NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly.

The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.

Altered structural connectivity networks in a mouse model of complete and partial dysgenesis of the corpus callosum.

Corpus callosum dysgenesis (CCD) describes a collection of brain malformations in which the main fiber tract connecting the two hemispheres is either absent (complete CCD, or 'agenesis of the corpus callosum') or reduced in size (partial CCD). Humans with these neurodevelopmental disorders have a wide range of cognitive outcomes, including seemingly preserved features of interhemispheric communication in some cases. However, the structural substrates that could underlie this variability in outcome remain to be fully elucidated. Here, for the first time, we characterize the global brain connectivity of a mouse model of complete and partial CCD. We demonstrate features of structural brain connectivity that model those predicted in humans with CCD, including Probst bundles in complete CCD and heterotopic sigmoidal connections in partial CCD. Crucially, we also histologically validate the recently predicted ectopic sigmoid bundle present in humans with partial CCD, validating the utility of this mouse model for fine anatomical studies of this disorder. Taken together, this work describes a mouse model of altered structural connectivity in variable severity CCD and forms a foundation for future studies investigating the function and mechanisms of development of plastic tracts in developmental disorders of brain connectivity.

Implementing lung cancer screening: baseline results from a community-based 'Lung Health Check' pilot in deprived areas of Manchester.

We report baseline results of a community-based, targeted, low-dose CT (LDCT) lung cancer screening pilot in deprived areas of Manchester. Ever smokers, aged 55-74 years, were invited to 'lung health checks' (LHCs) next to local shopping centres, with immediate access to LDCT for those at high risk (6-year risk ≥1.51%, PLCOM2012 calculator). 75% of attendees (n=1893/2541) were ranked in the lowest deprivation quintile; 56% were high risk and of 1384 individuals screened, 3% (95% CI 2.3% to 4.1%) had lung cancer (80% early stage) of whom 65% had surgical resection. Taking lung cancer screening into communities, with an LHC approach, is effective and engages populations in deprived areas.

Second round results from the Manchester 'Lung Health Check' community-based targeted lung cancer screening pilot.

We report results from the second annual screening round (T1) of Manchester's 'Lung Health Check' pilot of community-based lung cancer screening in deprived areas (undertaken June to August 2017). Screening adherence was 90% (n=1194/1323): 92% of CT scans were classified negative, 6% indeterminate and 2.5% positive; there were no interval cancers. Lung cancer incidence was 1.6% (n=19), 79% stage I, treatments included surgery (42%, n=9), stereotactic ablative radiotherapy (26%, n=5) and radical radiotherapy (5%, n=1). False-positive rate was 34.5% (n=10/29), representing 0.8% of T1 participants (n=10/1194). Targeted community-based lung cancer screening promotes high screening adherence and detects high rates of early stage lung cancer.

Automated Canine Scent-Detection Apparatus: Technical Description and Training Outcomes.

To date, laboratory scent-detection work with dogs has been a manual process whereby some or all aspects of the procedures are mediated by researchers. Automation of this process would eliminate issues associated with cuing, subjectivity in data collection, and reinforcement delivery. Herein, I describe an automated apparatus that can accommodate almost any type of sample that can be brought into the laboratory. The apparatus consists of a 17-segment carousel that rotates behind a panel. Dogs can access a single sample at a time through a port in the panel. Infrared beams are used to detect sample observations and indications, and a dog-activated switch is used to advance the carousel to the next sample. Correct indications are reinforced with an automated feeder. After screening 12 dogs, 5 dogs were selected and trained to use the apparatus to classify samples containing amyl acetate. All dogs achieved hit rates and correct rejection rates at or near 100% in fewer than 25 half-days of training (mean: 19.6, range: 12-24). These data suggest that the apparatus can be used to obtain accurate sample classification without excessive training requirements. Future improvements to the apparatus and training protocols may reduce the training requirements further.

DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome.

The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus-specific LOVD (https://databases.lovd.nl/shared/genes/DCC).

EMX1 regulates NRP1-mediated wiring of the mouse anterior cingulate cortex.

Transcription factors act during cortical development as master regulatory genes that specify cortical arealization and cellular identities. Although numerous transcription factors have been identified as being crucial for cortical development, little is known about their downstream targets and how they mediate the emergence of specific neuronal connections via selective axon guidance. The EMX transcription factors are essential for early patterning of the cerebral cortex, but whether EMX1 mediates interhemispheric connectivity by controlling corpus callosum formation remains unclear. Here, we demonstrate that in mice on the C57Bl/6 background EMX1 plays an essential role in the midline crossing of an axonal subpopulation of the corpus callosum derived from the anterior cingulate cortex. In the absence of EMX1, cingulate axons display reduced expression of the axon guidance receptor NRP1 and form aberrant axonal bundles within the rostral corpus callosum. EMX1 also functions as a transcriptional activator of Nrp1 expression in vitro, and overexpression of this protein in Emx1 knockout mice rescues the midline-crossing phenotype. These findings reveal a novel role for the EMX1 transcription factor in establishing cortical connectivity by regulating the interhemispheric wiring of a subpopulation of neurons within the mouse anterior cingulate cortex.

