Report from the field: A model of behavioral health integration with pediatric providers.

Children with mental health needs are currently not able to access adequate resources. This report from the field describes the ongoing implementation of an integrated behavioral health model in the state of Texas. The Child Psychiatry Access Network (CPAN) leverages primary care providers (PCPs) in the treatment and management of childhood psychiatric disorders. Data are reported as of November 2021 from consultations placed by PCPs over the preceding 17 months. During that time period, following consultation with the CPAN team, over 90% of PCPs were comfortable delivering the recommended mental health care directly to their patients. This suggests that CPAN is a feasible integrated behavioral health approach to address the shortage of child and adolescent psychiatrists.

Causes of Sudden Unexpected Death in Childhood: Autopsy Findings from a Specialist Centre.

OBJECTIVES: To investigate the aetiologies of sudden unexpected death from natural causes in children aged 1-18 years by retrospective examination of autopsy records from a single centre. MATERIALS AND METHODS: The post-mortem findings from 548 children (1996-2015) were examined. Details were entered into an established research database and categorized according to >400 pre-defined criteria. RESULTS: There were 265 previously apparently healthy children and 283 with pre-existing, potentially life-limiting, conditions. There were more males than females (M:F 1.4:1), and deaths were more frequent in the winter. Infection was commonest accounting for 43% of all deaths. Non-infectious diseases were identified as cause of death in 28%, and 29% of all deaths were unexplained. There was no significant difference in the proportions of deaths in each category between the previously healthy children and those with pre-existing conditions. CONCLUSION: Sudden unexpected death is a rare presentation of death in childhood and those with pre-existing conditions may be more at risk. Standardisation of the post-mortem procedure in such cases may result in more ancillary investigations performed as routine and may reduce the number of cases that are 'unexplained'.

SARS-COV2 placentitis and pregnancy outcome: A multicentre experience during the Alpha and early Delta waves of coronavirus pandemic in England.

Background: Pregnant women with SARS-CoV-2 infection experience higher rates of stillbirth and preterm birth. A unique pattern of chronic histiocytic intervillositis (CHI) and/or massive perivillous fibrin deposition (MPFD) has emerged, coined as SARS-CoV-2 placentitis. Methods: The aim of this study was to describe a cohort of placentas diagnosed with SARS-CoV-2 placentitis during October 2020-March 2021. Cases with a histological diagnosis of SARS-CoV-2 placentitis and confirmatory immunohistochemistry were reported. Maternal demographic data, pregnancy outcomes and placental findings were collected. Findings: 59 mothers delivered 61 infants with SARS-CoV-2 placentitis. The gestational age ranged from 19 to 41 weeks with most cases (78.6%) being third trimester. 30 infants (49.1%) were stillborn or late miscarriages. Obese mothers had higher rates of pregnancy loss when compared with those with a BMI <30 [67% (10/15) versus 41% (14/34)]. 47/59 (79.7%) mothers had a positive SARS-CoV-2 PCR test either at the time of labour or in the months before, of which 12 (25.5%) were reported to be asymptomatic. Ten reported only CHI, two cases showed MPFD only and in 48 placentas both CHI and MPFD was described. Interpretation: SARS-CoV2 placentitis is a distinct entity associated with increased risk of pregnancy loss, particularly in the third trimester. Women can be completely asymptomatic and still experience severe placentitis. Unlike 'classical' MPFD, placentas with SARS-CoV-2 are generally normal in size with adequate fetoplacental weight ratios. Further work should establish the significance of the timing of maternal SARS-CoV-2 infection and placentitis, the significance of SARS-CoV2 variants, and rates of vertical transmission associated with this pattern of placental inflammation. Funding: There was not funding associated with this study.

Harry Potter and the Osteopathic Medical School Part 2: Creating a Virtual Harry Potter-Themed Day as a High-Yield Review for Final Examinations.

