aquifers. This paradox is commonly explained by the occurrence of small-scale anoxic microenvironments generated by the coupling of bacterial respiration and the heterogeneous oxygen (O2) transport by porewater. Such microenvironments allow facultatively and obligately anaerobic bacteria to proliferate in oxic environments. Microenvironment dynamics are still poorly understood due to the challenge of directly observing biomass and O2 distributions at the microscale within an opaque sediment and soil matrix. To overcome these limitations, we integrated a microfluidic device with transparent O2 planar optical sensors to measure the temporal behavior of dissolved O2 concentrations and biomass distributions with time-lapse video-microscopy. Our results reveal that bacterial colony morphology, which is highly variable in flowing porous systems, controls the formation of anoxic microenvironments. We rationalize our observations through a colony-scale Damkohler number comparing dissolved O2 diffusion and bacterial O2 uptake rate. Our Damkholer number enables predicting the pore space occupied by anoxic microenvironments in our system, and, given the bacterial organization, it can be applied to 3D porous systems., Comment: 29 pages + 19 pages (Supp Mat), 6 figures + 11 figures (Supp Mat)

To investigate the relationships between percentage fat mass (%FM), percentage lean mass (%LM), and the ratio of %FM to %LM with pro-inflammatory adipokines and metabolic syndrome in individuals with chronic spinal cord injury (SCI).Observational, cross-sectional. Linear and logistic regression were used to examine the associations between the %FM, %LM, and the %FM to %LM ratio with inflammatory markers and metabolic syndrome, respectively.Seventy chronic SCI men and women.%FM, %LM, %FM to %LM ratio; fasting lipids, glucose, and tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and high-sensitivity c-reactive protein (hs-CRP); metabolic syndrome as determined by The International Diabetes Federation criteria.There were significant correlations between %FM, %LM and the %FM to %LM ratio with hs-CRP. The %LM beta coefficient value was negative and greater than the beta coefficient value for %FM. The %FM to %LM ratio had the strongest correlation with hs-CRP and showed the only significant relationship with IL-6. There were strong significant correlations between %FM, %LM and the %FM to %LM ratio with metabolic syndrome. However, the %FM to %LM ratio, again, showed the strongest relationship indicating that it may be the best predictor of metabolic syndrome.Both higher %FM and lower %LM affect cardiometabolic health and can be used as predictors for metabolic syndrome. However, the %FM to %LM ratio was the best predictor of systemic inflammation and cardiometabolic disorders in this group of SCI participants, suggesting that they both contribute to the statistical model.

Background Biologic therapies are used to treat moderate-to-severe Crohn’s Disease (CD), but many patients eventually lose response to them. With new potential therapies for CD, understanding their efficacy after patients undergo biologic treatment is important for clinical decision-making. This post hoc analysis assessed the outcomes of upadacitinib (UPA), an oral selective Janus kinase inhibitor, in patients with CD who had failed a biologic, by the number and type of prior biologic therapies. Methods In the 2 induction studies, U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836), patients with moderate-to-severe CD received oral UPA 45 mg once daily (QD) therapy or placebo (PBO) for 12 weeks. Patients achieving clinical response to UPA induction were re-randomised in the maintenance study, U-ENDURE (NCT03345823), to receive UPA 15 mg QD, UPA 30 mg QD, or PBO for 52 weeks. This analysis assessed clinical, endoscopic, and safety outcomes in patients with inadequate response or intolerance to biologic therapy by number and type of biologics failed. Data from the U-EXCEL and U-EXCEED studies were pooled. Results At baseline, patient (n=733) characteristics were similar for UPA vs PBO within each subgroup by number of prior biologics (1, n=279; 2, n=223; >2, n=231); patients who received ≥ 2 prior biologics had longer disease duration (median, years: 1, 6.2; 2, 9.4; >2, 12.9) and were more likely to have used steroids (1, 27.7%; 2, 40.4%; >2, 45.0%). Across subgroups, greater proportions of patients receiving UPA vs PBO achieved clinical remission (Figure 1) and endoscopic response and remission (Figure 2) at week 12 of induction and week 52 of maintenance; response rates were generally higher for patients who had failed fewer biologics. When analyzed by type of prior biologic (tumor necrosis factor inhibitor [yes/no], n=704/29; ustekinumab [yes/no], n=272/461; vedolizumab or natalizumab [yes/no], n=220/513), the proportion of patients achieving clinical and endoscopic outcomes was slightly higher for those without prior exposure to each biologic. Adverse events (AEs) occurred at numerically higher rates for patients who had failed multiple biologics in the induction and maintenance studies across both PBO and UPA treatment arms. AEs of special interest occurred at similar rates across subgroups. No non-melanoma skin cancers, major adverse cardiovascular events, or venous thromboembolic events were reported. Conclusion Clinical and endoscopic improvements were observed with UPA induction and maintenance therapy in patients with moderate-to-severe CD, regardless of number and type of prior biologics failed; greater benefits and fewer AEs were observed in patients who failed fewer biologic therapies.

