Challenges and support needs of parents and children when a parent is at end of life: A systematic review

Background: Preparing children for the death of a parent is challenging. Parents are often uncertain if and how to communicate and support their children. Many parents feel it is protecting their children by not telling them about the prognosis. Children less prepared for parental death from a terminal illness are more susceptive to later adversities. To facilitate coping and moderate for such adversities, there is a need to gain insight and understand the experience and challenges confronted by families. Aim: This review synthesised evidence on the experiences of parents and children when a parent is at end of life to discern their challenges, support needs and factors that facilitated good practice. Design: Mixed-methods systematic review. Data sources: Four electronic databases (CINAHL, PubMed, PsycINFO and Ovid MEDLINE) using MeSH terms and word searches in October 2018. Studies were not limited by year of publication, language or country. Grey literature searches were also completed on Google Scholar and OpenGrey. Results: In all, 7829 records were identified; 27 qualitative and 0 quantitative studies met the inclusion criteria. Eight descriptive themes were identified, further categorised into two broad themes: (1) barriers and facilitators in sharing the news that a parent is dying and (2) strategies to manage the changing situation. Conclusion: Lack of understanding in relation to the parent’s prognosis, denial and feeling ill-equipped were suggested as barriers for parents to share the news with their children. Engagement with social networks, including extended family relatives and peers, and maintaining routines such as attending school were suggested supportive by parents and children. Findings are limited primarily to White, middle-class two-parent families. A number of areas for future research are identified.</p

A genome-wide scan for common alleles affecting risk for autism

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C

Validation of a low-cost virtual reality system for training street-crossing. A comparative study in healthy, neglected and non-neglected stroke individuals

