Search

Abstract Objective To examine the impact of schizophrenia, its treatment and treatment-related adverse events related to antipsychotics, on quality of life from the perspective of schizophrenia patients and laypersons. Methods Health state descriptions for stable schizophrenia, extra pyramidal symptoms (EPS), hyperprolactinemia, diabetes, weight gain and relapse were developed based on a review of the literature and expert opinion. The quality of life impact of each health state was elicited using a time trade-off instrument administered by interview to 49 stable schizophrenia patients and 75 laypersons. Regression techniques were employed to examine the importance of subject characteristics on health-related utility scores. Results Patients and laypersons completed the interview in similar times. Stable schizophrenia had the highest mean utility (0.87 and 0.92 for laypersons and patients respectively), while relapse (0.48 and 0.60) had the lowest mean utility. Of the treatment-related adverse events, EPS had the lowest mean utility (0.57 and 0.72, respectively). Age, gender and PANSS score did not influence the utility results independently of health state. On average, patient utilities are 0.077 points higher than utilities derived from laypersons, although the ranking was similar between the two groups. Conclusion Events associated with schizophrenia and treatment of schizophrenia can bring about a significant detriment in patient quality of life, with relapse having the largest negative impact. Results indicate that patients with stable schizophrenia are less willing to trade years of life to avoid schizophrenia-related symptoms compared to laypersons. Both sets of respondents showed equal ability to complete the questionnaire.

Psychological science has thrived thanks to new methods and innovative practices. Journals, including Behavior Research Methods (BRM), continue to support the dissemination and evaluation of research assets including data, software/hardware, statistical code, and databases of stimuli. However, such research assets rarely allow for computational reproducibility, meaning they are difficult to reuse. Therefore, in this preregistered report, we explore how BRM's authors and BRM structures shape the landscape of functional research assets. Our broad research questions concern: (1) How quickly methods and analytical techniques reported in BRM can be used and developed further by other scientists; (2) Whether functionality has improved following changes to BRM journal policy in support of computational reproducibility; (3) Whether we can disentangle such policy changes from changes in reproducibility over time. We randomly sampled equal numbers of papers (N = 204) published in BRM before and after the implementation of policy changes. Pairs of researchers recorded how long it took to ensure assets (data, software/hardware, statistical code, and materials) were fully operational. They also coded the completeness and reusability of the assets. While improvements were observed in all measures, only changes to completeness were altered significantly following the policy changes (d = .37). The effects varied between different types of research assets, with data sets from surveys/experiments showing the largest improvements in completeness and reusability. Perhaps more importantly, changes to policy do appear to have improved the life span of research products by reducing natural decline. We conclude with a discussion of how, in the future, research and policy might better support computational reproducibility within and beyond psychological science., (© 2024. The Author(s).)

Many academics and pundits contend that social media use is the primary cause of an international youth mental health crisis. However, these claims often rely on correlational evidence, ignoring the confounding effects of developmental, environmental, social, and psychological factors that influence mental health. This oversimplifies the complex etiology of mental health problems. We call for a more nuanced understanding of the role of social media in youth mental health that avoids oversimplification. Additionally, we urge researchers to move beyond vague, narrative-driven verbal theories and encode them into precise, testable causal models. Using simulation techniques and specification curve analyses, we show how misspecified models that ignore these confounding factors can lead to biased conclusions about social media's adverse effects. This simplistic focus on social media use diverts attention from the broader factors contributing to youth mental health problems, hindering the development of effective interventions and support. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Importance: In response to widespread concerns about social media's influence on adolescent mental health, most research has studied adolescents from the general population, overlooking clinical groups., Objective: To synthesize, quantify, and compare evidence on the association between social media use and internalizing symptoms in adolescent clinical and community samples., Data Sources: Peer-reviewed publications from MEDLINE, Web of Science, PsycInfo, and Scopus (initially reviewed in May 2022 and updated in October 2023) and preprints from Europe PubMed Central (February 2023) published in English between 2007 and 2023., Study Selection: Two blinded reviewers initially identified 14 211 cross-sectional and longitudinal studies quantifying the association between social media use and internalizing symptoms, excluding experimental studies and randomized clinical trials., Data Extraction and Synthesis: PRISMA and MOOSE guidelines were followed, pooling data using a random-effects model and robust variance estimation. The quality of evidence was assessed using the Quality of Survey Studies in Psychology Checklist., Main Outcomes and Measures: Articles were included if they reported at least 1 quantitative measure of social media use (time spent, active vs passive use, activity, content, user perception, and other) and internalizing symptoms (anxiety, depression, or both)., Results: The 143 studies reviewed included 1 094 890 adolescents and 886 effect sizes, 11% of which examined clinical samples. In these samples, a positive and significant meta-correlation was found between social media use and internalizing symptoms, both for time spent (n = 2893; r, 0.08; 95% CI, 0.01 to 0.15; P = .03; I2, 57.83) and user engagement (n = 859; r, 0.12; 95% CI, 0.09 to 0.15; P = .002; I2, 82.67). These associations mirrored those in community samples., Conclusions and Relevance: The findings in this study highlight a lack of research on clinical populations, a critical gap considering public concerns about the increase in adolescent mental health symptoms at clinical levels. This paucity of evidence not only restricts the generalizability of existing research but also hinders our ability to evaluate and compare the link between social media use and mental health in clinical vs nonclinical populations.

Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type- and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.

Background: The Ehlers-Danlos syndromes (EDS) are heritable disorders of connective tissue (HDCT), reclassified in the 2017 nosology into 13 subtypes. The genetic basis for hypermobile Ehlers-Danlos syndrome (hEDS) remains unknown., Methods: Whole exome sequencing (WES) was undertaken on 174 EDS patients recruited from a national diagnostic service for complex EDS and a specialist clinic for hEDS. Patients had already undergone expert phenotyping, laboratory investigation and gene sequencing, but were without a genetic diagnosis. Filtered WES data were reviewed for genes underlying Mendelian disorders and loci reported in EDS linkage, transcriptome and genome-wide association studies (GWAS). A genetic burden analysis (Minor Allele Frequency (MAF) <0.05) incorporating 248 Avon Longitudinal Study of Parents and Children (ALSPAC) controls sequenced as part of the UK10K study was undertaken using TASER methodology., Results: Heterozygous pathogenic (P) or likely pathogenic (LP) variants were identified in known EDS and Loeys-Dietz (LDS) genes. Multiple variants of uncertain significance where segregation and functional analysis may enable reclassification were found in genes associated with EDS, LDS, heritable thoracic aortic disease (HTAD), Mendelian disorders with EDS symptomatology and syndromes with EDS-like features. Genetic burden analysis revealed a number of novel loci, although none reached the threshold for genome-wide significance. Variants with biological plausibility were found in genes and pathways not currently associated with EDS or HTAD., Conclusions: We demonstrate the clinical utility of large panel-based sequencing and WES for patients with complex EDS in distinguishing rare EDS subtypes, LDS and related syndromes. Although many of the P and LP variants reported in this cohort would be identified with current panel testing, they were not at the time of this study, highlighting the use of extended panels and WES as a clinical tool for complex EDS. Our results are consistent with the complex genetic architecture of EDS and suggest a number of novel hEDS and HTAD candidate genes and pathways., Competing Interests: Competing interests: TA is co-founder and director of the company BioCaptiva. There are no other competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

There is growing recognition that many people feel the need to regulate their use of the internet and other digital technologies to support their wellbeing. In this study, we used Mozilla Firefox browser telemetry to investigate the role played by various usage factors in desires to regulate time spent online. In particular, we investigated how six metrics pertaining to time spent on the internet, and the diversity and intensity of use, predict participants' ( n = 8,094) desires to spend more or less time online. Across all six metrics, we did not find evidence for a relationship between browser usage metrics and participants wanting to spend more or less time online. This finding was robust across various analytical pathways. The study highlights a number of considerations and concerns that need to be addressed in future industry-academia collaborations that draw on trace data or usage telemetry.