In the US, newborn screening (NBS) is a unique health program that supports health equity and screens virtually every baby after birth, and has brought timely treatments to babies since the 1960's. With the decreasing cost of sequencing and the improving methods to interpret genetic data, there is an opportunity to add DNA sequencing as a screening method to facilitate the identification of babies with treatable conditions that cannot be identified in any other scalable way, including highly penetrant genetic neurodevelopmental disorders (NDD). However, the lack of effective dietary or drug-based treatments has made it nearly impossible to consider NDDs in the current NBS framework, yet it is anticipated that any treatment will be maximally effective if started early. Hence there is a critical need for large scale pilot studies to assess if and how NDDs can be effectively screened at birth, if parents desire that information, and what impact early diagnosis may have. Here we attempt to provide an overview of the recent advances in NDD treatments, explore the possible framework of setting up a pilot study to genetically screen for NDDs, highlight key technical, practical, and ethical considerations and challenges, and examine the policy and health system implications.

The evolution of genomic incompatibilities causing postzygotic barriers to hybridization is a key step in species divergence. Incompatibilities take two general forms – structural divergence between chromosomes leading to severe hybrid sterility in F1hybrids and epistatic interactions between genes causing reduced fitness of hybrid gametes or zygotes (Dobzhansky-Muller incompatibilities). Despite substantial recent progress in understanding the molecular mechanisms and evolutionary origins of both types of incompatibility, how each behaves across multiple generations of hybridization remains relatively unexplored. Here, we use genetic mapping in F2and RIL hybrid populations between the phenotypically divergent but naturally hybridizing monkeyflowersMimulus cardinalisandM. parishiito characterize the genetic basis of hybrid incompatibility and examine its changing effects over multiple generations of experimental hybridization. In F2s, we found severe hybrid pollen inviability (< 50% reduction vs. parental genotypes) and pseudolinkage caused by a reciprocal translocation between Chromosomes 6 and 7 in the parental species. RILs retained excess heterozygosity around the translocation breakpoints, which caused substantial pollen inviability when interstitial crossovers had not created compatible heterokaryotypic configurations. Strong transmission ratio distortion and inter-chromosomal linkage disequilibrium in both F2s and RILs identified a novel two-locus genic incompatibility causing sex-independent gametophytic (haploid) lethality. The latter interaction eliminated three of the expected nine F2genotypic classes via F1gamete loss without detectable effects on the pollen number or viability of F2double heterozygotes. Along with the mapping of numerous milder incompatibilities, these key findings illuminate the complex genetics of plant hybrid breakdown and are an important step toward understanding the genomic consequences of natural hybridization in this model system.

