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Background: The increased number of cancer survivors and the recognition of physical and psychosocial challenges, present from cancer diagnosis through active treatment and beyond, led to the discipline of cancer survivorship. Design and methods: Herein, we reflected on the different components of survivorship care, existing models and priorities, in order to facilitate the promotion of high-quality European survivorship care and research. Results: We identified five main components of survivorship care: (i) physical effects of cancer and chronic medical conditions; (ii) psychological effects of cancer; (iii) social, work and financial effects of cancer; (iv) surveillance for recurrences and second cancers; and (v) cancer prevention and overall health and well-being promotion. Survivorship care can be delivered by structured care models including but not limited to shared models integrating primary care and oncology services. The choice of the care model to be implemented has to be adapted to local realities. High-quality care should be expedited by the generation of: (i) focused and shared European recommendations, (ii) creation of tools to facilitate implementation of coordinated care and (iii) survivorship educational programs for health care teams and patients. The research agenda should be defined with the participation of health care providers, researchers, policy makers, patients and caregivers. The following patient-centered survivorship research areas were highlighted: (i) generation of a big data platform to collect long-term real-world data in survivors and healthy controls to (a) understand the resources, needs and preferences of patients with cancer, and (b) understand biological determinants of survivorship issues, and (ii) develop innovative effective interventions focused on the main components of survivorship care. Conclusions: The European Society for Medical Oncology (ESMO) can actively contribute in the efforts of the oncology community toward (a) promoting the development of high-quality survivorship care programs, (b) providing educational material and (c) aiding groundbreaking research by reflecting on priorities and by supporting research networking.

Ossifying fibroma of the craniofacial bones is a fibro-osseous lesion characterized by varied patterns of bone formation in a fibroblastic stroma. Ossifying fibroma is a putatively benign lesion with no reports of malignant transformation or metastasis. Differentiation from other fibro-osseous lesions can be challenging necessitating synthesis of clinical, radiological and pathological findings. The molecular pathogenesis of ossifying fibroma is poorly understood but recent studies have reported MDM2 gene amplification and chromosomal copy number changes in a subset of ossifying fibromas. MDM2 amplification in ossifying fibroma, if true, presents a diagnostic problem because this genetic event, at least among craniofacial fibro-osseous lesions, was previously considered specific for low-grade osteosarcoma. In the present study, we investigated the utility of MDM2 and CDK4 immunohistochemistry, and fluorescence in situ hybridization for MDM2 gene amplification, in the diagnosis of 44 craniofacial bone ossifying fibromas. Focal MDM2 and CDK4 nuclear immunoreactivity was found in 11 and 1 ossifying fibromas, respectively, but none demonstrated MDM2 amplification by fluorescence in situ hybridization. A single tumor displayed MDM2 amplification without nuclear immunoreactivity to either MDM2 or CDK4. Our data suggest that while focal MDM2 and CDK4 nuclear expression may be detected in a minority of ossifying fibromas, this expression does not correlate with MDM2 amplification. In addition, MDM2 amplification is extremely rare in ossifying fibroma so the detection of this genetic abnormality should continue to raise concern for osteosarcoma.

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SOX7 is a transcription factor-encoding gene located in a region on chromosome 8p23.1 that is recurrently deleted in individuals with ventricular septal defects (VSDs). We have previously shown that Sox7−/− embryos die of heart failure around E11.5. Here, we demonstrate that these embryos have hypocellular endocardial cushions with severely reduced numbers of mesenchymal cells. Ablation of Sox7 in the endocardium also resulted in hypocellular endocardial cushions, and we observed VSDs in rare E15.5 Sox7flox/−;Tie2-Cre and Sox7flox/flox;Tie2-Cre embryos that survived to E15.5. In atrioventricular explant studies, we showed that SOX7 deficiency leads to a severe reduction in endocardial-to-mesenchymal transition (EndMT). RNA-seq studies performed on E9.5 Sox7−/− heart tubes revealed severely reduced Wnt4 transcript levels. Wnt4 is expressed in the endocardium and promotes EndMT by acting in a paracrine manner to increase the expression of Bmp2 in the myocardium. Both WNT4 and BMP2 have been previously implicated in the development of VSDs in individuals with 46,XX sex reversal with dysgenesis of kidney, adrenals and lungs (SERKAL) syndrome and in individuals with short stature, facial dysmorphism and skeletal anomalies with or without cardiac anomalies 1 (SSFSC1) syndrome, respectively. We now show that Sox7 and Wnt4 interact genetically in the development of VSDs through their additive effects on endocardial cushion development with Sox7+/−;Wnt4+/− double heterozygous embryos having hypocellular endocardial cushions and perimembranous and muscular VSDs not seen in their Sox7+/− and Wnt4+/− littermates. These results provide additional evidence that SOX7, WNT4 and BMP2 function in the same pathway during mammalian septal development and that their deficiency can contribute to the development of VSDs in humans.