Unilateral spatial neglect is a common consequence of stroke that directly affects the performance of activities of daily living. This impairment is traditionally assessed with paper-and-pencil tests that can lack correspondence to real life and are easily compensated. Virtual reality can immerse patients in more ecological scenarios, thus providing therapists with new tools to assess and train the effects of this impairment in simulated real tasks. This paper presents the clinical validation and convergent validity of a low-cost virtual reality system for training street-crossing in stroke patients with and without neglect. The performance of neglect patients was significantly worse than the performance of non-neglect and healthy participants. In addition, several correlations between the scores in the system and in the traditional scales were detected.This study was funded in part by Ministerio de Educacion y Ciencia Spain, Projects Consolider-C (SEJ2006-14301/PSIC), "CIBER of Physiopathology of Obesity and Nutrition, an initiative of ISCIII" and the Excellence Research Program PROMETEO (Generalitat Valenciana. Conselleria de Educacion, 2008-157).Navarro, MD.; Llorens Rodríguez, R.; Noé, E.; Ferri, J.; Alcañiz Raya, ML. (2013). Validation of a low-cost virtual reality system for training street-crossing. A comparative study in healthy, neglected and non-neglected stroke individuals. Neuropsychological Rehabilitation. 23(4):597-618. https://doi.org/10.1080/09602011.2013.806269S597618234Allegri, R. F. (2000). Atención y negligencia: bases neurológicas, evaluación y trastornos. Revista de Neurología, 30(05), 491. doi:10.33588/rn.3005.99645Appelros, P., Karlsson, G. M., Seiger, &#x000C5;ke, & Nydevik, I. (2002). Neglect and Anosognosia After First-Ever Stroke: Incidence and Relationship to Disability. Journal of Rehabilitation Medicine, 34(5), 215-220. doi:10.1080/165019702760279206Baheux, K., Yoshizawa, M., & Yoshida, Y. (2007). Simulating hemispatial neglect with virtual reality. Journal of NeuroEngineering and Rehabilitation, 4(1). doi:10.1186/1743-0003-4-27Boian, R. F., Burdea, G. C., Deutsch, J. E. and Winter, S. H. Street crossing using a virtual environment mobility simulator.Paper presented at 3rd Annual International Workshop on Virtual Reality. Lausanne, Switzerland.Broeren, J., Samuelsson, H., Stibrant-Sunnerhagen, K., Blomstrand, C., & Rydmark, M. (2007). Neglect assessment as an application of virtual reality. Acta Neurologica Scandinavica, 116(3), 157-163. doi:10.1111/j.1600-0404.2007.00821.xBuxbaum, L. J., Ferraro, M. K., Veramonti, T., Farne, A., Whyte, J., Ladavas, E., … Coslett, H. B. (2004). Hemispatial neglect: Subtypes, neuroanatomy, and disability. Neurology, 62(5), 749-756. doi:10.1212/01.wnl.0000113730.73031.f4Buxbaum, L. J., Palermo, M. A., Mastrogiovanni, D., Read, M. S., Rosenberg-Pitonyak, E., Rizzo, A. A., & Coslett, H. B. (2008). Assessment of spatial attention and neglect with a virtual wheelchair navigation task. Journal of Clinical and Experimental Neuropsychology, 30(6), 650-660. doi:10.1080/13803390701625821Castiello, U., Lusher, D., Burton, C., Glover, S., & Disler, P. (2004). Improving left hemispatial neglect using virtual reality. Neurology, 62(11), 1958-1962. doi:10.1212/01.wnl.0000128183.63917.02Conners, C. K., Epstein, J. N., Angold, A., & Klaric, J. (2003). Journal of Abnormal Child Psychology, 31(5), 555-562. doi:10.1023/a:1025457300409Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). «Mini-mental state». Journal of Psychiatric Research, 12(3), 189-198. doi:10.1016/0022-3956(75)90026-6Fordell, H., Bodin, K., Bucht, G., & Malm, J. (2011). A virtual reality test battery for assessment and screening of spatial neglect. Acta Neurologica Scandinavica, 123(3), 167-174. doi:10.1111/j.1600-0404.2010.01390.xGupta, V., Knott, B. A., Kodgi, S., & Lathan, C. E. (2000). Using the «VREye» System for the Assessment of Unilateral Visual Neglect: Two Case Reports. Presence: Teleoperators and Virtual Environments, 9(3), 268-286. doi:10.1162/105474600566790Hartman-Maeir, A., & Katz, N. (1995). Validity of the Behavioral Inattention Test (BIT): Relationships With Functional Tasks. American Journal of Occupational Therapy, 49(6), 507-516. doi:10.5014/ajot.49.6.507Jannink, M. J. A., Aznar, M., de Kort, A. C., van de Vis, W., Veltink, P., & van der Kooij, H. (2009). Assessment of visuospatial neglect in stroke patients using virtual reality: a pilot study. International Journal of Rehabilitation Research, 32(4), 280-286. doi:10.1097/mrr.0b013e3283013b1cJehkonen, M., Laihosalo, M., & Kettunen, J. (2006). Anosognosia after stroke: assessment, occurrence, subtypes and