PURPOSEThe terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation, and to support variant classification within the ACMG/AMP framework.METHODSTerminology for inheritance, allelic requirement, and both structural and functional consequences of a variant used by Gene Curation Coalition (GenCC) members and partner organizations was collated and reviewed. Harmonized terminology with definitions and use examples was created, reviewed, and validated.RESULTSWe present a standardized terminology to describe gene-disease relationships, and to support variant annotation. We demonstrate application of the terminology for classification of variation in the ACMG SF 2.0 genes recommended for reporting of secondary findings. Consensus terms were agreed and formalized in both sequence ontology (SO) and human phenotype ontology (HPO) ontologies. GenCC member groups intend to use or map to these terms in their respective resources.CONCLUSIONThe terminology standardization presented here will improve harmonization, facilitate the pooling of curation datasets across international curation efforts and, in turn, improve consistency in variant classification and genetic test interpretation.

Purpose:In this era of precision-based medicine, for optimal patient care, results reported from commercial next-generation sequencing (NGS) assays should adequately reflect the burden of somatic mutations in the tumor being sequenced. Here, we sought to determine the prevalence of clonal hematopoiesis leading to possible misattribution of tumor mutation calls on unpaired Foundation Medicine NGS assays.Experimental Design:This was a retrospective cohort study of individuals undergoing NGS of solid tumors from two large cancer centers. We identified and quantified mutations in genes known to be frequently altered in clonal hematopoiesis (DNMT3A, TET2, ASXL1, TP53, ATM, CHEK2, SF3B1, CBL, JAK2) that were returned to physicians on clinical Foundation Medicine reports. For a subset of patients, we explored the frequency of true clonal hematopoiesis by comparing mutations on Foundation Medicine reports with matched blood sequencing.Results:Mutations in genes that are frequently altered in clonal hematopoiesis were identified in 65% (1,139/1,757) of patients undergoing NGS. When excluding TP53, which is often mutated in solid tumors, these events were still seen in 35% (619/1,757) of patients. Utilizing paired blood specimens, we were able to confirm that 8% (18/226) of mutations reported in these genes were true clonal hematopoiesis events. The majority of DNMT3A mutations (64%, 7/11) and minority of TP53 mutations (4%, 2/50) were clonal hematopoiesis.Conclusions:Clonal hematopoiesis mutations are commonly reported on unpaired NGS testing. It is important to recognize clonal hematopoiesis as a possible cause of misattribution of mutation origin when applying NGS findings to a patient's care.See related commentary by Pollyea, p. 5790

Supplementary data file

The leaf epidermis is the outermost cell layer forming the interface between plants and the atmosphere that must both provide a robust barrier against (a)biotic stressors and facilitate carbon dioxide uptake and leaf transpiration.1 To achieve these opposing requirements, the plant epidermis developed a wide range of specialized cell types such as stomata and hair cells. Although factors forming these individual cell types are known,2,3,4,5 it is poorly understood how their number and size are coordinated. Here, we identified a role for BdPRX76/BdPOX, a class III peroxidase, in regulating hair cell and stomatal size in the model grass Brachypodium distachyon. In bdpox mutants, prickle hair cells were smaller and stomata were longer. Because stomatal density remained unchanged, the negative correlation between stomatal size and density was disrupted in bdpox and resulted in higher stomatal conductance and lower intrinsic water-use efficiency. BdPOX was exclusively expressed in hair cells, suggesting that BdPOX cell-autonomously promotes hair cell size and indirectly restricts stomatal length. Cell-wall autofluorescence and lignin stainings indicated a role for BdPOX in the lignification or crosslinking of related phenolic compounds at the hair cell base. Ectopic expression of BdPOX in the stomatal lineage increased phenolic autofluorescence in guard cell (GC) walls and restricted stomatal elongation in bdpox. Together, we highlight a developmental interplay between hair cells and stomata that optimizes epidermal functionality. We propose that cell-type-specific changes disrupt this interplay and lead to compensatory developmental defects in other epidermal cell types.