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Purpose: Problems in management of oral cancers or precancers include identification of patients at risk for metastasis, tumor recurrence, and second primary tumors or risk for progression of precancers (dysplasia) to cancer. Thus, the objective of this study was to clarify the role of genomic aberrations in oral cancer progression and metastasis.Experimental Design: The spectrum of copy number alterations in oral dysplasia and squamous cell carcinomas (SCC) was determined by array comparative genomic hybridization. Associations with clinical characteristics were studied and results confirmed in an independent cohort.Results: The presence of one or more of the chromosomal aberrations +3q24-qter, -8pter-p23.1, +8q12-q24.2, and +20 distinguishes a major subgroup (70%–80% of lesions, termed 3q8pq20 subtype) from the remainder (20%–30% of lesions, non-3q8pq20). The 3q8pq20 subtype is associated with chromosomal instability and differential methylation in the most chromosomally unstable tumors. The two subtypes differ significantly in clinical outcome with risk for cervical (neck) lymph node metastasis almost exclusively associated with the 3q8pq20 subtype in two independent oral SCC cohorts.Conclusions: Two subtypes of oral lesions indicative of at least two pathways for oral cancer development were distinguished that differ in chromosomal instability and risk for metastasis, suggesting that +3q,–8p, +8q, and +20 constitute a biomarker with clinical utility for identifying patients at risk for metastasis. Moreover, although increased numbers of genomic alterations can be harbingers of progression to cancer, dysplastic lesions lacking copy number changes cannot be considered benign as they are potential precursors to non-3q8pq20 locally invasive, yet not metastatic oral SCC. Clin Cancer Res; 17(22); 7024–34. ©2011 AACR.

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Introduction: Off-label use of medicines is generally discouraged. However, several off-patent, low-cost cancer medicines remain off-label for indications in which they are commonly used in daily practice, supported by high-level evidence based on results of phase III clinical trials. This discrepancy may generate prescription and reimbursement obstacles as well as impaired access to established therapies.Methods: A list of cancer medicines that remain off-label in specific indications despite the presence of high-level evidence was generated and subjected to European Society for Medical Oncology (ESMO) expert peer review to assess for accountability of reasonableness. These medicines were then surveyed on approval procedures and workflow impact. The most illustrative examples of these medicines were reviewed by experts from the European Medicines Agency to ascertain the apparent robustness of the supporting phase III trial evidence from a regulatory perspective.Results: A total of 47 ESMO experts reviewed 17 cancer medicines commonly used off-label in six disease groups. Overall, high levels of agreement were recorded on the off-label status and the high quality of data supporting the efficacy in the off-label indications, often achieving high ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) scores. When prescribing these medicines, 51% of the reviewers had to implement a time-consuming process associated with additional workload, in the presence of litigation risks and patient anxiety. Finally, the informal regulatory expert review identified only 2 out of 18 (11%) studies with significant limitations that would be difficult to overcome in the context of a potential marketing authorisation application without additional studies.Conclusions: We highlight the common use of off-patent essential cancer medicines in indications that remain off-label despite solid supporting data as well as generate evidence on the adverse impact on patient access and clinic workflows. In the current regulatory framework, incentives to promote the extension of indications of off-patent cancer medicines are needed for all stakeholders.

