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Vertebrate embryos achieve developmental competency during zygotic genome activation (ZGA) by establishing chromatin states that silence yet poise developmental genes for subsequent lineage-specific activation. Here, we reveal the order of chromatin states in establishing developmental gene poising in preZGA zebrafish embryos. Poising is established at promoters and enhancers that initially contain open/permissive chromatin with ‘Placeholder’ nucleosomes (bearing H2A.Z, H3K4me1, and H3K27ac), and DNA hypomethylation. Silencing is initiated by the recruitment of polycomb repressive complex 1 (PRC1), and H2Aub1 deposition by catalytic Rnf2 during preZGA and ZGA stages. During postZGA, H2Aub1 enables Aebp2-containing PRC2 recruitment and H3K27me3 deposition. Notably, preventing H2Aub1 (via Rnf2 inhibition) eliminates recruitment of Aebp2-PRC2 and H3K27me3, and elicits transcriptional upregulation of certain developmental genes during ZGA. However, upregulation is independent of H3K27me3 – establishing H2Aub1 as the critical silencing modification at ZGA. Taken together, we reveal the logic and mechanism for establishing poised/silent developmental genes in early vertebrate embryos.

To examine pregnancy and birth outcomes among women with idiopathic thrombocytopenic purpura (ITP) or chronic ITP (cITP) diagnosed before or during pregnancy.A linkage of mothers and babies within a large U.S. health insurance database that combines enroll

Objective: Clubfoot, or talipes equinovarus (TEV), is commonly diagnosed on prenatal ultrasound. This study sought to visualize TEV and associated abnormalities on fetal magnetic resonance imaging (MRI) compared with ultrasound. Methods: This retrospective study included the MRI scans of 44 fetuses with TEV using postnatal assessment and autopsy as standard of reference. Isolated TEV was differentiated from complex TEV with associated abnormalities. MRI findings and previous ultrasound diagnoses were compared. Results: Isolated TEV was found in 19/44 (43.2%) fetuses and complex TEV in 25/44 (56.8%). Associated abnormalities consisted of the following: central nervous system/spinal abnormalities in 13/25 (52.0%) fetuses; musculoskeletal abnormalities in 7/25 (28.0%); thoracic abnormalities in 3/25 (12.0%); a tumor in one case; and hydrops fetalis in one. Of the 44 cases, 35 (79.5%) pregnancies were delivered, and nine (20.5%) pregnancies, which were terminated, all had complex TEV. Of the 42 available ultrasound reports, additional MRI findings were made in 8/42 (19.0%) cases. MRI did not add findings in isolated TEV on ultrasound. In 4/44 (9.1%) cases, autopsy revealed additional findings compared with prenatal imaging. Conclusion: Fetal MRI enables differentiation between isolated and complex TEV. Isolated TEV on ultrasound may not be an MRI indication, whereas MRI may be useful in cases of complex TEV. [ABSTRACT FROM AUTHOR]

Klaassens M, Reinstein E, Hilhorst-Hofstee Y, Schrander JJP, Malfait F, Staal H, ten Have LC, Blaauw J, Roggeveen HCJ, Krakow D, De Paepe A, van Steensel MAM, Pals G, Graham JM Jr, Schrander-Stumpel CTRM. Ehlers-Danlos arthrochalasia types (VIIA-B) - expanding the phenotype: from prenatal life through adulthood. The Ehlers-Danlos syndromes (EDS) form a clinically and genetically heterogeneous group of inherited connective-tissue disorders characterized by joint hypermobility, tissue fragility and skin abnormalities. Six subtypes have been well characterized based on clinical features and molecular genetic abnormalities. The arthrochalasia type EDS (formerly types VIIA and B) is characterized by severe generalized joint hypermobility with multiple dislocations including congenital bilateral dislocation of the hips, muscular hypotonia and distinct dysmorphic features. The diagnosis of the arthrochalasia type EDS is of importance in the neonatal period because of consequences of physical disability in later life. However, the differential diagnosis may be difficult because of overlap with other hypermobility syndromes. In addition, the significant hypotonia may direct the physician toward various neuromuscular diagnoses. As patients become older, the hypotonia decreases and facial features become less distinct. In this report, we describe seven patients at different ages. Timing of diagnosis varied from prenatal life to adult age. The diagnosis of EDS type VII was confirmed by biochemical studies or mutation analysis showing characteristic mutations in COL1A1 and COL1A2. These mutations result in skipping of exon 6, which leads to defective collagen synthesis. For physicians treating patients with EDS type VII, achieving mobility for the patient is the greatest challenge and it may be impossible because of recurrent dislocations of nearly all joints in severe cases. [ABSTRACT FROM AUTHOR]