impact on functional outcome reviewed. Acta Neurologica Scandinavica, 114(5), 293-306. doi:10.1111/j.1600-0404.2006.00723.xKatz, N., Ring, H., Naveh, Y., Kizony, R., Feintuch, U., & Weiss, P. L. (2005). Interactive virtual environment training for safe street crossing of right hemisphere stroke patients with Unilateral Spatial Neglect. Disability and Rehabilitation, 27(20), 1235-1244. doi:10.1080/09638280500076079Kim, D. Y., Ku, J., Chang, W. H., Park, T. H., Lim, J. Y., Han, K., … Kim, S. I. (2010). Assessment of post-stroke extrapersonal neglect using a three-dimensional immersive virtual street crossing program. Acta Neurologica Scandinavica, 121(3), 171-177. doi:10.1111/j.1600-0404.2009.01194.xKim, J., Kim, K., Kim, D. Y., Chang, W. H., Park, C.-I., Ohn, S. H., … Kim, S. I. (2007). Virtual Environment Training System for Rehabilitation of Stroke Patients with Unilateral Neglect: Crossing the Virtual Street. CyberPsychology & Behavior, 10(1), 7-15. doi:10.1089/cpb.2006.9998Kim, K., Kim, J., Ku, J., Kim, D. Y., Chang, W. H., Shin, D. I., … Kim, S. I. (2004). A Virtual Reality Assessment and Training System for Unilateral Neglect. CyberPsychology & Behavior, 7(6), 742-749. doi:10.1089/cpb.2004.7.742Kim, Y. M., Chun, M. H., Yun, G. J., Song, Y. J., & Young, H. E. (2011). The Effect of Virtual Reality Training on Unilateral Spatial Neglect in Stroke Patients. Annals of Rehabilitation Medicine, 35(3), 309. doi:10.5535/arm.2011.35.3.309Krakauer, J. W. (2006). Motor learning: its relevance to stroke recovery and neurorehabilitation. Current Opinion in Neurology, 19(1), 84-90. doi:10.1097/01.wco.0000200544.29915.ccMcComas, J., MacKay, M., & Pivik, J. (2002). Effectiveness of Virtual Reality for Teaching Pedestrian Safety. CyberPsychology & Behavior, 5(3), 185-190. doi:10.1089/109493102760147150Myers, R. L., & Bierig, T. A. (2000). Virtual Reality and Left Hemineglect: A Technology for Assessment and Therapy. CyberPsychology & Behavior, 3(3), 465-468. doi:10.1089/10949310050078922Peskine, A., Rosso, C., Box, N., Galland, A., Caron, E., Rautureau, G., … Pradat-Diehl, P. (2010). Virtual reality assessment for visuospatial neglect: importance of a dynamic task. Journal of Neurology, Neurosurgery & Psychiatry, 82(12), 1407-1409. doi:10.1136/jnnp.2010.217513Romero, M., Sánchez, A., Marín, C., Navarro, M. D., Ferri, J., & Noé, E. (2012). Utilidad clínica de la versión en castellano del Mississippi Aphasia Screening Test (MASTsp): validación en pacientes con ictus. Neurología, 27(4), 216-224. doi:10.1016/j.nrl.2011.06.006Rose, F. D., Brooks, B. M., & Rizzo, A. A. (2005). Virtual Reality in Brain Damage Rehabilitation: Review. CyberPsychology & Behavior, 8(3), 241-262. doi:10.1089/cpb.2005.8.241Schwebel, D. C., & McClure, L. A. (2010). Using virtual reality to train children in safe street-crossing skills. Injury Prevention, 16(1), e1-e1. doi:10.1136/ip.2009.025288Simpson, G., Johnston, L., & Richardson, M. (2003). An investigation of road crossing in a virtual environment. Accident Analysis & Prevention, 35(5), 787-796. doi:10.1016/s0001-4575(02)00081-7Smith, J., Hebert, D., & Reid, D. (2007). Exploring the effects of virtual reality on unilateral neglect caused by stroke: Four case studies. Technology and Disability, 19(1), 29-40. doi:10.3233/tad-2007-19104Sugarman, H., Weisel-Eichler, A., Burstin, A. and Brown, R.Use of novel virtual reality system for the assessment and treatment of unilateral spatial neglect: A feasibility study. Paper presented at International Conference on Virtual Rehabilitation. Zürich.Tanaka, T., Sugihara, S., Nara, H., Ino, S., & Ifukube, T. (2005). Journal of NeuroEngineering and Rehabilitation, 2(1), 31. doi:10.1186/1743-0003-2-31Thomson, J. A., Tolmie, A. K., Foot, H. C., Whelan, K. M., Sarvary, P., & Morrison, S. (2005). Influence of Virtual Reality Training on the Roadside Crossing Judgments of Child Pedestrians. Journal of Experimental Psychology: Applied, 11(3), 175-186. doi:10.1037/1076-898x.11.3.175Weiss, P. L. (Tamar), Naveh, Y., & Katz, N. (2003). Design and testing of a virtual environment to train stroke patients with unilateral spatial neglect to cross a street safely. Occupational Therapy International, 10(1), 39-55. doi:10.1002/oti.176Witmer, B. G., & Singer, M. J. (1998). Measuring Presence in Virtual Environments: A Presence Questionnaire. Presence: Teleoperators and Virtual Environments, 7(3), 225-240. doi:10.1162/105474698565686Wu, H., Ashmead, D. H. and Bodenheimer, B.Using immersive virtual reality to evaluate pedestrian street crossing decisions at a roundabout. Paper presented at 6th Symposium on appied perception in Graphics and Visualization. Chania