The role of gamification and active learning has been common topics of conversation in higher education for many years. These learning tools have been correlated with a multitude of positive effects, including increased student engagement, collaboration, and motivation to learn. This article explores the role of gamification and active learning in a virtual setting using a gamified Harry Potter-themed final examination review session for first-year osteopathic medical students. We also discuss how gamification can be used to improve the connectivity and wellness of students as they attend classes almost entirely online during the COVID-19 global pandemic. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40670-022-01501-4.

Harry Potter and the Osteopathic Medical School: Creating a Harry Potter-Themed Day as a High-Yield Review for Final Exams.

Incorporating contemporary fiction into educational activities that are interactive and memorable creates a positive learning environment for students. The current article describes how our medical school created a Harry Potter-themed educational event to review didactic material before a final exam. Students were sorted into Hogwarts houses and collected house points in the 8 themed classrooms that reviewed material for the individual disciplines. The event also included a Quidditch tournament and a Yule Ball. The event received positive feedback from students, encouraging the school's faculty to look for other opportunities to create similar educational experiences during preclinical medical education.

Values-Based Interventions in Patient Engagement for Those with Complex Needs.

The objective was to evaluate a novel intervention that integrates a psychological, values-based approach with coordinated care management. This paper describes an integrated comprehensive health record system to enhance engagement with a subset of those with complex needs; those who are high-needs, high-cost (HNHC). Patients are selected after conducting data analysis on the most costly and complex patients of a payer system that works with HNHC patients. Specifically, the Patient Care Intervention Center in Houston TX, applies the values-based intervention to HNHC patients. This pilot study reports data from 18 HNHC patients over 6 months; specifically, outcomes related to daily functioning, depression, working alliance, stages of change, and overall well-being. Additionally, this paper reports preliminary findings from qualitative monitoring of provider experiences implementing the values-based approach and integrated evaluation. HNHC patients improved their daily functioning over 4 months but no other significant changes were found over time. Patients self-reported mild depression, strong working alliances with their provider, being in the contemplation phase of change, and moderate well-being. There also was variation when patients completed the assessments and data points were collected. Although this is a small sample and short time frame, preliminary results suggest that the intervention has a positive impact on HNHC patient daily functioning. Provider accounts of the implementation describe using the evaluation items to inform their interactions with patients, and also suggest that patient literacy level impacts when data can be collected. Other changes to the approach are suggested.

Myc-driven chromatin accessibility regulates Cdc45 assembly into CMG helicases.

Myc-driven tumorigenesis involves a non-transcriptional role for Myc in over-activating replication origins. We show here that the mechanism underlying this process involves a direct role for Myc in activation of Cdc45-MCM-GINS (CMG) helicases at Myc-targeted sites. Myc induces decondensation of higher-order chromatin at targeted sites and is required for chromatin access at a chromosomal origin. Myc-driven chromatin accessibility promotes Cdc45/GINS recruitment to resident MCMs, and activation of CMGs. Myc-Box II, which is necessary for Myc-driven transformation, is required for Myc-induced chromatin accessibility, Cdc45/GINS recruitment, and replication stimulation. Myc interactors GCN5, Tip60, and TRRAP are essential for chromatin unfolding and recruitment of Cdc45, and co-expression of GCN5 or Tip60 with MBII-deficient Myc rescues these events and promotes CMG activation. Finally, Myc and Cdc45 interact and physiologic conditions for CMG assembly require the functions of Myc, MBII, and GCN5 for Cdc45 recruitment and initiation of DNA replication.

Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes.

Germline SAMD9 and SAMD9L mutations cause a spectrum of multisystem disorders that carry a markedly increased risk of developing myeloid malignancies with somatic monosomy 7. Here, we describe 16 siblings, the majority of which were phenotypically normal, from 5 families diagnosed with myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7; OMIM 252270) who primarily had onset of hematologic abnormalities during the first decade of life. Molecular analyses uncovered germline SAMD9L (n = 4) or SAMD9 (n = 1) mutations in these families. Affected individuals had a highly variable clinical course that ranged from mild and transient dyspoietic changes in the bone marrow to a rapid progression of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with monosomy 7. Expression of these gain-of-function SAMD9 and SAMD9L mutations reduces cell cycle progression, and deep sequencing demonstrated selective pressure favoring the outgrowth of clones that have either lost the mutant allele or acquired revertant mutations. The myeloid malignancies of affected siblings acquired cooperating mutations in genes that are also altered in sporadic cases of AML characterized by monosomy 7. These data have implications for understanding how SAMD9 and SAMD9L mutations contribute to myeloid transformation and for recognizing, counseling, and treating affected families.

