Biallelic disruption of PKDCC is associated with a skeletal disorder characterised by rhizomelic shortening of extremities and dysmorphic features.

BACKGROUND: During mouse embryonic development the protein kinase domain containing, cytoplasmic (Pkdcc) gene, also known as Vlk, is expressed in several tissues including the ventral midbrain, with particularly strong expression in branchial arches and limb buds. Homozygous Pkdcc knockout mice have dysmorphic features and shortened long bones as the most obvious morphological abnormalities. The human PKDCC gene has currently not been associated with any disorders. OBJECTIVE: To use clinical diagnostic exome sequencing (DES) for providing genetic diagnoses to two apparently unrelated patients with similar skeletal abnormalities comprising rhizomelic shortening of limbs and dysmorphic features. METHODS: Patient-parents trio DES was carried out and the identified candidate variants were confirmed by Sanger sequencing. RESULTS: Each patient had a homozygous gene disrupting variant in PKDCC considered to explain the skeletal phenotypes shared by both. The first patient was homozygous for the nonsense variant p.(Tyr217*) (NM_1 38 370 c.651C>A) expected to result in nonsense-mediated decay of the mutant transcripts, whereas the second patient was homozygous for the splice donor variant c.639+1G>T predicted to abolish the donor splice site by three in silico splice prediction algorithms. CONCLUSIONS: Biallelic gene disrupting variants in PKDCC in humans, just like in mice, cause dysmorphic features and rhizomelic shortening of limbs.

Role-Playing Computer Ethics: Designing and Evaluating the Privacy by Design (PbD) Simulation.

There is growing consensus that teaching computer ethics is important, but there is little consensus on how to do so. One unmet challenge is increasing the capacity of computing students to make decisions about the ethical challenges embedded in their technical work. This paper reports on the design, testing, and evaluation of an educational simulation to meet this challenge. The privacy by design simulation enables more relevant and effective computer ethics education by letting students experience and make decisions about common ethical challenges encountered in real-world work environments. This paper describes the process of incorporating empirical observations of ethical questions in computing into an online simulation and an in-person board game. We employed the Values at Play framework to transform empirical observations of design into a playable educational experience. First, we conducted qualitative research to discover when and how values levers-practices that encourage values discussions during technology development-occur during the design of new mobile applications. We then translated these findings into gameplay elements, including the goals, roles, and elements of surprise incorporated into a simulation. We ran the online simulation in five undergraduate computer and information science classes. Based on this experience, we created a more accessible board game, which we tested in two undergraduate classes and two professional workshops. We evaluated the effectiveness of both the online simulation and the board game using two methods: a pre/post-test of moral sensitivity based on the Defining Issues Test, and a questionnaire evaluating student experience. We found that converting real-world ethical challenges into a playable simulation increased student's reported interest in ethical issues in technology, and that students identified the role-playing activity as relevant to their technical coursework. This demonstrates that roleplaying can emphasize ethical decision-making as a relevant component of technical work.

Negotiated Sharing of Pandemic Data, Models, and Resources.

Urgent responses to the COVID-19 pandemic depend on increased collaboration and sharing of data, models, and resources among scientists and researchers. In many scientific fields and disciplines, institutional norms treat data, models, and resources as proprietary, emphasizing competition among scientists and researchers locally and internationally. Concurrently, long-standing norms of open data and collaboration exist in some scientific fields and have accelerated within the last two decades. In both cases-where the institutional arrangements are ready to accelerate for the needed collaboration in a pandemic and where they run counter to what is needed-the rules of the game are "on the table" for institutional-level renegotiation. These challenges to the negotiated order in science are important, difficult to study, and highly consequential. The COVID-19 pandemic offers something of a natural experiment to study these dynamics. Preliminary findings highlight: the chilling effect of politics where open sharing could be expected to accelerate; the surprisingly conservative nature of contests and prizes; open questions around whether collaboration will persist following an inflection point in the pandemic; and the strong potential for launching and sustaining pre-competitive initiatives.

De novo missense variants in MEIS2 recapitulate the microdeletion phenotype of cardiac and palate abnormalities, developmental delay, intellectual disability and dysmorphic features.