Reproducibility of African giant pouched rats detecting Mycobacterium tuberculosis.

BACKGROUND: African pouched rats sniffing sputum samples provided by local clinics have significantly increased tuberculosis case findings in Tanzania and Mozambique. The objective of this study was to determine the reproducibility of rat results. METHODS: Over an 18-month period 11,869 samples were examined by the rats. Intra-rater reliability was assessed through Yule's Q. Inter-rater reliability was assessed with Krippendorff's alpha. RESULTS: Intra-rater reliability was high, with a mean Yule's Q of 0.9. Inter-rater agreement was fair, with Krippendorf's alpha ranging from 0.15 to 0.45. Both Intra- and Inter-rater reliability was independent of the sex of the animals, but they were positively correlated with age. Both intra- and inter-rater agreement was lowest for samples designated as smear-negative by the clinics. CONCLUSION: Overall, the reproducibility of tuberculosis detection rat results was fair and diagnostic results were therefore independent of the rats used.

A combined hands-on teaching programme and clinical pathway focused on pleural ultrasound and procedure supervision transforms pleural procedure outcomes.

BACKGROUND: Management of pleural effusions is a common diagnostic and management problem. AIMS: We reviewed the outcomes from pleural procedures after the instigation of pleural effusion management guidelines, focusing on pleural ultrasound and a hands-on teaching programme followed by procedure supervision that enabled many operators to perform such procedures. METHODS: This is a retrospective analysis of all procedures performed for pleural effusions on medical patients. Outcomes were assessed prior to the instigation of pleural effusion management guidelines (pleural pathway) and hands-on teaching (January 2010 to June 2011) and following these interventions (January 2012 to June 2013). RESULTS: A total of 171 procedures involving 129 patients (pre-pathway group) and 146 procedures involving 115 patients (post-pathway group) was analysed. The rate of complications prior to the pleural pathway was 22.2% (38 of 171 procedures). Following the pathway, the rate of complications declined to 7.5% (11 of 146 procedures, P < 0.003). The use of pleural ultrasound increased dramatically (72.5 vs 90.2%). The number of patients who underwent repeated procedures (defined as ≥3) reduced dramatically (21 vs 7, P < 0.01). This improvement occurred using many supervised operators who completed the hands-on teaching programme (n = 32) and followed the pleural pathway (127 of 146 procedures). CONCLUSION: The instigation of a clinical pathway focused on the use of bedside pleural ultrasound, and teaching of drainage techniques with procedure supervision vastly improved patient outcomes. This not only allowed better quality of care for patients, it also provided the acquisition of new skills to medical staff, not limiting these skills to specialised staff.

Altered structural connectome in adolescent socially isolated mice.

Social experience is essential for adolescent development and plasticity of social animals. Deprivation of the experience by social isolation impairs white matter microstructures in the prefrontal cortex. However, the effect of social isolation may involve highly distributed brain networks, and therefore cannot be fully explained by a change of a single region. Here, we compared the connectomes of adolescent socially-isolated mice and normal-housed controls via diffusion magnetic resonance imaging. The isolated mice displayed an abnormal connectome, characterized by an increase in degree and reductions in measures such as modularity, small-worldness, and betweenness. The increase in degree was most evident in the dorsolateral orbitofrontal cortex, entorhinal cortex, and perirhinal cortex. In a connection-wise comparison, we revealed that most of the abnormal edges were inter-modular and inter-hemispheric connections of the dorsolateral orbitofrontal cortex. Further tractography-based analyses and histological examinations revealed microstructural changes in the forceps minor and lateral-cortical tracts that were associated with the dorsolateral orbitofrontal cortex. These changes of connectomes were correlated with fear memory deficits and hyper-locomotion activities induced by social isolation. Considering the key role of the orbitofrontal cortex in social behaviors, adolescent social isolation may primarily disrupt the orbitofrontal cortex and its neural pathways thereby contributing to an abnormal structural connectome.

In-Transit Metastasis From Squamous Cell Carcinoma.