The prognosis of allocentric and egocentric neglect : evidence from clinical scans

We contrasted the neuroanatomical substrates of sub-acute and chronic visuospatial deficits associated with different aspects of unilateral neglect using computed tomography scans acquired as part of routine clinical diagnosis. Voxel-wise statistical analyses were conducted on a group of 160 stroke patients scanned at a sub-acute stage. Lesion-deficit relationships were assessed across the whole brain, separately for grey and white matter. We assessed lesions that were associated with behavioural performance (i) at a sub-acute stage (within 3 months of the stroke) and (ii) at a chronic stage (after 9 months post stroke). Allocentric and egocentric neglect symptoms at the sub-acute stage were associated with lesions to dissociated regions within the frontal lobe, amongst other regions. However the frontal lesions were not associated with neglect at the chronic stage. On the other hand, lesions in the angular gyrus were associated with persistent allocentric neglect. In contrast, lesions within the superior temporal gyrus extending into the supramarginal gyrus, as well as lesions within the basal ganglia and insula, were associated with persistent egocentric neglect. Damage within the temporo-parietal junction was associated with both types of neglect at the sub-acute stage and 9 months later. Furthermore, white matter disconnections resulting from damage along the superior longitudinal fasciculus were associated with both types of neglect and critically related to both sub-acute and chronic deficits. Finally, there was a significant difference in the lesion volume between patients who recovered from neglect and patients with chronic deficits. The findings presented provide evidence that (i) the lesion location and lesion size can be used to successfully predict the outcome of neglect based on clinical CT scans, (ii) lesion location alone can serve as a critical predictor for persistent neglect symptoms, (iii) wide spread lesions are associated with neglect symptoms at the sub-acute stage but only some of these are critical for predicting whether neglect will become a chronic disorder and (iv) the severity of behavioural symptoms can be a useful predictor of recovery in the absence of neuroimaging findings on clinical scans. We discuss the implications for understanding the symptoms of the neglect syndrome, the recovery of function and the use of clinical scans to predict outcome

De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.

We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk

Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication

<p>Abstract</p> <p>Background</p> <p>SHANK3 is a protein in the core of the postsynaptic density (PSD) and has a critical role in recruiting many key functional elements to the PSD and to the synapse, including components of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA), metabotropic glutamate (mGlu) and <it>N</it>-methyl-D-aspartic acid (NMDA) glutamate receptors, as well as cytoskeletal elements. Loss of a functional copy of the <it>SHANK3 </it>gene leads to the neurobehavioral manifestations of 22q13 deletion syndrome and/or to autism spectrum disorders. The goal of this study was to examine the effects of haploinsufficiency of full-length <it>Shank3 </it>in mice, focusing on synaptic development, transmission and plasticity, as well as on social behaviors, as a model for understanding <it>SHANK3 </it>haploinsufficiency in humans.</p> <p>Methods</p> <p>We used mice with a targeted disruption of <it>Shank3 </it>in which exons coding for the ankyrin repeat domain were deleted and expression of full-length Shank3 was disrupted. We studied synaptic transmission and plasticity by multiple methods, including patch-clamp whole cell recording, two-photon time-lapse imaging and extracellular recordings of field excitatory postsynaptic potentials. We also studied the density of GluR1-immunoreactive puncta in the CA1 stratum radiatum and carried out assessments of social behaviors.</p> <p>Results</p> <p>In <it>Shank3 </it>heterozygous mice, there was reduced amplitude of miniature excitatory postsynaptic currents from hippocampal CA1 pyramidal neurons and the input-output (I/O) relationship at Schaffer collateral-CA1 synapses in acute hippocampal slices was significantly depressed; both of these findings indicate a reduction in basal neurotransmission. Studies with specific inhibitors demonstrated that the decrease in basal transmission reflected reduced AMPA receptor-mediated transmission. This was further supported by the observation of reduced numbers of GluR1-immunoreactive puncta in the stratum radiatum. Long-term potentiation (LTP), induced either with θ-burst pairing (TBP) or high-frequency stimulation, was impaired in <it>Shank3 </it>heterozygous mice, with no significant change in long-term depression (LTD). In concordance with the LTP results, persistent expansion of spines was observed in control mice after TBP-induced LTP; however, only transient spine expansion was observed in <it>Shank3 </it>heterozygous mice. Male <it>Shank3 </it>heterozygotes displayed less social sniffing and emitted fewer ultrasonic vocalizations during interactions with estrus female mice, as compared to wild-type littermate controls.</p> <p>Conclusions</p> <p>We documented specific deficits in synaptic function and plasticity, along with reduced reciprocal social interactions in <it>Shank3 </it>heterozygous mice. Our results are consistent with altered synaptic development and function in <it>Shank3 </it>haploinsufficiency, highlighting the importance of Shank3 in synaptic function and supporting a link between deficits in synapse function and neurodevelopmental disorders. The reduced glutamatergic transmission that we observed in the <it>Shank3 </it>heterozygous mice represents an interesting therapeutic target in <it>Shank3</it>-haploinsufficiency syndromes.</p