OBJECTIVE: In view of the increasing use of fetal magnetic resonance imaging (MRI) as an adjunct to prenatal ultrasonography, we sought to demonstrate the visualization of upper extremity abnormalities and associated defects on MRI, with regard to fetal outcomes and compared with ultrasound imaging. METHODS: This retrospective study included 29 fetuses with upper extremity abnormalities visualized with fetal MRI following suspicious ultrasound findings and confirmed by postnatal assessment or autopsy. On a 1.5-Tesla unit, dedicated sequences were applied to image the extremities. Central nervous system (CNS) and extra-CNS anomalies were assessed to define extremity abnormalities as isolated or as complex, with associated defects. Fetal outcome was identified from medical records. MRI and ultrasound findings, when available, were compared. RESULTS: Isolated upper extremity abnormalities were found in three (10.3%) fetuses. In 26 (89.7%) fetuses complex abnormalities, including postural extremity disorders (21/26) and structural extremity abnormalities (15/26), were demonstrated. Associated defects involved: face (15/26); musculoskeletal system (14/26); thorax and cardio/pulmonary system (12/26); lower extremities (12/26); brain and skull (10/26); and abdomen (8/26). Of the 29 cases, 18 (62.1%) pregnancies were delivered and 11 (37.9%) were terminated. MRI and US findings were compared in 27/29 cases: the diagnosis was concordant in 14 (51.9%) of these cases, and additional findings were made on MRI in 13/27 (48.1%) cases. CONCLUSIONS: Visualization of upper extremity abnormalities on fetal MRI enables differentiation between isolated defects and complex ones, which may be related to poor fetal prognosis. MRI generally confirms the ultrasound diagnosis, and may provide additional findings in certain cases. Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Using lessons learned from the US Department of Health and Human Services National Donation Breakthrough Collaborative, New York-Presbyterian Healthcare System (NYPHS) partnered with 5 donor service areas covering its member hospitals to improve donation across the system. By integrating established communication networks with the 'spread' techniques of the Breakthrough Collaborative, the NYPHS identified hospital champions and best practices and established standardized outcome metrics. The improvements that resulted were a sustained increase of 40.23% in consent rate and an initial 41.7% increase in conversion rate during the first 6 months, although that conversion rate was not sustainable. During the 8 measured periods, 21 hospitals met or exceeded the 75% conversion rate during 1 or more quarters. NYPHS was able to spread these successes and outcome metrics through its established communication networks of quarterly report cards, regular senior leader meetings, and real-time access to a secure member-only Web site, thus keeping organ and tissue donation at the forefront of hospital leaders' priorities. [ABSTRACT FROM AUTHOR]

A review of current opinion concerning 'auditory neuropathy' is presented. It is suggested that electrophysiological tests, including electrocochleography, auditory brainstem responses and electrically evoked auditory brainstem responses, together with imaging, can provide information regarding the site of the underlying pathological conditions that may produce the combination of otoacoustic emissions in the absence of auditory brainstem responses in children with hearing loss. It is suggested that in 75% of cases auditory neuropathy can merely be a result of surviving outer hair cells when inner hair cell function is compromised. The remaining cases of auditory neuropathy may have dysfunction of the afferent neural synapse, cochlear nerve, cochlear nucleus, auditory brainstem tracts and central auditory system. Rather than continuing to use a blanket and often misleading term, we are now in a better position to describe each individual case exhibiting this phenomenon according to the correct site of lesion. [ABSTRACT FROM AUTHOR]