Allo-grooming networks in primate social groups are thought to have favored the evolution of vocal recognition systems, including vocal imitation in humans, as a more effective means of maintaining social bonds in large groups. Select avian taxa converged on vocal learning, but it is not clear what role analogues of allo-grooming might have played. Unlike allo-grooming in most primates, allo-preening in birds is usually limited to pair-bonds. One exception to this is during nestling development when siblings preen each other, but it is unknown how allo-preening influences vocal learning. We addressed this question in wild Green-rumped Parrotlets (Forpus passerinus) in Venezuela. Nestlings learn signature contact calls from adult templates. Large broods, age hierarchies and protracted development in this species create the potential for complex allo-preening networks and a unique opportunity to test how early sociality makes the development of vocal learning labile. From audio-video recordings inside nest cavities and a balanced design of different brood sizes, we quantified allo-preening interactions between marked nestlings, to compare to signature contact calls. Controlling for brood size and age hierarchy, the propensity to preen a larger number of individuals (i.e., out-strength) correlated positively with the age at first contact call. Allo-preening and acoustic similarity matrices did not reveal clear correlations within broods, instead larger broods produced greater contact call diversity. Results indicate that allo-preening elongates the period during which contact calls develop, which might allow individuals time to form a unique signature under the computationally challenging social conditions inherent to large groups.

BackgroundIt remains unknown why ~30% of patients with psychotic disorders fail to respond to treatment. Previous genomic investigations of treatment-resistant psychosis have been inconclusive, but some evidence suggests a possible link between rare disease-associated copy number variants (CNVs) and worse clinical outcomes in schizophrenia. Here, we identified schizophrenia-associated CNVs in patients with treatment-resistant psychotic symptoms and then compared the prevalence of these CNVs to previously published schizophrenia cases not selected for treatment resistance.MethodsCNVs were identified using chromosomal microarray (CMA) and whole exome sequencing (WES) in 509 patients with treatment-resistant psychosis (a lack of clinical response to ≥3 adequate antipsychotic medication trials over at least 5 years of psychiatric hospitalization). Prevalence of schizophrenia-associated CNVs in this sample was compared to that in a previously published large schizophrenia cohort study.ResultsIntegrating CMA and WES data, we identified 47 cases (9.2%) with at least one CNV of known or possible neuropsychiatric risk. 4.7% (n = 24) carried a known neurodevelopmental risk CNV. The prevalence of well-replicated schizophrenia-associated CNVs was 4.1%, with duplications of the 16p11.2 and 15q11.2-q13.1 regions, and deletions of the 22q11.2 chromosomal region as the most frequent CNVs. Pairwise loci-based analysis identified duplications of 15q11.2-q13.1 to be independently associated with treatment resistance.ConclusionsThese findings suggest that CNVs may uniquely impact clinical phenotypes beyond increasing risk for schizophrenia and may potentially serve as biological entry points for studying treatment resistance. Further investigation will be necessary to elucidate the spectrum of phenotypic characteristics observed in adult psychiatric patients with disease-associated CNVs.

Despite recent calls to action and a heavy emphasis on timeliness of care in guidelines for common inborn errors of metabolism, there is a dearth of specific measurable quality metrics for these conditions and little to no electronic decision support for their management. We have developed a novel set of process-oriented metrics based on the aforementioned guidelines that can be calculated from data already contained in most major EHRs, which we believe are responsive to the needs of the metabolism community.

Biological N2 fixation was key to the expansion of life on early Earth. The N2-fixing microorganisms and the nitrogenase type used in the Proterozoic are unknown, although it has been proposed that the canonical molybdenum-nitrogenase was not used due to low molybdenum availability. We investigate N2 fixation in Lake Cadagno, an analogue system to the sulfidic Proterozoic continental margins, using a combination of biogeochemical, molecular and single cell techniques. In Lake Cadagno, purple sulfur bacteria (PSB) are responsible for high N2 fixation rates, to our knowledge providing the first direct evidence for PSB in situ N2 fixation. Surprisingly, no alternative nitrogenases are detectable, and N2 fixation is exclusively catalyzed by molybdenum-nitrogenase. Our results show that molybdenum-nitrogenase is functional at low molybdenum conditions in situ and that in contrast to previous beliefs, PSB may have driven N2 fixation in the Proterozoic ocean., Nature Communications, 12 (1), ISSN:2041-1723