Follicular helper CD4 + T cells (TFH) are highly permissive to HIV and major foci of virus expression in both untreated and treated infection. Follicular regulatory CD4 + T cells (TFR) limit TFH numbers and function in vitro and in vivo . We evaluated the hypothesis that TFR suppress HIV replication in TFH using a well-established model of ex vivo HIV infection that employs tonsil cells from HIV uninfected individuals spinoculated with CXCR4- and CCR5-tropic HIV-GFP reporter viruses. Both CXCR4 and CCR5-tropic HIV replication were reduced in TFH cultured with TFR as compared to controls. Blocking antibodies to CD39, CTLA-4, IL-10, and TGF-beta failed to reverse suppression of HIV replication by TFR, and there were no sex differences in TFR suppressive activity. TFR reduced viability of TFH and even more so reduced HIV infected TFH as assessed by total and integrated HIV DNA. Exogenous IL-2 enhanced TFH viability and particularly numbers of GFP+ TFH in a concentration dependent manner. TFR reduced productively infected TFH at low and moderate IL-2 concentrations, and this was associated with decreases in extracellular IL-2. Both IL-2 expressing cells and larger numbers of FoxP3+CD4+ cells were detected in follicles and germinal centers of lymph nodes of people living with HIV. TFR may deplete TFH in vivo through restriction of IL-2 and thereby contribute to decay of HIV expressing cells in B cell follicles during HIV infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ollerton, Folkvord, La Mantia, Parry, Meditz, McCarter, D’Aquila and Connick.)

Due to the methodological challenges inherent in studying social media use (SMU), as well as the methodological choices that have shaped research into the effects of SMU on well-being, clear conclusions regarding relationships between SMU and well-being remain elusive. We provide a review of five methodological developments poised to provide increased understanding in this domain: (a) increased use of longitudinal and experimental designs; (b) the adoption of behavioural (rather than self-report) measures of SMU; (c) focusing on more nuanced aspects of SMU; (d) embracing effect heterogeneity; and (e) the use of formal modelling and machine learning. We focus on how these advances stand to bring us closer to understanding relations between SMU and well-being, as well as the challenges associated with these developments., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: To investigate the molecular basis of recessively inherited congenital cataract, microcornea, and corneal opacification with or without coloboma and microphthalmia in two consanguineous families., Methods: Conventional autozygosity mapping was performed using single nucleotide polymorphism (SNP) microarrays. Whole-exome sequencing was completed on genomic DNA from one affected member of each family. Exome sequence data were also used for homozygosity mapping and copy number variation analysis. PCR and Sanger sequencing were used to confirm the identification of mutations and to screen further patients. Evolutionary conservation of protein sequences was assessed using CLUSTALW, and protein structures were modeled using PyMol., Results: In family MEP68, a novel homozygous nucleotide substitution in SIX6 was found, c.547G>C, that converts the evolutionarily conserved aspartic acid residue at the 183 rd amino acid in the protein to a histidine, p.(Asp183His). This residue mapped to the third helix of the DNA-binding homeobox domain in SIX6, which interacts with the major groove of double-stranded DNA. This interaction is likely to be disrupted by the mutation. In family F1332, a novel homozygous 1034 bp deletion that encompasses the first exon of SIX6 was identified, chr14:g.60975890&#95;60976923del. Both mutations segregated with the disease phenotype as expected for a recessive condition and were absent from publicly available variant databases., Conclusions: Our findings expand the mutation spectrum in this form of inherited eye disease and confirm that homozygous human SIX6 mutations cause a developmental spectrum of ocular phenotypes that includes not only the previously described features of microphthalmia, coloboma, and congenital cataract but also corneal abnormalities., (Copyright © 2022 Molecular Vision.)

SRC is a nonreceptor tyrosine kinase with key roles in breast cancer development and progression. Despite this, SRC tyrosine kinase inhibitors have so far failed to live up to their promise in clinical trials, with poor overall response rates. We aimed to identify possible synergistic gene-drug interactions to discover new rational combination therapies for SRC inhibitors. An unbiased genome-wide CRISPR-Cas9 knockout screen in a model of triple-negative breast cancer revealed that loss of integrin-linked kinase (ILK) and its binding partners α-Parvin and PINCH-1 sensitizes cells to bosutinib, a clinically approved SRC/ABL kinase inhibitor. Sensitivity to bosutinib did not correlate with ABL dependency; instead, bosutinib likely induces these effects by acting as a SRC tyrosine kinase inhibitor. Furthermore, in vitro and in vivo models showed that loss of ILK enhanced sensitivity to eCF506, a novel and highly selective inhibitor of SRC with a unique mode of action. Whole-genome RNA sequencing following bosutinib treatment in ILK knockout cells identified broad changes in the expression of genes regulating cell adhesion and cell-extracellular matrix. Increased sensitivity to SRC inhibition in ILK knockout cells was associated with defective adhesion, resulting in reduced cell number as well as increased G1 arrest and apoptosis. These findings support the potential of ILK loss as an exploitable therapeutic vulnerability in breast cancer, enhancing the effectiveness of clinical SRC inhibitors., Significance: A CRISPR-Cas9 screen reveals that loss of integrin-linked kinase synergizes with SRC inhibition, providing a new opportunity for enhancing the clinical effectiveness of SRC inhibitors in breast cancer., (©2021 The Authors; Published by the American Association for Cancer Research.)