Coefficient alpha, the most commonly used estimate of internal consistency, is often considered a lower bound estimate of reliability, though the extent of its underestimation is not typically known. Many researchers are unaware that coefficient alpha is based on the essentially tau-equivalent measurement model. It is the violation of the assumptions required by this measurement model that are often responsible for coefficient alpha's underestimation of reliability. This article presents a hierarchy of measurement models that can be used to estimate reliability and illustrates a procedure by which structural equation modeling can be used to test the fit of these models to a set of data. Test and data characteristics that can influence the extent to which the assumption of tau-equivalence is violated are discussed. Both heuristic and applied examples are used to augment the discussion. [ABSTRACT FROM AUTHOR]

Recent advances in genetic testing can help to provide a specific diagnosis to children born with syndromes that result in congenital anomalies and developmental delay. One such emerging condition is the 22g13 deletion syndrome. With the introduction of subtelomeric fluorescencein-situ hybridization (FISH) analysis, the 22g13 deletion has become recognized as a relatively widespread and underdiagnosed cause of mental retardation. Primary-care physicians play an important role in the care of children with 22g13 deletion syndrome, from suspecting the diagnosis in a developmentally delayed child through the medical, developmental, and behavioral aspects of their care. Furthermore, they serve as a valuable source of support and advocacy for the family and a resource for other care providers. The remainder of this article addresses the current state of knowledge regarding 22813 deletion syndrome and offers the primary-care physician a framework in which to provide care and information. [ABSTRACT FROM AUTHOR]

The 2002 Graham Fraser Memorial Lecture deals first with the French origins of cochlear implantation in Paris in the 1950s and the role of Andre Djourno and Charles Eyries. Following this work in Paris Dr William House in Los Angeles continued work on cochlear implants and, subsequently, experimental implant programmes were started in California, Paris, Vienna and Melbourne. The next section of this lecture covers the experimental work of Galvani in establishing the role of electricity in physiology. The results of his first experiments were published in 1791, the year that Mondini produced the first account of a cochlear malformation in a congenitally deaf child. At around the same time sign language for congenitally deaf children was being developed for the first time in Paris by Epee and the first disputes occurred between oralists and those who promoted signing for the education of congenitally deaf children. In a present day cochlear implant programme good results from implanting congenitally deaf children at an early age and implanting adults who have become profoundly deaf are now taken for granted. We do have much to learn, however, from more complex implant candidates and some examples of such candidates are presented. Lastly, looking to the future, the use of PET scanning to try and gain information about how the brain handles the information provided to it by a cochlear implant is described. [ABSTRACT FROM AUTHOR]

Herein, we disclose the nickel-catalyzed reductive cyanation of alkenyl tosylates and triflates. Both cyclic and acyclic alkenyl nitriles are produced in moderate to good yield using 2-(4-methoxyphenyl)-2-methylmalononitrile (MeO-MPMN), a novel transnitrilation, or nitrile transfer, reagent. A robustness screen was undertaken to demonstrate the functional group tolerance of this method.

Study Design: Retrospective analysis of difficult airway alerts in a major tertiary centre., Objective: To investigate the completeness, utility and efficacy of difficult airway alerts and their impact on future airway management episodes., Design, Data Sources and Methods: Patients who had a "difficult airway" entry on electronic medical records (EMR) from 2011 to 2021 were included. Each alert was analyzed by a team of anesthetists with expertise in difficult airway management for its quality, appropriateness, and impact on future airway management episodes. Alert quality was defined as to whether the content of the alert contained pertinent information for emergent airway management. Alert appropriateness was defined as to whether the experts would be unhappy to perform a rapid sequence induction and intubation, if required, following review of all available documentation., Results: 141 patients were included for this study, with a mean age of 58.6 +/- 15.3 years. Ninety-three (66%) alerts were created by medical staff, of which 52 were recorded by consultant anesthetists. 117 alerts (83%) were deemed to be appropriate by the airway expert team, but only 40 alerts (28%) were found to have sufficient quality to be helpful in emergent airway management. Sixty-five patients (47%) had at least one subsequent airway management episode, of which 35 patients (56%) underwent a change of management following alert creation. We proceeded to modify 103 alerts (73%) to improve their quality to aid future encounters., Conclusion: Difficult Airway encounters are an uncommon event in anesthesia, but clear, comprehensive and effectively communicated documentation is required to minimize the risk in future encounters. In our institution, while most difficult airway alerts were appropriate, we found significant heterogeneity in the quality of this documentation, which limits the clinical utility of the alert system. We have taken measures to improve local processes of difficult airway documentation and considered the implications of our project for the broader airway management community., Trial Registration: Not applicable., (© 2024. The Author(s).)