BACKGROUND: Premature infants are born with immature lungs that demonstrate abnormal pulmonary function with differences in passive respiratory system compliance and resistance, and functional residual capacity. To our knowledge, no studies have evaluated differences in neonatal pulmonary function based on the type of twin gestation, or chorionicity. Given the effect of chorionicity on outcomes, we aimed to study the effect of twin type, monochorionic monoamniotic (MCMA) vs dichorionic diamniotic (DCDA), on neonatal early pulmonary function tests. METHODS: In this prospective cohort study, 5 sets of DCDA twins were matched to 5 sets of MCMA twins on gestational age at delivery, latency from antenatal corticosteroid exposure, birthweight, race and gender. Mean values were compared for passive respiratory system compliance and resistance, functional residual capacity, and tidal volume. RESULTS: MCMA infants had a significantly lower compliance (0.64 vs 1.25 mL/cm H2O /kg; p = 0.0001) and significantly higher resistance (0.130 vs 0.087 cm H2O /mL/sec; p = 0.0003) than DCDA infants. Functional residual capacity was lower for MCMA than DCDA infants (17.5 vs 23.4 mL/kg; p = 0.17). Further, 80% of MCMA infants required intubation for surfactant administration compared to 20% of DCDA infants, indicating the clinical significance of these objective measures. CONCLUSIONS: Due to the matched case-control design, causality cannot be established. However, we speculate that these differences in lung function may derive from differential exposure to preterm labor and endogenous maternal corticosteroid exposure. Further study is necessary to establish the true causal relationship.

Coherent magnetization dynamics at terahertz (THz) frequencies is achieved by directly incorporating ferromagnetic Ni80Fe20 thin films into Fe/Au bilayer spintronic THz emitters. Electrooptical (EO) sampling demonstrates a generation of THz pulses centered near ~2.8 THz with a bandwidth in the 1–4 THz range. Ni80Fe20 magnetization is directly coupled to the magnetic component of the THz wave, in which the large-amplitude magnetization precession is found phase locked with the THz pulse. The THz-induced magnetization dynamics can be controlled by external bias magnetic fields. The micromagnetic and analytical models based on the Landau–Lifshitz–Gilbert (LLG) equation are in good agreement with experimental findings and verify that the underlying mechanism of the THz-induced magnetization dynamics is the Zeeman coupling between the magnetic component of the THz field and Ni80Fe20 magnetization. Our results open the opportunities for the use of low-cost metallic spintronic THz emitters in the studies of THz-induced magnetization dynamics in magnetic thin films.

OBJECTIVE: The objective of this study was to compare serial changes in pulmonary function in contemporary infants with congenital diaphragmatic hernias managed with a gentle ventilation approach. STUDY DESIGN: Observational cohort, single-center study of infants ≥35(0/7) weeks gestation at delivery with congenital diaphragmatic hernia. Functional residual capacity (FRC), passive respiratory compliance, and passive respiratory resistance were measured presurgical and postsurgical repair and within 2 weeks of discharge. A 1-way analysis of variance for repeated measures was used to evaluate the change in FRC, passive respiratory compliance, and passive respiratory resistance over these repeated measures. RESULTS: Twenty-eight infants were included in the analysis with a mean gestational age of 38.3 weeks and birth weight of 3139 g. We found a significant increase in FRC across the 3 time points (mean in mL/kg [SD]: 10.9 [3.6] to 18.5 [5.2] to 24.2 [4.4]; P < .0001). There was also a significant increase in passive respiratory compliance and decrease in passive respiratory resistance. In contrast to a previous report, there were survivors in the current cohort with a preoperative FRC of