BALB/c Mice Deficient in CD4+ T Cell IL-4Rα Expression Control Leishmania mexicana Load although Female but Not Male Mice Develop a Healer Phenotype

Immunologically intact BALB/c mice infected with Leishmania mexicana develop non-healing progressively growing lesions associated with a biased Th2 response while similarly infected IL-4Rα-deficient mice fail to develop lesions and develop a robust Th1 response. In order to determine the functional target(s) for IL-4/IL-13 inducing non-healing disease, the course of L. mexicana infection was monitored in mice lacking IL-4Rα expression in specific cellular compartments. A deficiency of IL-4Rα expression on macrophages/neutrophils (in LysMcreIL-4Rα−/lox animals) had minimal effect on the outcome of L. mexicana infection compared with control (IL-4Rα−/flox) mice. In contrast, CD4+ T cell specific (LckcreIL-4Rα−/lox) IL-4Rα−/− mice infected with L. mexicana developed small lesions, which subsequently healed in female mice, but persisted in adult male mice. While a strong Th1 response was manifest in both male and female CD4+ T cell specific IL-4Rα−/− mice infected with L. mexicana, induction of IL-4 was manifest in males but not females, independently of CD4+ T cell IL-4 responsiveness. Similar results were obtained using pan-T cell specific (iLckcreIL-4Rα−/lox) IL-4Rα−/− mice. Collectively these data demonstrate that upon infection with L. mexicana, initial lesion growth in BALB/c mice is dependent on non-T cell population(s) responsive to IL-4/IL-13 while progressive infection is dependent on CD4+ T cells responsive to IL-4

Mutation analysis of the NSD1 gene in patients with autism spectrum disorders and macrocephaly

<p>Abstract</p> <p>Background</p> <p>Sotos syndrome is an overgrowth syndrome characterized by macrocephaly, advanced bone age, characteristic facial features, and learning disabilities, caused by mutations or deletions of the <it>NSD1 </it>gene, located at 5q35. Sotos syndrome has been described in a number of patients with autism spectrum disorders, suggesting that <it>NSD1 </it>could be involved in other cases of autism and macrocephaly.</p> <p>Methods</p> <p>We screened the <it>NSD1 </it>gene for mutations and deletions in 88 patients with autism spectrum disorders and macrocephaly (head circumference 2 standard deviations or more above the mean). Mutation analysis was performed by direct sequencing of all exons and flanking regions. Dosage analysis of <it>NSD1 </it>was carried out using multiplex ligation-dependent probe amplification.</p> <p>Results</p> <p>We identified three missense variants (R604L, S822C and E1499G) in one patient each, but none is within a functional domain. In addition, segregation analysis showed that all variants were inherited from healthy parents and in two cases were also present in unaffected siblings, indicating that they are probably nonpathogenic. No partial or whole gene deletions/duplications were observed.</p> <p>Conclusion</p> <p>Our findings suggest that Sotos syndrome is a rare cause of autism spectrum disorders and that screening for <it>NSD1 </it>mutations and deletions in patients with autism and macrocephaly is not warranted in the absence of other features of Sotos syndrome.</p