Background Risankizumab (RZB), an anti-IL-23 p19 inhibitor, was well-tolerated and superior to placebo (PBO) in inducing clinical remission and endoscopic response in patients (pts) with moderate-to-severe Crohn’s disease (CD) in two phase 3 studies at 12 weeks. Aims FORTIFY (NCT03105102), was a 52-week (wk) phase 3 double-blind, re-randomized responder withdrawal study that evaluated the efficacy and safety of continuing RZB as subcutaneous (SC) maintenance therapy versus withdrawal to placebo in pts achieving induction response to RZB Methods Week 12 IV RZB responders were re-randomized 1:1:1 to: RZB SC 360mg (N=141), RZB 180mg (N=157), or PBO (withdrawal from IV RZB; N=164) every 8wks for 52wks. Co-primary endpoints were clinical remission (per CD Activity Index [CDAI] (US); or stool frequency/abdominal pain score [SF/APS] (OUS) and endoscopic response at wk52. Other clinical and endoscopic endpoints, inflammatory biomarkers, RZB serum levels, and safety were assessed over time. Results Rates of clinical remission (CDAI, SF/APS) and clinical response were similar for RZB and PBO groups through wk24, with rates lower for PBO thereafter. At wk52, clinical remission (CDAI, SF/APS) and endoscopic response rates were significantly higher with RZB 360mg than PBO ( P Conclusions In pts with moderate-to-severe CD, a robust pharmacodynamic effect on the IL-23 pathway after 12wks RZB IV induction was maintained with RZB SC maintenance therapy. The durability of RZB was demonstrated with high rates of efficacy over the 52-wk study. RZB was superior to PBO for achieving clinical remission and endoscopic response at wk52. Results for the more stringent endpoints (endoscopic remission\deep remission) and persistent improvements in inflammatory biomarkers are consistent with a dose response relationship. Continued RZB SC maintenance treatment was generally safe and well-tolerated. Funding Agencies AbbVie

OBJECTIVE: Sequencing cell-free DNA now allows detection of large chromosomal abnormalities and dominant Mendelian disorders in the prenatal period. Improving upon these methods would allow newborn screening programs to begin with prenatal genetics, ultimately improving the management of rare genetic disorders. METHODS: As a pilot study, we performed exome sequencing on the cell-free DNA from three mothers with singleton pregnancies to assess the viability of broad sequencing modalities in a noninvasive prenatal setting. RESULTS: We found poor resolution of maternal and fetal genotypes due to both sampling and technical issues. CONCLUSION: We find broad sequencing modalities inefficient for noninvasive prenatal applications. Alternatively, we suggest a more targeted path forward for noninvasive prenatal genotyping.

Statistical population reconstruction using age-at-harvest and catch-effort data has recently emerged as a robust and versatile approach to estimating the demographic dynamics of harvested populations of wildlife. Although most reconstruction efforts employ the multinomial likelihood approach to identify which set of model parameters best describes the observed age-at-harvest and catch-effort data, using a [Formula: see text] objective function may provide a suitable alternative with a less steep learning curve. Using a harvested population of North American river otter (Lontra canadensis) in Kentucky as a case study, we investigated the performance of population reconstruction using multinomial likelihood and chi-square formulations. We simulated populations under a range of conditions and found that both the accuracy and precision of reconstruction estimates were similar under the two approaches. These results illustrate the potential benefits of using the [Formula: see text] approach, which may also allow agencies to incorporate auxiliary information from studies for which the corresponding likelihood contributions have yet to be developed.