Purpose: Picky eating (PE) can occur in adulthood and is associated with mental health concerns. PE is often conceptualized as distinct from disordered eating, but recent research maps positive relationships between these maladaptive eating phenotypes. Relatedly, recent research suggests PE is more strongly related to eating concerns, a facet of disordered eating, via inflexible eating and mental health concerns, but precisely what PE facets explain these relations remain unknown.Methods: A large, undergraduate sample (N=509) completed an online survey assessing PE facets (Adult Picky Eating Questionnaire; meal presentation, food variety, meal disengagement, and taste aversion), disordered eating (Eating Disorder Examination Questionnaire), specifically eating concerns, mental health concerns (Depression, Anxiety and Stress Scale - 21 Items), and inflexible eating (Inflexible Eating Questionnaire).Results: Positive relationships emerged between PE facets, eating concerns, inflexible eating, and mental health concerns. Meal disengagement was more strongly associated with eating concerns when inflexible eating was higher, whereas food variety and meal presentation were more strongly associated with eating concerns when mental health concerns was higher. Inflexible eating and mental health concerns did not significantly interact with taste aversion to explain variance in eating concerns.Conclusions: Considering PE multidimensionally may yield important insights beyond the broader construct. Mental health concerns and inflexible eating may be treatment and research targets in addressing the overlap between PE facets such as meal presentation, meal disengagement, and food variety and eating concerns. Level of Evidence: Level V, cross-sectional descriptive study.

Objective First Contact Physiotherapy (FCP) is a primary care model where expert musculoskeletal (MSK) physiotherapists undertake the first patient consultation, to enhance MSK-patient care and free-up GP capacity. The authors report the quantitative findings from the FCP National Evaluation (Phase 3) which evaluated the FCP model against success criteria. Design and setting A mixed-methods 24-month service evaluation involving 40 FCP sites and 240 FCPs across England. Methods An online platform collected patient-reported experience and outcomes following the FCP consultation and at 1, 2 and 3-months follow-up. These included the Keele STarT MSK Tool, pain intensity (0–10 NRS scale), Musculoskeletal Health Questionnaire (MSK-HQ, range 0–56), and Friends-and-Family Test. Results Over 13 months, 2825 patients were invited by email and 24% (n = 680) completed their initial questionnaire. Their mean age was 56.2 (14.9 SD), 61% were female, ethnicity was 97% white, mean pain intensity was 6.1 (2.13 SD) and mean MSK-HQ score was 33.8 (9.5 SD). At 3-months follow-up (n = 370) there was a 2.8 (CI 2.5, 3.1) mean pain intensity reduction from baseline, a mean 7.1 (6.0, 8.2) score improvement in MSK-HQ and 64% reporting overall improvement (much better/better) since seeing the FCP. One of the six success criteria was not met; 29% of those in employment reported receiving specific work advice from the FCP (target ≥75%). Conclusion Ahead of the planned scale-up of the FCP primary care model across the UK, this evaluation provides useful data on patients who access this service, their short-term clinical outcomes and whether key success criteria are being met.

Purpose: Picky eating (PE) can occur in adulthood and is associated with mental health concerns. PE is often conceptualized as distinct from disordered eating (DE), but recent research maps positive relationships between these maladaptive eating phenotypes. Precisely what PE facets relate to DE remain unknown, as do factors such as negative psychological correlates that might explain relationships between PE facets and DE.Methods: A large, undergraduate sample (N=509) completed an online survey assessing PE facets (Adult Picky Eating Questionnaire; meal presentation, food variety, meal disengagement, and taste aversion), disordered eating (Eating Disorder Examination Questionnaire), specifically eating concerns, and negative psychological correlates such as mental health concerns (Depression, Anxiety and Stress Scale - 21 Items) and inflexible eating (Inflexible Eating Questionnaire).Results: Positive relationships emerged between PE facets, eating concerns, and negative psychological correlates. Negative psychological correlates moderated relationships between PE facets and eating concerns. Meal presentation, meal disengagement, and taste aversion were more strongly associated with eating concerns when mental health concerns and inflexible eating were higher. Food variety did not significantly explain variance in eating concerns.Conclusions: Considering PE multidimensionally may yield important insights beyond the broader construct. Mental health concerns and inflexible eating may be treatment and research targets in addressing the overlap between PE facets such as meal presentation, meal disengagement, and taste aversion and eating concerns. Level of Evidence: Level V, cross-sectional descriptive study.

Carnitine-acylcarnitine translocase (CACT) deficiency is a rare disorder of long chain fatty acid oxidation with a very high mortality rate due to cardiomyopathy or multiorgan failure. We present the course of a very premature infant with early onset CACT deficiency complicated by multiple episodes of necrotizing enterocolitis, sepsis, and liver insufficiency, followed by eventual demise. The complications of prematurity, potentiated by the overlay of CACT deficiency, contributed to the difficulty of reaching the ultimate diagnosis of CACT deficiency.