BACKGROUND: In-transit metastasis from cutaneous squamous cell carcinoma (SCC) is an uncommon form of metastasis through lymphatics and occurs more commonly in immunosuppressed patients. OBJECTIVE: To identify cases of in-transit SCC and determine patient characteristics, tumor features, management, and prognosis. METHODS AND MATERIALS: A multicenter case series treated by Australian and New Zealand clinicians. RESULTS: In 31 patients, median age was 72 years (range 52-99) and 68% were immunocompetent. Tumors occurred on the head and neck in 94% of cases, with 71% of all tumors occurring on the scalp, forehead, or temple. The median time to presentation with in-transit SCC from treatment of the initial tumor was 5 months. Management included surgery (94%), radiotherapy (77%), chemotherapy (10%), and reduction of immunosuppression (3%). Median follow-up was 12 months. Overall survival at 3 and 5 years were 27% and 13%, respectively. CONCLUSION: In-transit metastases are described in 31 patients, of whom the majority was immunocompetent. The scalp, forehead, and temple were the most common sites. New clinical and histological diagnostic criteria are proposed. Prognosis was poor with 5-year survival of 13%. Recommended management is a combination of surgery and adjuvant radiotherapy. Reduction of any iatrogenic immunosuppression should be considered.

Clinical, genetic and imaging findings identify new causes for corpus callosum development syndromes.

The corpus callosum is the largest fibre tract in the brain, connecting the two cerebral hemispheres, and thereby facilitating the integration of motor and sensory information from the two sides of the body as well as influencing higher cognition associated with executive function, social interaction and language. Agenesis of the corpus callosum is a common brain malformation that can occur either in isolation or in association with congenital syndromes. Understanding the causes of this condition will help improve our knowledge of the critical brain developmental mechanisms required for wiring the brain and provide potential avenues for therapies for callosal agenesis or related neurodevelopmental disorders. Improved genetic studies combined with mouse models and neuroimaging have rapidly expanded the diverse collection of copy number variations and single gene mutations associated with callosal agenesis. At the same time, advances in our understanding of the developmental mechanisms involved in corpus callosum formation have provided insights into the possible causes of these disorders. This review provides the first comprehensive classification of the clinical and genetic features of syndromes associated with callosal agenesis, and provides a genetic and developmental framework for the interpretation of future research that will guide the next advances in the field.

Advanced paramedics' restraint decision-making when managing acute behavioural disturbance (ABD) in the UK pre-hospital ambulance setting: A qualitative investigation.

Acute behavioural disturbance (ABD), sometimes called 'excited delirium', is a medical emergency. In the UK, some patients presenting with ABD are managed by advanced paramedics (APs), however little is known about how APs make restraint decisions. The aim of this research is to explore the decisions made by APs when managing restraint in the context of ABD, in the UK pre-hospital ambulance setting. Seven semi-structured interviews were undertaken with APs. All participants were experienced APs with post-registration, post-graduate advanced practice education and qualifications. The resulting data were analysed using reflexive thematic analysis, informed by critical realism. We identified four interconnected themes from the interview data. Firstly, managing complexity and ambiguity in relation to identifying ABD patients and determining appropriate treatment plans. Secondly, feeling vulnerable to professional consequences from patients deteriorating whilst in the care of APs. Thirdly, negotiating with other professionals who have different roles and priorities. Finally, establishing primacy of care in relation to incidents which involve police officers and other professionals. A key influence was the need to characterise incidents as medical, as an enabler to establishing clinical leadership and decision-making control. APs focused on de-escalation techniques and sought to reduce physical restraint, intervening with pharmacological interventions if necessary to achieve this. The social relationships and interactions with patients and other professionals at the scene were key to success. Decisions are a source of anxiety, with fears of professional detriment accompanying poor patient outcomes. Our results indicate that APs would benefit from education and development specifically in relation to making ABD decisions, acknowledging the context of inter-professional relationships and the potential for competing and conflicting priorities. A focus on joint, high-fidelity training with the police may be a helpful intervention.

Case report: A proposed role for cardiopulmonary exercise testing in detecting cardiac dysfunction in asymptomatic at-risk adolescents.

Noninvasive cardiopulmonary exercise testing (CPET) provides the valuable capacity to analyze pulmonary gas exchange and cardiovascular responses that can be used to differentiate normal cardiopulmonary responses from abnormal. This case report highlights a proposed role for CPET in identifying potential cardiac pathologies in at-risk adolescents. An abnormal CPET response in an asymptomatic adolescent revealed a family history of early-age CAD. The significance of the abnormal CPET response was further supported by the presence of an elevated concentration of circulating high sensitivity C-reactive protein (hs-CRP). These findings emphasize the importance of a thorough clinical evaluation in at-risk adolescents, as CPET can aid in the early detection and management of cardiac pathologies, especially when combined with other relevant biomarkers such as plasma hs-CRP concentration, which can further suggest underlying pathology. Management considerations using serial CPET evaluations are recommended. Thus, CPET abnormalities combined with elevated hs-CRP should be taken seriously and provide justification for further evaluation and monitoring in adolescents at risk for cardiovascular disease.