Gross deletions involving the MEIS2 gene have been described in a small number of patients with overlapping phenotypes of atrial or ventricular septal defects, cleft palate, and variable developmental delays and intellectual disability. Non-specific dysmorphic features were noted in some patients, including broad forehead with high anterior hairline, arched eyebrows, thin or tented upper lip, and short philtrum. Recently, a patient with a de novo single amino acid deletion, c.998_1000delGAA (p.Arg333del), and a patient with a de novo nonsense variant, (c.611C>G, p.Ser204*), were reported with a similar, but apparently more severe phenotypes. Clinical whole exome sequencing (WES) performed at our clinical molecular diagnostic laboratory identified four additional patients with predicted damaging de novo MEIS2 missense variants. Our patients' features closely resembled those previously reported in patients with gross deletions, but also included some less commonly reported features, such as autism spectrum disorder, hearing loss, and short stature, as well as features that may be unique to nucleotide-level variants, such as hypotonia, failure to thrive, gastrointestinal, skeletal, limb, and skin abnormalities. All of the observed missense variants, Pro302Leu, Gln322Leu, Arg331Lys, and Val335Ala, are located in the functionally important MEIS2 homeodomain. Pro302Leu is found in the region between helix 1 and helix 2, while the other three are located in the DNA-binding helix 3. To our knowledge, these are the first described de novo missense variants in MEIS2, expanding the known mutation spectrum of the newly recognized human disorder caused by aberrations in this gene.

The role of IQSEC2 in syndromic intellectual disability: Narrowing the diagnostic odyssey.

While X-linked intellectual disability (XLID) syndromes pose a diagnostic challenge for clinicians, an increasing number of recognized disorders and their genetic etiologies are providing answers for patients and their families. The availability of clinical exome sequencing is broadening the ability to identify mutations in genes previously unrecognized as causing XLID. In recent years, the IQSEC2 gene, located at Xp11.22, has emerged as the cause of multiple cases of both nonsyndromic and syndromic XLID. Herein we present a case series of six individuals (five males, one female) with intellectual disability and seizures found to have alterations in IQSEC2. In all cases, the diagnostic odyssey was extensive and expensive, often including invasive testing such as muscle biopsies, before ultimately reaching the diagnosis. We report these cases to demonstrate the exhaustive work-up prior to finding the changes in IQSEC2 gene, recommend that this gene be considered earlier in the diagnostic evaluation of individuals with global developmental delay, microcephaly, and severe, intractable epilepsy, and support the use of intellectual disability panels including IQSEC2 in the first-line evaluation of these patients.

Round Table Discussion.

The 1st International Carnitine Working Group concluded with a round table discussion addressing several areas of relevance. These included the design of future studies that could increase the amount of evidence-based data about the role of carnitine in the treatment of fatty acid oxidation defects, for which substantial controversy still exists. There was general consensus that future trials on the effect of carnitine in disorders of fatty acid oxidation should be randomized, double-blinded, multicentered and minimally include the following diagnoses: medium-chain acyl coenzyme A (CoA) dehydrogenase deficiency, very long-chain acyl-CoA dehydrogenase deficiency, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and mitochondrial trifunctional protein deficiency. Another area that generated interest was trials of carnitine in cardiomyopathy and, especially, the use of biomarkers to identify patients at greater risk of cardiotoxicity following treatment with anthracyclines. The possibility that carnitine treatment may lead to improvements in autistic behaviors was also discussed, although the evidence is still not sufficient to make any firm conclusions in this regard. Preliminary data on carnitine levels in children and adolescents with primary hypertension, low birth weight and nephrotic syndrome was also presented. Lastly, the panelists stressed that there remains an objective need to harmonize the terminology used to describe carnitine deficiencies (e.g., primary, secondary and systemic deficiency).

MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways.

MEF2C haploinsufficiency syndrome is an emerging neurodevelopmental disorder associated with intellectual disability, autistic features, epilepsy, and abnormal movements. We report 16 new patients with MEF2C haploinsufficiency, including the oldest reported patient with MEF2C deletion at 5q14.3. We detail the neurobehavioral phenotype, epilepsy, and abnormal movements, and compare our subjects with those previously reported in the literature. We also investigate Mef2c expression in the developing mouse forebrain. A spectrum of neurofunctional deficits emerges, with hyperkinesis a consistent finding. Epilepsy varied from absent to severe, and included intractable myoclonic seizures and infantile spasms. Subjects with partial MEF2C deletion were statistically less likely to have epilepsy. Finally, we confirm that Mef2c is present both in dorsal primary neuroblasts and ventral gamma-aminobutyric acid(GABA)ergic interneurons in the forebrain of the developing mouse. Given interactions with several key neurodevelopmental genes such as ARX, FMR1, MECP2, and TBR1, it appears that MEF2C plays a role in several developmental stages of both dorsal and ventral neuronal cell types.

Quantification of intraoral pressures during nutritive sucking: methods with normal infants.