Deletions of chromosome 1p36 are the most common telomeric deletions in humans and are associated with an increased risk of orofacial clefting. Deletion/phenotype mapping, combined with data from human and mouse studies, suggests the existence of multiple 1p36 genes associated with orofacial clefting including SKI, PRDM16, PAX7 and GRHL3. The arginine–glutamic acid dipeptide (RE) repeats gene (RERE) is located in the proximal critical region for 1p36 deletion syndrome and encodes a nuclear receptor co-regulator. Pathogenic RERE variants have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye or heart (NEDBEH). Cleft lip has previously been described in one individual with NEDBEH. Here we report the first individual with NEDBEH to have a cleft palate. We confirm that RERE is broadly expressed in the palate during mouse embryonic development, and we demonstrate that the majority of RERE-deficient mouse embryos on C57BL/6 background have cleft palate. We go on to show that ablation of Rere in cranial neural crest (CNC) cells, mediated by a Wnt1-Cre, leads to delayed elevation of the palatal shelves and cleft palate and that proliferation of mesenchymal cells in the palatal shelves is significantly reduced in Rereflox/flox; Wnt1-Cre embryos. We conclude that loss of RERE function contributes to the development of orofacial clefts in individuals with proximal 1p36 deletions and NEDBEH and that RERE expression in CNC cells and their derivatives is required for normal palatal development.

Background: After injection into a brachial vein, high contrast media concentration in axillary and subclavian veins can cause artifacts that impair diagnostic utility. This study assessed artifact reduction by artifact-reduction-algorithms (ARA) and virtual-monoenergetic-images (VMI), as well as their combination (VMIARA) compared to conventional CT-images (CI). Methods: Forty-six spectral-detector-CT (SDCT) examinations of patients that received ARA-reconstructions due to perivenous-artifacts were included in this retrospective study. CI, ARA, VMI, and VMIARA (range: 70-200 keV) were reconstructed. Objective analysis was performed with ROI-based assessment of mean and standard deviation of attenuation (HU) in hypo- and hyperdense artifacts and impaired muscle and arteries as well as artifact-free reference-tissue. Extent of artifact reduction, assessment of surrounding soft tissue and vessels, and appearance of new artifacts were rated visually by two radiologists. Results: Hypo- and hyperdense artifacts showed significant improvement as evidenced by decreasing attenuation differences between artifact impaired and artifact-free reference tissue in ARA, VMI ≥80 keV, and VMIARA between 70-200 keV (e.g., CI/ARA/VMI100keV/VMIARA100keV: hypodense artifacts, (-)264.8±150.9/(-)87.1±78.9/(-)48.6±64.6/9.9±63.9 HU; P

SOX7 is located in a region on chromosome 8p23.1 that is recurrently deleted in individuals with septal defects. Sox7−/− embryos die of heart failure around E11.5 due to defects in vascular remodeling. These embryos have hypocellular endocardial cushions with severely reduced numbers of mesenchymal cells. We also observed a ventricular septal defect in a rare Sox7flox/−;Tie2-Cre embryo that escaped early lethality. This led us to hypothesize that SOX7 plays a critical developmental role in the endocardium of the atrioventricular (AV) canal. We subsequently used AV explant studies to show that SOX7 deficiency leads to a severe reduction in endocardial-to-mesenchymal transition (EndMT). Since SOX7 is a transcription factor, we hypothesized that it functions in the endocardium by regulating the expression of EndMT-related genes. To identify these genes in an unbiased manner, we performed RNA-seq on pooled E9.5 hearts tubes harvested from Sox7−/− embryos and their wild-type littermates. We found that Wnt4 transcript levels were severely reduced, which we confirmed by RNA in situ hybridization. Previous studies have shown that WNT4 is expressed in the endocardium and promotes EndMT by acting in a paracrine manner to increase the expression of BMP2 in the myocardium. Consistent with these findings, we found that Bmp2 transcript levels were diminished in Sox7−/− embryonic hearts. We conclude that SOX7 promotes EndMT in the developing AV canal by modulating the expression of Wnt4 and Bmp2. These data also provide additional evidence that haploinsufficiency of SOX7 contributes to the congenital heart defects seen in individuals with recurrent 8p23.1 microdeletions.SUMMARY STATEMENTIn the developing atrioventricular canal, SOX7 promotes endocardial-to-mesenchymal transition (EndMT) by positively regulating Wnt4 and Bmp2 expression. SOX7 deficiency leads to the development of hypocellular endothelial cushions and ventricular septal defects.