The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair 1 . In microorganisms, transcription has been demonstrated to be mutagenic 2,3 ; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes 4 . Here we show that ID4-a cancer insertion-deletion (indel) mutation signature of unknown aetiology 5 characterized by short (2 to 5 base pair) deletions -is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutations in the germline. Thus, although topoisomerases protect against genome instability by relieving topological stress 6 , their activity may also be an important source of mutations in the human genome., (© 2022. The Author(s).)

The use of instant messaging groups for various academic purposes is a rising, but largely understudied, trend in higher education institutions. In the present study we investigate the use purposes and outcomes of three types of academic instant messaging groups or AIMGs. Formal AIMGs are created and managed by teaching staff, class AIMGs are created by students and joined by all members of a particular class, and study AIMGs are smaller groups created by students that know each other personally or collaborate in group assignments. To advance understanding of the role of these groups in students' wellbeing and academic development, we pose research questions concerning their associations with academic performance, academic stress, and students' course experiences. We adopt an exploratory frame and survey methodology to collect data from a large sample of undergraduate students ( n = 1752). Our findings indicate that, at the institution where data were collected, high rates of AIMG participation is the norm, with class AIMGs emerging as particularly popular. We find statistically significant interaction between formal and study AIMGs and academic performance, as well as between study AIMGs and academic stress. Participation in these groups also predicts students' social experience of a learning community, as well as their perception of the teaching they receive. Throughout, however, the observed effects are small and their practical significance is questioned., Competing Interests: Conflict of InterestsThe author(s) declare that there are no conflicts of interest with respect to the authorship or the publication of this article., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021.)

There is widespread public and academic interest in understanding the uses and effects of digital media. Scholars primarily use self-report measures of the quantity or duration of media use as proxies for more objective measures, but the validity of these self-reports remains unclear. Advancements in data collection techniques have produced a collection of studies indexing both self-reported and log-based measures. To assess the alignment between these measures, we conducted a pre-registered meta-analysis of this research. Based on 106 effect sizes, we found that self-reported media use correlates only moderately with logged measurements, that self-reports were rarely an accurate reflection of logged media use and that measures of problematic media use show an even weaker association with usage logs. These findings raise concerns about the validity of findings relying solely on self-reported measures of media use., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is the most common form of primordial dwarfism, caused by bialleic mutations in the pericentrin gene (PCNT). Aside from its classic features, there are multiple associated medical complications, including a well-documented risk of neurovascular disease. Over the past several years, it has become apparent that additional vascular issues, as well as systemic hypertension and kidney disease may also be related to MOPDII. However, the frequency and extent of the vasculopathy was unclear. To help address this question, a vascular substudy was initiated within our Primordial Dwarfism Registry., Results: Medical records from 47 individuals, living and deceased, ranging in age from 3 to 41 years of age were interrogated for this purpose. Of the total group, 64% were diagnosed with moyamoya, intracranial aneurysms, or both. In general, the age at diagnosis for moyamoya was younger than aneurysms, but the risk for neurovascular disease was throughout the shortened lifespan. In addition to neurovascular disease, renal, coronary and external carotid artery involvement are documented. 43% of the total group was diagnosed with hypertension, and 17% had myocardial infarctions. A total of 32% of the entire cohort had some form of chronic kidney disease, with 4% of the total group necessitating a kidney transplant. In addition, 38% had diabetes/insulin resistance. Ages of diagnoses, treatment modalities employed, and location of vasculopathies were notated as available and applicable, as well as frequencies of other comorbidities., Conclusions: It is now clear that vascular disease in MOPDII is global and screening of the cardiac and renal vessels is warranted along with close monitoring of blood pressure. We recommend a blood pressure of 110/70 mmHg as a starting point for an upper limit, especially if the individual has a history of neurovascular disease, chronic kidney disease and/or diabetes. Additionally, providers need to be at high alert for the possibility of myocardial infarctions in young adults with MOPDII, so that appropriate treatment can be initiated promptly in an acute situation.