Experimental analysis of canine behavior and cognition: Introduction to the special issue.

Over the last 3 decades, the use and popularity of canid models for basic and applied behavioral research has grown dramatically, and for good reasons. Dogs are uniquely among the human world, living and working in our homes and places of employment while an even greater population lives on the outskirts of human life, scavenging and navigating the city life. This provides a rich continuum of environmental contexts for the canine experience, leading to some unique and even human-like behaviors in animals. The articles in this special issue provide additional insight into factors that influence canine welfare, methods for evaluating dogs' preferences and the reinforcing effectiveness of stimuli, trick learning and retention, concept learning, and scent detection performance under sparse reinforcement conditions. Here we provide an overview of these articles and their contribution to our understanding of canine behavior.

Extracting spatial information from temporal odor patterns: insights from insects.

Extracting spatial information from temporal stimulus patterns is essential for sensory perception (e.g. visual motion direction detection or concurrent sound segregation), but this process remains understudied in olfaction. Animals rely on olfaction to locate resources and dangers. In open environments, where odors are dispersed by turbulent wind, detection of wind direction seems crucial for odor source localization. However, recent studies showed that insects can extract spatial information from the odor stimulus itself, independently from sensing wind direction. This remarkable ability is achieved by detecting the fine-scale temporal pattern of odor encounters, which contains information about the location and size of an odor source, and the distance between different odor sources.

Mirror movements and callosal dysgenesis in a family with a DCC mutation: Neuropsychological and neuroimaging outcomes.

Corpus callosum dysgenesis is a congenital abnormality whereby the corpus callosum fails to develop normally, and has been associated with a range of neuropsychological outcomes. One specific finding in some individuals with corpus callosum dysgenesis is "congenital mirror movement disorder", which is the presence of involuntary movements on one side of the body that mimic voluntary movements of the other side. Mirror movements have also been associated with mutations in the deleted in colorectal carcinoma (DCC) gene. The current study aims to comprehensively document the neuropsychological outcomes and neuroanatomical mapping of a family (a mother, daughter and son) with known DCC mutations. All three family members experience mirror movements, and the son additionally has partial agenesis of the corpus callosum (pACC). All family members underwent extensive neuropsychological testing, spanning general intellectual functioning, memory, language, literacy, numeracy, psychomotor speed, visuospatial perception, praxis and motor functioning, executive functioning, attention, verbal/nonverbal fluency, and social cognition. The mother and daughter had impaired memory for faces, and reduced spontaneous speech, and the daughter demonstrated scattered impairments in attention and executive functioning, but their neuropsychological abilities were largely within normal limits. By contrast, the son showed areas of significant impairment across multiple domains including reduced psychomotor speed, fine motor dexterity and general intellectual functioning, and he was profoundly impaired across areas of executive functioning and attention. Reductions in his verbal/non-verbal fluency, with relatively intact core language, resembled dynamic frontal aphasia. His relative strengths included aspects of memory and he demonstrated largely sound theory of mind. Neuroimaging revealed an asymmetric sigmoid bundle in the son, connecting, via the callosal remnant, the left frontal cortex with contralateral parieto-occipital cortex. Overall, this study documents a range of neuropsychological and neuroanatomical outcomes within one family with DCC mutations and mirror movements, including one with more severe consequences and pACC.

Out-of-hospital cardiac arrest complicated by hyperthermia.

Background: The aims of this study were to establish epidemiology, clinical management and outcomes in cases of adult out-of-hospital cardiac arrest complicated by hyperthermia attended by the London Ambulance Service NHS Trust between January 2018 and December 2019. Where evidence is available in relation to this sub-set of cardiac arrest patients it is generally limited to small case series and we therefore we sought to improve knowledge and target therapeutic interventions. Methods and results: Retrospective analysis of 253 cases was undertaken following abstraction from an established cardiac arrest database. Age ranged from 18-99 years with a median of 72 years (IQR 28) and 53.4% (n = 135) of patients were female. Overall thirty-day mortality was 94.5% (n = 239), with 48.2% (n = 122) of patients recognised life extinct in the out-of-hospital phase following termination of resuscitation. No significant differences in clinical characteristics stratified according to temperature group were identified. The presumed aetiology was infective in 62.8% (n = 159) of patients, and due to drug ingestion or heat illness in 7.5% (n = 19) and 2% (n = 5) respectively. In the remaining cases (27.7%, n = 70) it was not possible to determine the likely cause of the arrest. Conclusions: Previous research relating to cardiac arrest complicated by hyperthermia is limited to case reports and small case series, suggesting that the current study represents the most comprehensive analysis of this sub-group of out-of-hospital cardiac arrest patients currently available. Most cases were associated with evidence of infection compared with drug related aetiologies and heat illness. Where indicated, cooling was applied infrequently using inconsistent methods.