We established an international consortium to review and discuss relevant clinical evidence in order to develop expert consensus statements related to cancer management during the severe acute respiratory syndrome coronavirus 2-related disease (COVID-19) pandemic. The steering committee prepared 10 working packages addressing significant clinical questions from diagnosis to surgery. During a virtual consensus meeting of 62 global experts and one patient advocate, led by the European Society for Medical Oncology, statements were discussed, amended and voted upon. When consensus could not be reached, the panel revised statements until a consensus was reached. Overall, the expert panel agreed on 28 consensus statements that can be used to overcome many of the clinical and technical areas of uncertainty ranging from diagnosis to therapeutic planning and treatment during the COVID-19 pandemic.

For healthy individuals, it is increasingly accepted that lung function follows along an individual percentile established early in life and that the level of maximal function reached as a young adult can affect the subsequent development of lung disease that occurs with the normal aging process. This emphasizes the need to maximize early lung function. The trajectories of lung function are at least partially established by perinatal factors, including prematurity and in utero exposures (tobacco exposure, nutrition, inflammation, etc), although they can also be affected by a variety of additional factors and exposures throughout the life span. Whether lung function trajectories can be impacted or reset if established under suboptimal conditions is an unanswered question, offering new avenues for research. In this review, we will summarize important articles outlining lung function trajectories and linking pediatric lung function tests to adult lung function tests decades later. We will focus on perinatal factors and outline progress and opportunities for further investigation into the potential ability to reset trajectories to impact long-term lung health.

To assess the effects of Bifidobacteriumlongum subsp. infantis EVC001 (Binfantis EVC001) administration on the incidence of necrotizing enterocolitis (NEC) in preterm infants in a single level IV neonatal intensive care unit (NICU).Nonconcurrent retrospective analysis of 2 cohorts of very low birth weight (VLBW) infants not exposed and exposed to Binfantis EVC001 probiotic at Oregon HealthScience University from 2014 to 2020. Outcomes included NEC incidence and NEC-associated mortality, including subgroup analysis of extremely low birth weight (ELBW) infants. Log-binomial regression models were used to compare the incidence and risk of NEC-associated outcomes between the unexposed and exposed cohorts.The cumulative incidence of NEC diagnoses decreased from 11.0% (n = 301) in the no EVC001 (unexposed) cohort to 2.7% (n = 182) in the EVC001 (exposed) cohort (P .01). The EVC001 cohort had a 73% risk reduction of NEC compared with the no EVC001 cohort (adjusted risk ratio, 0.27; 95% CI, 0.094-0.614; P .01) resulting in an adjusted number needed to treat of 13 (95% CI, 10.0-23.5) for Binfantis EVC001. NEC-associated mortality decreased from 2.7% in the no EVC001 cohort to 0% in the EVC001 cohort (P = .03). There were similar reductions in NEC incidence and risk for ELBW infants (19.2% vs 5.3% [P .01]; adjusted risk ratio, 0.28; 95% CI, 0.085-0.698 [P = .02]) and mortality (5.6% vs 0%; P .05) in the 2 cohorts.In this observational study of 483 VLBW infants, Binfantis EVC001 administration was associated with significant reductions in the risk of NEC and NEC-related mortality. Binfantis EVC001 supplementation may be considered safe and effective for reducing morbidity and mortality in the NICU.