Objective: The effects of off-task media use in academic settings on academic performance have been widely reported. In response, a range of interventions have been proposed. Among these have been calls for the cultivation of more effective self-regulation of media use. Against this backdrop, the present study investigates students' self-regulation of off-task media in academic settings. Method: A series of focus groups was conducted involving 30 undergraduate students at a large, South African university. A combination of inductive and deductive analysis was conducted on the basis of prominent theories of self-regulation. Results: The presences of off-task media in academic settings create ongoing experiences of goal-conflict and many students become trapped in cycles of repeated self-regulation failure, ultimately culminating in procrastination. Conclusions: We refer to this phenomenon as the media procrastination cycle and argue that it contributes to negative affect, stress, and anxiety among students.

Purpose: Lamins are the major component of nuclear lamina, maintaining structural integrity of the nucleus. Lamin A/C variants are well established to cause a spectrum of disorders ranging from myopathies to progeria, termed laminopathies. Phenotypes resulting from variants in LMNB1 and LMNB2 have been much less clearly defined., Methods: We investigated exome and genome sequencing from the Deciphering Developmental Disorders Study and the 100,000 Genomes Project to identify novel microcephaly genes., Results: Starting from a cohort of patients with extreme microcephaly, 13 individuals with heterozygous variants in the two human B-type lamins were identified. Recurrent variants were established to be de novo in nine cases and shown to affect highly conserved residues within the lamin ɑ-helical rod domain, likely disrupting interactions required for higher-order assembly of lamin filaments., Conclusion: We identify dominant pathogenic variants in LMNB1 and LMNB2 as a genetic cause of primary microcephaly, implicating a major structural component of the nuclear envelope in its etiology and defining a new form of laminopathy. The distinct nature of this lamin B-associated phenotype highlights the strikingly different developmental requirements for lamin paralogs and suggests a novel mechanism for primary microcephaly warranting future investigation.

Autosomal-recessive cerebellar hypoplasia and ataxia constitute a group of heterogeneous brain disorders caused by disruption of several fundamental cellular processes. Here, we identified 10 families showing a neurodegenerative condition involving pontocerebellar hypoplasia with microcephaly (PCHM). Patients harbored biallelic mutations in genes encoding the spliceosome components Peptidyl-Prolyl Isomerase Like-1 (PPIL1) or Pre-RNA Processing-17 (PRP17). Mouse knockouts of either gene were lethal in early embryogenesis, whereas PPIL1 patient mutation knockin mice showed neuron-specific apoptosis. Loss of either protein affected splicing integrity, predominantly affecting short and high GC-content introns and genes involved in brain disorders. PPIL1 and PRP17 form an active isomerase-substrate interaction, but we found that isomerase activity is not critical for function. Thus, we establish disrupted splicing integrity and "major spliceosome-opathies" as a new mechanism underlying PCHM and neurodegeneration and uncover a non-enzymatic function of a spliceosomal proline isomerase., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

With the ongoing COVID-19 (Coronavirus Disease 2019) pandemic, caused by the novel coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), there is a need for sensitive, specific, and affordable diagnostic tests to identify infected individuals, not all of whom are symptomatic. The most sensitive test involves the detection of viral RNA using RT-qPCR (quantitative reverse transcription PCR), with many commercial kits now available for this purpose. However, these are expensive, and supply of such kits in sufficient numbers cannot always be guaranteed. We therefore developed a multiplex assay using well-established SARS-CoV-2 targets alongside a human cellular control (RPP30) and a viral spike-in control (Phocine Herpes Virus 1 [PhHV-1]), which monitor sample quality and nucleic acid extraction efficiency, respectively. Here, we establish that this test performs as well as widely used commercial assays, but at substantially reduced cost. Furthermore, we demonstrate >1,000-fold variability in material routinely collected by combined nose and throat swabbing and establish a statistically significant correlation between the detected level of human and SARS-CoV-2 nucleic acids. The inclusion of the human control probe in our assay therefore provides a quantitative measure of sample quality that could help reduce false-negative rates. We demonstrate the feasibility of establishing a robust RT-qPCR assay at approximately 10% of the cost of equivalent commercial assays, which could benefit low-resource environments and make high-volume testing affordable., Competing Interests: The authors have declared that no competing interests exist.