The leaf epidermis is the outermost cell layer forming the interface between plants and the atmosphere that must both provide a robust barrier against (a)biotic stressors and facilitate carbon dioxide uptake and leaf transpiration1. To achieve these opposing requirements, the plant epidermis developed a wide range of specialized cell types such as stomata and hair cells. While factors forming these individual cell types are known2–5, it is poorly understood how their number and size is coordinated. Here, we identified a role forBdPRX76/BdPOX, a class III peroxidase, in regulating hair cell and stomatal size in the model grassBrachypodium distachyon. Inbdpoxmutants prickle hair cells were smaller and stomata were longer. Because stomatal density remained unchanged, the negative correlation between stomatal size and density was disrupted inbdpoxand resulted in higher stomatal conductance and lower intrinsic water-use efficiency.BdPOXwas exclusively expressed in hair cells suggesting thatBdPOXcell-autonomously promotes hair cell size and indirectly restricts stomatal length. Cell wall autofluorescence and lignin stainings indicated a role for BdPOX in lignification or crosslinking of related phenolic compounds at the hair cell base. Ectopic expression ofBdPOXin the stomatal lineage increased phenolic autofluorescence in guard cell walls and restricted stomatal elongation inbdpox. Together, we highlight a developmental interplay between hair cells and stomata that optimizes epidermal functionality. We propose that cell-type-specific changes disrupt this interplay and lead to compensatory developmental defects in other epidermal cell types.

The dilemma of how to categorize and classify diseases has been debated for centuries. The field of medical genetics has historically approached nosology based on clinical phenotypes observed in patients and families. Advances in genomic sequencing and understanding of genetic contributions to disease often provoke a need to reassess these classifications. The Clinical Genome Resource (ClinGen) has developed frameworks to classify the strength of evidence underlying monogenic gene-disease relationships, variant pathogenicity, and clinical actionability. It is therefore necessary to define the disease entity being evaluated, which can be challenging for genes associated with multiple conditions and/or a broad phenotypic spectrum. We therefore developed criteria to guide "lumping and splitting" decisions and improve consistency in defining monogenic gene-disease relationships. Here, we outline the precuration process, the lumping and splitting guidelines with examples, and describe the implications for clinical diagnosis, informatics, and care management.

Prelinguistic babbling is a critical phase in infant language development and is best understood in temperate songbirds where it occurs primarily in males at reproductive maturity and is modulated by sex steroids. Parrots of both sexes are icons of tropical vocal plasticity, but vocal babbling is unreported in this group and whether the endocrine system is involved is unknown. Here we show that vocal babbling is widespread in a wild parrot population in Venezuela, ensues in both sexes during the nestling stage, occurs amidst a captive audience of mixed-aged siblings, and is modulated by corticosteroids. Spectrographic analysis and machine learning found phoneme diversity and combinatorial capacity increased precipitously for the first week, thereafter, crystalizing into a smaller repertoire, consistent with the selective attrition model of language development. Corticosterone-treated nestlings differed from unmanipulated birds and sham controls in several acoustic properties and crystallized a larger repertoire post-treatment. Our findings indicate babbling occurs during an early life-history stage in which corticosteroids help catalyse the transition from a universal learning programme to one finely tuned for the prevailing ecological environment, a potentially convergent scenario in human prelinguistic development.

BackgroundNewborn screening aims to identify individual patients who could benefit from early management, treatment, and/or surveillance practices. As sequencing technologies have progressed and we move into the era of precision medicine, genomic sequencing has been introduced to this area with the hopes of detecting variants related to a vastly expanded number of conditions. Though implementation of genomic sequencing for newborn screening in public health and clinical settings is limited, commercial laboratories have begun to offer genomic screening panels for neonates.MethodsWe examined genes listed on four commercial laboratory genomic screening panels for neonates and assessed their clinical actionability using an established age-based semi-quantitative metric to categorize them. We identified genes that were included on multiple panels or distinct between panels.ResultsThree hundred and nine genes appeared on one or more commercial panels: 74 (23.9%) genes were included in all four commercial panels, 45 (14.6%) were on only three panels, 76 (24.6%) were on only two panels, and 114 (36.9%) genes were listed on only one of the four panels. Eighty-two genes (26.5%) listed on one or more panels were assessed by our method to be inappropriate for newborn screening and to require additional parental decision-making. Conversely, 249 genes that we previously identified as being highly actionable were not listed on any of the four commercial laboratory genomic screening panels.ConclusionsCommercial neonatal genomic screening panels have heterogeneous content and may contain some conditions with lower actionability than would be expected for public health newborn screening; conversely, some conditions with higher actionability may be omitted from these panels. The lack of transparency about how conditions are selected suggests a need for greater detail about panel content in order for parents to make informed decisions. The nuanced activity of gene list selection for genomic screening should be iteratively refined with evidence-based approaches to provide maximal benefit and minimal harm to newborns.