Aborted Tracheo-esophageal Fistula in a Neonate.

Esophageal atresia (EA) is an uncommon congenital anomaly which is often associated with a tracheoesophageal fistula. An isolated EA is a rarer anomaly and its diagnosis has implications for the ongoing treatment and outcome of the infant. For the first time, we report a case of a premature newborn with a pure EA and a tracheal diverticulum, containing both respiratory and esophageal mucosa. We have termed this an aborted trachea-esophageal fistula. Recognition of these very rare variations of foregut anomalies may contribute to our understanding of their pathogenesis.

The genomic landscape of pediatric myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are uncommon in children and have a poor prognosis. In contrast to adult MDS, little is known about the genomic landscape of pediatric MDS. Here, we describe the somatic and germline changes of pediatric MDS using whole exome sequencing, targeted amplicon sequencing, and/or RNA-sequencing of 46 pediatric primary MDS patients. Our data show that, in contrast to adult MDS, Ras/MAPK pathway mutations are common in pediatric MDS (45% of primary cohort), while mutations in RNA splicing genes are rare (2% of primary cohort). Surprisingly, germline variants in SAMD9 or SAMD9L were present in 17% of primary MDS patients, and these variants were routinely lost in the tumor cells by chromosomal deletions (e.g., monosomy 7) or copy number neutral loss of heterozygosity (CN-LOH). Our data confirm that adult and pediatric MDS are separate diseases with disparate mechanisms, and that SAMD9/SAMD9L mutations represent a new class of MDS predisposition.

Family hostility and depressive symptoms in middle-aged couples: Moderating effect of marital integration.

This study examined (a) the associations between family hostility (husband-wife marital hostility and child hostility) and middle-aged husbands' and wives' depressive symptoms over an 11-year time period and (b) the moderating influence of couples' marital integration on these associations as measured by their joint activity. Higher order family-level latent constructs captured chronic husband-wife (marital) hostility using husbands' and wives' reports of chronic hostile interactions from 1990 to 1992, while a higher order latent construct of chronic child hostility toward parents was measured using parental reports of children's hostile behaviors from 1990 to 1992. Structural equation modeling with data from 370 families depicted the longitudinal impact of family hostility on depressive symptoms of both husbands and wives in 2001 after accounting for earlier levels of depressive symptoms in 1991. Separate models were fit for couples with high and low levels of marital integration. For couples who experienced low levels of marital integration, chronic marital hostility and child hostility were related to depressive symptoms in husbands and wives. However, for those with high marital integration, these influences were largely diminished. (PsycINFO Database Record

Childhood neoplasms presenting at autopsy: A 20-year experience.

OBJECTIVE: The aims of the review are to establish the number of undiagnosed neoplasms presenting at autopsy in a single centre and to determine the incidence and most common causes of sudden unexpected death due to neoplasia in infancy and childhood (SUDNIC). DESIGN: Retrospective observational study of paediatric autopsies performed on behalf of Her Majesty's Coroner over a 20-year period (1996-2015; n = 2,432). Neoplasms first diagnosed at autopsy were identified from an established database and cases meeting the criteria for sudden unexpected death were further categorised. RESULTS: Thirteen previously undiagnosed neoplasms were identified, including five haematological malignancies, two medulloblastomas, two neuroblastomas, two cardiac tumours and two malignancies of renal origin. Eight cases met the criteria for SUDNIC (0.33% of autopsies), the commonest group of which were haematological malignancies (n = 3). CONCLUSIONS: Neoplasms presenting as unexpected death in infancy and childhood and diagnosed at autopsy are rare. The findings suggest that haematological malignancies are the commonest cause of SUDNIC and highlight the importance of specialist autopsy in cases of sudden unexpected death.