DNA replication is fundamental for cell proliferation in all organisms. Nonetheless, components of the replisome have been implicated in human disease, and here we report PRIM1 encoding the catalytic subunit of DNA primase as a novel disease gene. Using a variant classification agnostic approach, biallelic mutations in PRIM1 were identified in five individuals. PRIM1 protein levels were markedly reduced in patient cells, accompanied by replication fork asymmetry, increased interorigin distances, replication stress, and prolonged S-phase duration. Consequently, cell proliferation was markedly impaired, explaining the patients' extreme growth failure. Notably, phenotypic features distinct from those previously reported with DNA polymerase genes were evident, highlighting differing developmental requirements for this core replisome component that warrant future investigation., (© 2020 Parry et al.; Published by Cold Spring Harbor Laboratory Press.)

Microcephalic primordial dwarfism (MPD) is a group of rare single-gene disorders characterized by the extreme reduction in brain and body size from early development onwards. Proteins encoded by MPD-associated genes play important roles in fundamental cellular processes, notably genome replication and repair. Here we report the identification of four MPD individuals with biallelic variants in DNA2, which encodes an adenosine triphosphate (ATP)-dependent helicase/nuclease involved in DNA replication and repair. We demonstrate that the two intronic variants (c.1764-38&#95;1764-37ins(53) and c.74+4A>C) found in these individuals substantially impair DNA2 transcript splicing. Additionally, we identify a missense variant (c.1963A>G), affecting a residue of the ATP-dependent helicase domain that is highly conserved between humans and yeast, with the resulting substitution (p.Thr655Ala) predicted to directly impact ATP/ADP (adenosine diphosphate) binding by DNA2. Our findings support the pathogenicity of these variants as biallelic hypomorphic mutations, establishing DNA2 as an MPD disease gene., (© 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc.)

Several branches of the facial nerve are known to anastomose with branches of the cervical plexus, other cranial nerves, and the trigeminal nerve. Communication between the sensory transverse cervical nerve (C2, 3) and marginal mandibular nerve is, however, less well known, and in a previous study of 86 neck dissections we reported a 2.3% incidence of anastomoses between them. In this prospective study, we meticulously searched for more examples using both formalin-fixed cadavers and neck dissections. A total of 102 necks were included (both sides of 36 cadavers (n=72 necks), and 30 patients who had neck dissection for the management of squamous cell carcinoma). We found communications between these nerves on one side of a cadaver and in one neck dissection. When combined with the numbers from our previous study, the overall incidence was 2.1% in 188 necks. The marginal mandibular nerve was inseparable from the anastomosis with the transverse cervical nerve, and the variant should not be forgotten if we are to reduce the chance of postoperative weakness of the lower lip, particularly when operative exposure is more limited (such as during removal of the submandibular gland)., (Copyright © 2019 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl -/- murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl -/- zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

DNA methylation and Polycomb are key factors in the establishment of vertebrate cellular identity and fate. Here we report de novo missense mutations in DNMT3A, which encodes the DNA methyltransferase DNMT3A. These mutations cause microcephalic dwarfism, a hypocellular disorder of extreme global growth failure. Substitutions in the PWWP domain abrogate binding to the histone modifications H3K36me2 and H3K36me3, and alter DNA methylation in patient cells. Polycomb-associated DNA methylation valleys, hypomethylated domains encompassing developmental genes, become methylated with concomitant depletion of H3K27me3 and H3K4me3 bivalent marks. Such de novo DNA methylation occurs during differentiation of Dnmt3a W326R pluripotent cells in vitro, and is also evident in Dnmt3a W326R/+ dwarf mice. We therefore propose that the interaction of the DNMT3A PWWP domain with H3K36me2 and H3K36me3 normally limits DNA methylation of Polycomb-marked regions. Our findings implicate the interplay between DNA methylation and Polycomb at key developmental regulators as a determinant of organism size in mammals.