We report quantitative measurements of ten parameters of nutritive sucking behavior in 91 normal full-term infants obtained using a novel device (an Orometer) and a data collection/analytical system (Suck Editor). The sucking parameters assessed include the number of sucks, mean pressure amplitude of sucks, mean frequency of sucks per second, mean suck interval in seconds, sucking amplitude variability, suck interval variability, number of suck bursts, mean number of sucks per suck burst, mean suck burst duration, and mean interburst gap duration. For analyses, test sessions were divided into 4 × 2-min segments. In single-study tests, 36 of 60 possible comparisons of ten parameters over six pairs of 2-min time intervals showed a p value of 0.05 or less. In 15 paired tests in the same infants at different ages, 33 of 50 possible comparisons of ten parameters over five time intervals showed p values of 0.05 or less. Quantification of nutritive sucking is feasible, showing statistically valid results for ten parameters that change during a feed and with age. These findings suggest that further research, based on our approach, may show clinical value in feeding assessment, diagnosis, and clinical management.

Organizational and training factors that promote team science: A qualitative analysis and application of theory to the National Institutes of Health's BIRCWH career development program.

INTRODUCTION: Research organizations face challenges in creating infrastructures that cultivates and sustains interdisciplinary team science. The objective of this paper is to identify structural elements of organizations and training that promote team science. METHODS: We qualitatively analyzed the National Institutes of Health's Building Interdisciplinary Research Careers in Women's Health, K12 using organizational psychology and team science theories to identify organizational design factors for successful team science and training. PRINCIPAL RESULTS: Seven key design elements support team science: (1) semiformal meta-organizational structure, (2) shared context and goals, (3) formal evaluation processes, (4) meetings to promote communication, (5) role clarity in mentoring, (6) building interpersonal competencies among faculty and trainees, and (7) designing promotion and tenure and other organizational processes to support interdisciplinary team science. CONCLUSION: This application of theory to a long-standing and successful program provides important foundational elements for programs and institutions to consider in promoting team science.

STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy.

OBJECTIVE: To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients. METHODS: We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients. RESULTS: We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or cognitive outcome. Neurologic comorbidities including autistic features and movement disorders are frequent. We also report 2 previously unreported adult patients with prominent extrapyramidal features. CONCLUSION: De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy.

Long chain alkanes in silk extracts of maize genotypes with varying resistance to Fusarium graminearum.

The alkane content of the silks of nine maize genotypes was analyzed to investigate the role of silk wax in resistance to Fusarium graminearum. Silk samples were collected 2, 4, 6, and 8 days after silk emergence and divided into three sections: exposed silk, silk channel silk, and silk that is under the husk and overlying the kernels. Four major unbranched alkanes (C(25), C(27), C(29), and C(31)) and three isoalkanes (C(27i), C(29i), and C(31i)) were identified. Total alkane contents were highest in the exposed silk followed by the silk channel silk, with the lowest in the youngest silk closest to the kernels. In the silk channel and overlying kernel silks, the moderately resistant inbred CO272 consistently had the highest alkane content. None of the other inbreds with improved resistance had as high a level of alkanes as CO272, indicating that alkane content is not a major mechanism of resistance.

Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders.

Small genomic rearrangements and copy-number variations (CNVs) involving a single gene have been associated recently with many neurocognitive phenotypes, including intellectual disability (ID), behavioral abnormalities, and autistic spectrum disorders (ASDs). Such small CNVs in the Autism susceptibility candidate 2 (AUTS2) gene have been shown to be associated with seizures, ID, and ASDs. We report four patients with small CNVs ranging in size between 133-319 kb that disrupt AUTS2. Two patients have duplications involving single exons, whereas two have deletions that removed multiple exons. All patients had developmental delay, whereas two patients had a diagnosis of ASDs. The CNVs were detected by an exon-targeted array CGH with dense oligonucleotide coverage in exons of genes known or hypothesized to be causative of multiple human phenotypes. Our report further shows that disruption of AUTS2 results in a variety of neurobehavioral phenotypes. More importantly, it demonstrates the utility of targeted exon array as a highly sensitive clinical diagnostic tool for the detection of small genomic rearrangements in the clinically relevant regions of the human genome.

A commentary on the pluralistic goals, logics of action, and institutional contexts of translational team science.

Teams have emerged as a pivotal form for organizing science efforts. Team goals and issues such as goal alignment are generally considered to be essential to team success. However, given the interdisciplinary and pluralistic goals associated with translational science, team goals become a challenging area for studies that cannot be reconciled without attention to the broader institutional contexts of translational teams. In this commentary, we draw attention to how different goals in team science can be rooted in the broader institutional context and associated logics of action. For the science of team science (SciTS) to impact practice, it is imperative that we be clear about the logic of team goals and their relation to preferred patterns of organizing. We conclude with a reflection on how contextual issues should be at the foreground of SciTS along with the other important issues of team science.