Suppression of Reserve MCM Complexes Chemosensitizes to Gemcitabine and 5-Fluorouracil.

UNLABELLED: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and is very difficult to treat with conventional chemotherapeutic regimens. Gemcitabine and 5-fluorouracil are used in the management of PDAC and act by indirectly blocking replicative forks. However, these drugs are not highly effective at suppressing disease progression, indicating a need for the development of innovative therapeutic approaches. Recent studies indicate that suppression of the MCM helicase may provide a novel means to sensitize cancer cells to chemotherapeutic agents that inhibit replicative fork progression. Mammalian cells assemble more MCM complexes on DNA than are required to start S-phase. The excess MCM complexes function as backup initiation sites under conditions of replicative stress. The current study provides definitive evidence that cosuppression of the excess/backup MCM complexes sensitizes PDAC tumor lines to both gemcitabine and 5-FU, leading to increased loss of proliferative capacity compared with drugs alone. This occurs because reduced MCM levels prevent efficient recovery of DNA replication in tumor cells exposed to drug. PDAC tumor cells are more sensitive to MCM loss in the presence of gemcitabine than are nontumor, immortalized epithelial cells. Similarly, colon tumor cells are rendered less viable when cosuppression of MCM complexes occurs during exposure to the crosslinking agent oxaliplatin or topoisomerase inhibitor etoposide. IMPLICATIONS: These studies demonstrate that suppressing the backup complement of MCM complexes provides an effective sensitizing approach with the potential to increase the therapeutic index of drugs used in the clinical management of PDAC and other cancers.

Analysis of DNA replication associated chromatin decondensation: in vivo assay for understanding chromatin remodeling mechanisms of selected proteins.

Of critical importance to many of the events underlying transcriptional control of gene expression are modifications to core and linker histones that regulate the accessibility of trans-acting factors to the DNA substrate within the context of chromatin. Likewise, control over the initiation of DNA replication, as well as the ability of the replication machinery to proceed during elongation through the multiple levels of chromatin condensation that are likely to be encountered, is known to involve the creation of chromatin accessibility. In the latter case, chromatin access will likely need to be a transient event so as to prevent total genomic unraveling of the chromatin that would be deleterious to cells. While there are many molecular and biochemical approaches in use to study histone changes and their relationship to transcription and chromatin accessibility, few techniques exist that allow a molecular dissection of the events underlying DNA replication control as it pertains to chromatin changes and accessibility. Here, we outline a novel experimental strategy for addressing the ability of specific proteins to induce large-scale chromatin unfolding (decondensation) in vivo upon site-specific targeting to an engineered locus. Our laboratory has used this powerful system in novel ways to directly address the ability of DNA replication proteins to create chromatin accessibility, and have incorporated modifications to the basic approach that allow for a molecular genetic analysis of the mechanisms and associated factors involved in causing chromatin decondensation by a protein of interest. Alternative approaches involving co-expression of other proteins (competitors or stimulators), concurrent drug treatments, and analysis of co-localizing histone modifications are also addressed, all of which are illustrative of the utility of this experimental system for extending basic findings to physiologically relevant mechanisms. Although used by our group to analyze mechanisms underlying DNA replication associated chromatin accessibility, this unique and powerful experimental system has the propensity to be a valuable tool for understanding chromatin remodeling mechanisms orchestrated by other cellular processes such as DNA repair, recombination, mitotic chromosome condensation, or other chromosome dynamics involving chromatin alterations and accessibility.

Breakpoint mapping and haplotype analysis of three reciprocal translocations identify a novel recurrent translocation in two unrelated families: t(4;11)(p16.2;p15.4).