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Thoracic aortic aneurysm/aortic dissection (TAAD) is a disorder with highly variable age of onset and phenotype. We sought to determine the prevalence of pathogenic variants in TAAD-associated genes in a mixed cohort of sporadic and familial TAAD patients and identify relevant genotype-phenotype relationships., Methods: We used a targeted polymerase chain reaction and next-generation sequencing-based panel for genetic analysis of 15 TAAD-associated genes in 1,025 unrelated TAAD cases., Results: We identified 49 pathogenic or likely pathogenic (P/LP) variants in 47 cases (4.9% of those successfully sequenced). Almost half of the variants were in nonsyndromic cases with no known family history of aortic disease. Twenty-five variants were within FBN1 and two patients were found to harbor two P/LP variants. Presence of a related syndrome, younger age at presentation, family history of aortic disease, and involvement of the ascending aorta increased the risk of carrying a P/LP variant., Conclusion: Given the poor prognosis of TAAD that is undiagnosed prior to acute rupture or dissection, genetic analysis of both familial and sporadic cases of TAAD will lead to new diagnoses, more informed management, and possibly reduced mortality through earlier, preclinical diagnosis in genetically determined cases and their family members.

The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals' fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. This altered steady-state equilibrium led to a decrease in Golgi volume, as well as morphologic abnormalities with collapse of the Golgi stacks. Despite these abnormalities of the Golgi apparatus, protein glycosylation in sera and fibroblasts from affected subjects was not notably altered, but decorin, a proteoglycan secreted into the extracellular matrix, showed altered Golgi-dependent glycosylation. In summary, we define a specific heterozygous COG4 substitution as the molecular basis of Saul-Wilson syndrome, a rare skeletal dysplasia distinct from biallelic COG4-CDG., (Published by Elsevier Inc.)

As clinicians, we sometimes fail to look after ourselves properly and do not regularly eat healthy foods or drink enough. Sleep is another factor that we often neglect. A lack of it can compromise our personal health and performance at work, and the "sleep debt" that results when this is chronic can take far longer to recover from than one might think. Now that junior doctors work more shift rotas and senior colleagues have onerous on-call responsibilities, we all need to be aware of the effects of sleep deprivation, which can lower the mood and motivation, weaken leadership, and result in more clinical errors. In this review we consider what might constitute enough sleep, the consequences of inadequate sleep, and how these might be addressed for surgeons., (Copyright © 2018 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Workplace-related illness is common in the UK, and in healthcare more than five million working days over 10years have been lost as a result. Occupational stress is well known and can affect clinicians at any stage, yet many healthcare professionals continue to work with this or other psychological problems (including anxiety, chronic fatigue, and burnout) as they do not wish to let their colleagues down. Mental health issues might be dismissed, particularly in surgery, because there is a misconception that surgeons can cope better with stress than those working in other specialties, and are better protected from clinical burnout. The benefit of exercise on physical health is clear, but its role in the maintenance of good mental health and well-being should not be underestimated. As society adopts an increasingly sedentary lifestyle, exercise for many has a lower priority than other activities. In this article we give an overview of the mental health issues that might affect doctors and surgeons, and explore how exercise can benefit our well-being and clinical performance., (Copyright © 2018 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Objectives: This study investigated the effects of a previously recommended dose of sprint training (ST) in young male soccer players of differing maturity status., Design: Quasi-experimental design., Methods: Male soccer players from two professional academies were divided into Pre-PHV (Training: n=12; Control: n=13) and Mid-PHV (Training: n=7; Control=10) groups. The training groups completed 16 sprints of 20m with 90s recovery, once per week for 8weeks., Results: Between-group effect sizes (ES) were substantially larger in Pre-PHV (10m [1.54, CI: 0.74-2.23]; 20m [1.49, CI: 0.75-2.23]; 5-10-5 [0.92, CI: 0.23-1.61]) than in Mid-PHV (10m [-0.00, CI: -0.81 to 0.81]; 20m [-0.12, CI: -0.93 to 0.69]; 5-10-5 [-0.41, CI: -1.22 to 0.41]). Within-group effects demonstrated a similar, though less accentuated, trend which revealed ST to be effective in both Pre-PHV (10m [0.44, CI: -0.24 to 1.12]; 20m [0.45, CI: -0.23 to 1.13]; 5-10-5 [0.69, CI: 0.00-1.38]) and Mid-PHV (10m [0.51, CI: -0.38 to 1.40]; 20m [0.33, CI: -0.56 to 1.21]; 5-10-5 [0.43, CI: -0.46 to 1.32])., Conclusions: ST, in the amount of 16 sprints over 20m with a 90s rest, may be more effective in Pre-PHV youths than in Mid-PHV youths., (Copyright © 2017 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)