The spotted lanternfly (Lycorma delicatula) has recently spread from its native range to several other countries and forecasts predict that it may become a global invasive pest. In particular, since its confirmed presence in the United States in 2014 it has established itself as a major invasive pest in the Mid-Atlantic region where it is damaging both naturally occurring and commercially important farmed plants. Quarantine zones have been introduced to contain the infestation, but the spread to new areas continues. At present the pathways and drivers of spread are not well-understood. In particular, several human activity related factors have been proposed to contribute to the spread; however, which features of the current spread can be attributed to these factors remains unclear. Here we collect county level data on infestation status and four specific human activity related factors and use statistical methods to determine whether there is evidence for an association between the factors and infestation. Then we construct a network model based on the factors found to be associated with infestation and use it to simulate local spread. We find that the model reproduces key features of the spread 2014 to 2021. In particular, the growth of the main infestation region and the opening of spread corridors in the westward and southwestern directions is consistent with data and the model accurately forecasts the correct infestation status at the county level in 2021 with 81% accuracy. We then use the model to forecast the spread up to 2025 in a larger region. Given that this model is based on a few human activity related factors that can be targeted, it may prove useful to incorporate it into more elaborate predictive forecasting models and in informing management efforts focused on interstate highway transport and garden centers in the US and potentially for current and future invasions elsewhere globally., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Strömbom et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Genetics has become a critical component of medicine over the past five to six decades. Alongside genetics, a relatively new discipline, dysmorphology, has also begun to play an important role in providing critically important diagnoses to individuals and families. Both have become indispensable to unraveling rare diseases. Almost every medical specialty relies on individuals experienced in these specialties to provide diagnoses for patients who present themselves to other doctors. Additionally, both specialties have become reliant on molecular geneticists to identify genes associated with human disorders. Many of the medical geneticists, dysmorphologists, and molecular geneticists traveled a circuitous route before arriving at the position they occupied. The purpose of collecting the memoirs contained in this article was to convey to the reader that many of the individuals who contributed to the advancement of genetics and dysmorphology since the late 1960s/early 1970s traveled along a journey based on many chances taken, replying to the necessities they faced along the way before finding full enjoyment in the practice of medical and human genetics or dysmorphology. Additionally, and of equal importance, all exhibited an ability to evolve with their field of expertise as human genetics became human genomics with the development of novel technologies., (© 2024 Wiley Periodicals LLC.)

Importance: Delays in receiving vaccinations lead to greater vaccine-preventable disease risk. Timeliness of receipt of recommended vaccinations is not routinely tracked in the US, either overall or for populations that have known barriers to accessing routine health care, including lower-income families and children., Objective: To measure vaccination timeliness among US children aged 0 to 19 months, overall and by socioeconomic indicators., Design, Setting, and Participants: This serial, cross-sectional study analyzed nationally representative data from the 2011 to 2021 National Immunization Survey-Child (NIS-Child), an annual survey of parents, with immunization histories collected from clinicians administering vaccines. The 2020 and 2021 surveys largely reflected vaccinations in the US before the COVID-19 pandemic. Study participants included US children surveyed at ages 19 to 35 months. Data were analyzed from January to August 2023., Exposure: Survey year., Main Outcomes and Measures: The primary outcomes were average days undervaccinated (ADU) and percentage of children who received all vaccine doses on time (ie, 0 days undervaccinated) for the combined 7-vaccine series up to age 19 months. The mean adjusted annual change in on-time vaccination by socioeconomic indicators was calculated by use of multivariable log-linked binomial regression models., Results: The surveys included 179 154 children (92 248 boys [51.2%]); 74 479 (31.4%, weighted) lived above the federal poverty level with more than $75 000 in annual family income, 58 961 (32.4%) lived at or above the poverty level with $75 000 or less in annual family income, and 39 564 (30.2%) lived below the poverty level. Overall, the median (IQR) ADU for the combined 7-vaccine series in the US decreased from 22.3 (0.4-71.5) days in the 2011 survey to 11.9 (0.0-55.5) days in the 2021 survey. The prevalence of on-time receipt of the combined 7-vaccine series increased from 22.5% (95% CI, 21.4%-23.6%) to 35.6% (95% CI, 34.2%-37.0%). Although children with more than $75 000 in annual family income had a 4.6% (95% CI, 4.0%-5.2%) mean annual increase in on-time vaccination, the mean annual increase was 2.8% (95% CI, 2.0%-3.6%) for children living at or above the poverty level with $75 000 or less in annual family income and 2.0% (95% CI, 1.0%-3.0%) for children living below the poverty level., Conclusions and Relevance: In this cross-sectional study of NIS-Child data, improvements in vaccination timeliness were observed from the 2011 to the 2021 survey. However, widening disparities by socioeconomic indicators signal that increased efforts to facilitate timely vaccination among children in lower-income families are needed.