Particulate face masks for protection against airborne pathogens - one size does not fit all: an observational study.

OBJECTIVE: To determine the proportion of hospital staff who pass fit tests with each of three commonly used particulate face masks, and factors influencing preference and fit test results. DESIGN: Observational study. SETTING AND PARTICIPANTS: 50 healthy hospital staff volunteers in an 18-bed general intensive care unit in an Australian teaching hospital. INTERVENTIONS: Participants were administered a questionnaire about mask use and their preferred mask and underwent qualitative fit-testing with each of three different particulate masks: Kimberly-Clark Tecnol FluidShield N95 particulate filter respirator (KC), 3M Flat Fold 9320 particulate respirator and 3M 8822 particulate respirator with exhalation valve. Participants who failed fittesting were trained in correct mask donning, and fittesting was repeated. MAIN OUTCOME MEASURES: Proportion of participants who passed the fit test for each mask and the effect of training. RESULTS: The proportion of participants who passed a fit test was low for all three masks tested (KC, 16%; flat fold, 28%; and valved, 34%). Rates improved after training: the first mask tested fitted in 18% of participants pre-training and 40% post-training (P = 0.02). None of the masks fitted for 28% of participants. There were no significant predictors of fit-test results. CONCLUSIONS: A large proportion of individuals failed a fit test with any given mask, and we were not able to identify any factors that predicted mask fit in individuals. Training on mask use improved the rates of adequate fit. Hospitals should carry a range of P2 masks, and should conduct systematic P2 mask training and fit-testing programs for all staff potentially exposed to airborne pathogens.

Efficacy of field treatments to reduce body core temperature in hyperthermic subjects.

PURPOSE: To contrast the effects of three postcooling techniques in reducing body core temperature (Tc) in exercise-induced hyperthermic participants on the cessation of exercise. METHODS: Eleven healthy active male volunteers were cooled during a 40-min period using three different methods: ice packs to the neck, axillae, and groin (ICE); water spray and fan (FAN); and 2 L of chilled (20 degrees C) intravenous saline administered during a 20-min period (IV). Rate of decrease in Tc, cardiovascular responses, and any incidence of reported adverse effects were investigated. Trials were presented in a counterbalanced order with the volunteers' body core temperature being elevated to 40.0 degrees C on three occasions via an intermittent walk-run (2 min at 6 km x h and 4 min at 10 km x h) protocol conducted within a climate-controlled chamber (34.2 +/- 0.5 degrees C and 62.3 +/- 3.1% relative humidity). RESULTS: Rate of Tc reduction during the first 20 min of cooling was greater for FAN compared with ICE (0.09 +/- 0.02 degrees C.min vs 0.07 +/- 0.02 degrees C.min, P < 0.05), whereas IV did not differ with the other trials (0.08 +/- 0.01 degrees C.min, P > 0.05). Three participants complained of numbness or paresthesia in their arm or hand during administration of the chilled saline, although these symptoms resolved within 5 min of ceasing the infusion. CONCLUSIONS: All three cooling techniques reduced Tc and would be suitable for first aid application in a field setting during transportation to adequate medical facilities. Chilled IV saline did not produce any contraindications, providing a suitable alternative for Tc cooling.

A case study of landholder attitudes and behaviour toward the conservation of renosterveld, a critically endangered vegetation type in Cape Floral Kingdom, South Africa.

The attitudes and behaviours of private landholders toward the conservation of a highly transformed and critically endangered habitat, Overberg Coastal Renosterveld (OCR) (a grassy shrubland of the Cape Floral Region, South Africa) are described. Personal, semistructured interviews were conducted with landholders, representing 40 properties in the Overberg region, on topics such as management and utilisation of OCR, the depth of their knowledge of its conservation importance, what they perceive its value to be, and the extent of their willingness to conserve it. General attitudes toward conservation incentives and provincial conservation authorities were also investigated. Farmers more willing to conserve were younger, did not necessarily have a better education, and owned larger farms (>500 ha) with a greater amount of remnant renosterveld (>300 ha) than those less willing to conserve. Attitudes toward the OCR were largely negative, related to associated problem plants and animals and the fact that it is believed not to be economically advantageous to retain it. However, farmers are of the opinion that provision of incentives and increased extension support will provide practical positive inducements for conservation. Landholder education is paramount to prevent further transformation of critically endangered habitats. The success of private-conservation programs depends on the attitudes of landowners toward (1) the particular habitat or species to be conserved (which can vary depending on the type of land use practised and the associated benefits and disadvantages of that habitat type); (2) the conservation agency or extension officers responsible for that area; and (3) willingness of landowners to participate in a conservation program, which is influenced by landowner age, farm size, and the amount of natural habitat left to conserve.