Background Wild‐type transthyretin (ATTRwt) amyloidosis is the most common systemic amyloidosis in Western countries and manifests mainly as progressive restrictive cardiomyopathy. Objective To study the prevalence of ATTR deposits in ligament tissue in patients undergoing surgery for lumbar spinal stenosis and to assess whether these deposits are associated with cardiac amyloidosis. Materials and methods A total of 250 patients, aged 50–89 (57% women), none with known cardiovascular disease, were included. Ligaments were investigated microscopically for amyloid. ATTR type was determined by immunohistochemistry and fibril type by Western blot. The amount of amyloid was graded 0‐4. All patients with grade 3‐4 ATTR deposits were offered cardiac investigation including ECG, cardiac ultrasound, plasma NT‐proBNP and cardiac magnetic resonance (CMR), including modern tissue characterization. Results Amyloid was identified in 221 of the samples (88.4%). ATTR appeared in 93 samples (37%) of whom 42 (17 women and 25 men) were graded 3‐4; all had fibril type A (mixture of full‐length TTR and fragmented TTR). Twenty‐nine of 42 patients with grade 3‐4 ATTR deposits accepted cardiovascular investigations; none of them had definite signs of cardiac amyloidosis, but five men had a history of carpal tunnel syndrome. Conclusions The prevalence of ATTR deposits in ligamentum flavum in patients with lumbar spinal stenosis was high but not associated with manifest ATTR cardiac amyloidosis. However, the findings of fibril type A, the prevalence of previous carpal tunnel syndrome and ATTR amyloid in surrounding adipose and vascular tissue indicate that amyloid deposits in ligamentum flavum may be an early manifestation of systemic ATTR disease.

Chromium stable isotope composition (δ

Purpose: Advances in clinical genomic sequencing capabilities, including reduced costs and knowledge gains, have bolstered the consideration of genomic screening in healthy adult populations. Yet, little is known about the existing landscape of genomic screening programs in the United States. It can be difficult to find information on current implementation efforts and best practices, particularly in light of critical questions about equity, cost, and benefit. Methods: In 2020, we searched publicly available information on the Internet and the scientific literature to identify programs and collect information, including: setting, program funding, targeted population, test offered, and patient cost. Program representatives were contacted throughout 2020 and 2021 to clarify, update, and supplement the publicly available information. Results: Twelve programs were identified. Information was available on key program features, such as setting, genes tested, and target populations. Data on costs, outcomes, or long-term sustainability plans were not always available. Most programs offered testing at no or significantly reduced cost due to generous pilot funding, although the sustainability of these programs remains unknown. Gene testing lists were diverse, ranging from 11 genes (CDC tier 1 genes) to 59 genes (ACMG secondary findings list v.2) to broad exome and genome sequencing. This diversity presents challenges for harmonized data collection and assessment of program outcomes. Conclusions: Early programs are exploring the logistics and utility of population genomic screening in various settings. Coordinated efforts are needed to take advantage of data collected about uptake, infrastructure, and intervention outcomes to inform future research, evaluation, and program development.

To determine whether sleep quality mediates the relationship between traumatic life events and psychological wellbeing in college students. Methods: 40,646 undergraduate responses from the Spring 2...

Aim: Maximizing the utility and equity of genomic sequencing integration in clinical care requires engaging patients, their families, and communities. The NCGENES 2 study explores the impact of engagement between clinicians and caregivers of children with undiagnosed conditions in the context of a diagnostic genomic sequencing study. Methods: A Community Consult Team (CCT) of diverse parents and advocates for children with genetic and/or neurodevelopmental conditions was formed. Results: Early and consistent engagement with the CCT resulted in adaptations to study protocol and materials relevant to this unique study population. Discussion: This study demonstrates valuable contributions of community stakeholders to inform the implementation of translational genomics research for diverse participants.