Objective: Recurrent deletions involving 17q12 are associated with a variety of clinical phenotypes, including congenital abnormalities of the kidney and urinary tract (CAKUT), maturity onset diabetes of the young, type 5, and neurodevelopmental disorders. Structural and/or functional renal disease is the most common phenotypic feature, although the prenatal renal phenotypes and the postnatal correlates have not been well characterized., Method: We reviewed pre- and postnatal medical records of 26 cases with prenatally or postnatally identified 17q12/HNF1B microdeletions (by chromosomal microarray or targeted gene sequencing), obtained through a multicenter collaboration. We specifically evaluated 17 of these cases (65%) with reported prenatal renal ultrasound findings., Results: Heterogeneous prenatal renal phenotypes were noted, most commonly renal cysts (41%, n = 7/17) and echogenic kidneys (41%), although nonspecific dysplasia, enlarged kidneys, hydronephrosis, pelvic kidney with hydroureter, and lower urinary tract obstruction were also reported. Postnatally, most individuals developed renal cysts (73%, 11/15 live births), and there were no cases of end-stage renal disease during childhood or the follow-up period., Conclusion: Our findings demonstrate that copy number variant analysis to assess for 17q12 microdeletion should be considered for a variety of prenatally detected renal anomalies. It is important to distinguish 17q12 microdeletion from other etiologies of CAKUT as the prognosis for renal function and presence of associated findings are distinct and may influence pregnancy and postnatal management., (© 2023 John Wiley & Sons Ltd.)

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population., (© 2023 Wiley Periodicals LLC.)

Objectives: In the U.S., vaccination coverage is lower in rural versus urban areas. Spatial accessibility to immunization services has been a suspected risk factor for undervaccination in rural children. Our objective was to identify whether geographic factors, including driving distance to immunization providers, were associated with completion of recommended childhood vaccinations., Methods: We analyzed records from Montana's immunization information system for children born 2015-2017. Using geolocated address data, we calculated distance in road miles from children's residences to the nearest immunization provider. A multivariable log-linked binomial mixed model was used to identify factors associated with completion of the combined 7-vaccine series by age 24 months., Results: Among 26,085 children, 16,503 (63.3%) completed the combined 7-vaccine series by age 24 months. Distance to the nearest immunization provider ranged from 0 to 81.0 miles (median = 1.7; IQR = 3.2), with the majority (92.1%) of children living within 10 miles of a provider. Long distances (>10 miles) to providers had modest associations with not completing the combined 7-vaccine series (adjusted prevalence ratio [aPR]: 0.97, 95% confidence interval [CI]: 0.96-0.99). After adjustment for other factors, children living in rural areas (measured by rural-urban commuting area) were significantly less likely to have completed the combined 7-vaccine series than children in metropolitan areas (aPR: 0.88, 95% CI: 0.85-0.92)., Conclusions: Long travel distances do not appear to be a major barrier to childhood vaccination in Montana. Other challenges, including limited resources for clinic-based strategies to promote timely vaccination and parental vaccine hesitancy, may have greater influence on rural childhood vaccination., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Pathogenic variants in KMT5B , a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM # 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest ( n  = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B -related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.