Objectives To determine fluorescently labeled aerolysin (FLAER) binding and glycophosphatidylinositol–anchored protein expression in bone marrow (BM) cells of healthy volunteers and patients with paroxysmal nocturnal hemoglobinuria (PNH) detected in peripheral blood (PB); compare PNH clone size in BM and PB; and detect PNH in BM by commonly used antibodies. Methods Flow cytometry analysis of FLAER binding to leukocytes and expression of CD55/CD59 in erythrocytes. Analysis of CD16 in neutrophils and CD14 in monocytes in BM. Results FLAER binds to all normal BM leukocytes, and binding increases with cell maturation. In PNH, lymphocytic clones are consistently smaller than clones of other BM cells. PNH clones are detectable in mature BM leukocytes with high specificity and sensitivity using common antibodies. Conclusions PNH clone sizes measured in mature BM leukocytes and in PB are comparable, making BM suitable for PNH assessment. We further demonstrate that commonly used reagents (not FLAER or CD55/CD59) can reliably identify abnormalities of BM neutrophils and monocytes consistent with PNH cells.

Objective To evaluate if premature infants delivered ≤7 days after rescue antenatal steroid treatment (ideal treatment) have increased passive respiratory compliance compared to those delivered ˃7 days after treatment (remote treatment). Methods Secondary analysis of a randomized trial of rescue antenatal steroids on respiratory compliance. Infants in the treatment group were stratified by the interval between rescue antenatal steroids and delivery. We then compared the respiratory compliance in the ideal versus remote groups. Results 44 women (56 infants) received rescue antenatal steroids. 49 infants had evaluable respiratory compliance measurements, with 27 (GA 30.0 weeks, BW 1362g) “ideally” treated, and 22 (GA 33.8 weeks, BW 2248g) “remotely” treated. Respiratory compliance was significantly higher for the ideal compared to the remote group (1.32 vs 1.06 mL/cm H20/kg; p = 0.037). Conclusion Infants treated with rescue antenatal steroids have a significantly higher respiratory compliance if delivery occurs within 7 days after treatment.

Congenital diaphragmatic hernia (CDH) has been reported twice in individuals with a clinical diagnosis of Fraser syndrome, a genetic disorder that can be caused by recessive mutations affecting FREM2 and FRAS1. In the extracellular matrix, FREM2 and FRAS1 form a self-stabilizing complex with FREM1, a protein whose deficiency causes sac CDH in humans and mice. By sequencing FREM2 and FRAS1 in a CDH cohort, and searching online databases, we identified five individuals who carried recessive or double heterozygous, putatively deleterious variants in these genes which may represent susceptibility alleles. Three of these alleles were significantly enriched in our CDH cohort compared with ethnically matched controls. We subsequently demonstrated that 8% of Frem2(ne/ne) and 1% of Fras1(Q1263*/Q1263*) mice develop the same type of anterior sac CDH seen in FREM1-deficient mice. We went on to show that development of sac hernias in FREM1-deficient mice is preceded by failure of anterior mesothelial fold progression resulting in the persistence of an amuscular, poorly vascularized anterior diaphragm that is abnormally adherent to the underlying liver. Herniation occurs in the perinatal period when the expanding liver protrudes through this amuscular region of the anterior diaphragm that is juxtaposed to areas of muscular diaphragm. Based on these data, we conclude that deficiency of FREM2, and possibly FRAS1, are associated with an increased risk of developing CDH and that loss of the FREM1/FREM2/FRAS1 complex, or its function, leads to anterior sac CDH development through its effects on mesothelial fold progression.

Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype–phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7.

Medical student wellness is of great concern in the health care field. A growing number of studies point to increases in suicide, depression, anxiety, mood disorders, and burnout related to physician lifestyles. Mental health issues commencing in medical school have been suggested to have a significant impact on future physician lifestyle and burnout. Tracking the mental health of medical students at the University of Toledo College of Medicine and Life Sciences (UTCOMLS) with standardized indices will help elucidate triggers of poor mental health. Anonymous surveys were developed and distributed to preclinical medical students at five strategic time points throughout the 2018 2019 academic year. Surveys collected basic demographic information as well as inventories measuring perceived stress, burnout, resilience, and mindfulness. 172 M1s (83 males and 89 females) were included in the study and average response rate for the first 4 (out of 5) surveys averaged 74.8%. M1 males and females had on average increased personal burnout over time with females consistently scoring higher. Both males and females had an increase in stress from August to each subsequent month (p