The majority of constitutional reciprocal translocations appear to be unique rearrangements arising from independent events. However, a small number of translocations are recurrent, most significantly the t(11;22)(q23;q11). Among large series of translocations there may be multiple independently ascertained cases with the same cytogenetic breakpoints. Some of these could represent additional recurrent rearrangements, alternatively they could be identical by descent (IBD) or have subtly different breakpoints when examined under higher resolution. We have used molecular breakpoint mapping and haplotyping to determine the origin of three pairs of reciprocal constitutional translocations, each with the same cytogenetic breakpoints. FISH mapping showed one pair to have different breakpoints and thus to be distinct rearrangements. Another pair of translocations were IBD with identical breakpoint intervals and highly conserved haplotypes on the derived chromosomes. The third pair, t(4;11)(p16.2;p15.4), had the same breakpoint intervals by aCGH and fosmid mapping but had very different haplotypes, therefore they represent a novel recurrent translocation. Unlike the t(11;22)(q23;q11), the formation of the t(4;11)(p16.2;p15.4) may have involved segmental duplications and sequence homology at the breakpoints. Additional examples of recurrent translocations could be identified if the resources were available to study more translocations using the approaches described here. However, like the t(4;11)(p16.2;p15.4), such translocations are likely to be rare with the t(11;22) remaining the only common recurrent constitutional reciprocal translocation.

Investigation of the origins of human autosomal inversions.

A significant proportion of both pericentric and paracentric inversions have recurrent breakpoints and so could either have arisen through multiple independent events or be identical by descent (IBD) with a single common ancestor. Of two common variant inversions previously studied, the inv(2)(p11q13) was genuinely recurrent while the inv(10)(p11.2q21.2) was IBD in all cases tested. Excluding these two variants we have ascertained 257 autosomal inversion probands at the Wessex Regional Genetics Laboratory. There were 104 apparently recurrent inversions, representing 35 different breakpoint combinations and we speculated that at least some of these had arisen on more than one occasion. However, haplotype analysis identified no recurrent cases among eight inversions tested, including the variant inv(5)(p13q13). The cases not IBD were shown to have different breakpoints at the molecular cytogenetic level. No crossing over was detected within any of the inversions and the founder haplotypes extended for variable distances beyond the inversion breakpoints. Defining breakpoint intervals by FISH mapping identified no obvious predisposing elements in the DNA sequence. In summary the vast majority of human inversions arise as unique events. Even apparently recurrent inversions, with the exception of the inv(2)(p12q13), are likely to be either derived from a common ancestor or to have subtly different breakpoints. Presumably the lack of selection against most inversions allows them to accumulate and disperse amongst different populations over time.

The variant inv(2)(p11.2q13) is a genuinely recurrent rearrangement but displays some breakpoint heterogeneity.

Human chromosome 2 contains large blocks of segmental duplications (SDs), both within and between proximal 2p and proximal 2q, and these may contribute to the frequency of the common variant inversion inv(2)(p11.2q13). Despite their being cytogenetically homogeneous, we have identified four different breakpoint combinations by fluorescence in situ hybridization mapping of 40 cases of inv(2)(p11.2q13) of European origin. For the vast majority of inversions (35/40), the breakpoints fell within the same spanning BACs, which hybridized to both 2p11.2 and 2q13 on the normal and inverted homologues. Sequence analysis revealed that these BACs contain a significant proportion of intrachromosomal SDs with sequence homology to the reciprocal breakpoint region. In contrast, BACs spanning the rare breakpoint combinations contain fewer SDs and with sequence homology only to the same chromosome arm. Using haplotype analysis, we identified a number of related family subgroups with identical or very closely related haplotypes. However, the majority of cases were not related, demonstrating for the first time that the inv(2)(p11.2q13) is a truly recurrent rearrangement. Therefore, there are three explanations to account for the frequent observation of the inv(2)(p11.2q13): the majority have arisen independently in different ancestors, while a minority either have been transmitted from a common founder or have different breakpoints at the molecular cytogenetic level.