The state of integrated disease surveillance in seven countries: a synthesis report.

OBJECTIVES: Integrated disease surveillance (IDS) offers the potential for better use of surveillance data to guide responses to public health threats. However, the extent of IDS implementation worldwide is unknown. This study sought to understand how IDS is operationalized, identify implementation challenges and barriers, and identify opportunities for development. STUDY DESIGN: Synthesis of qualitative studies undertaken in seven countries. METHODS: Thirty-four focus group discussions and 48 key informant interviews were undertaken in Pakistan, Mozambique, Malawi, Uganda, Sweden, Canada, and England, with data collection led by the respective national public health institutes. Data were thematically analysed using a conceptual framework that covered governance, system and structure, core functions, finance and resourcing requirements. Emerging themes were then synthesised across countries for comparisons. RESULTS: None of the countries studied had fully integrated surveillance systems. Surveillance was often fragmented, and the conceptualization of integration varied. Barriers and facilitators identified included: 1) the need for clarity of purpose to guide integration activities; 2) challenges arising from unclear or shared ownership; 3) incompatibility of existing IT systems and surveillance infrastructure; 4) workforce and skills requirements; 5) legal environment to facilitate data sharing between agencies; and 6) resourcing to drive integration. In countries dependent on external funding, the focus on single diseases limited integration and created parallel systems. CONCLUSIONS: A plurality of surveillance systems exists globally with varying levels of maturity. While development of an international framework and standards are urgently needed to guide integration efforts, these must be tailored to country contexts and guided by their overarching purpose.

Spatially resolved diagnostics for optimization of large ion beam sources.

Giant negative ion sources for neutral beam injectors deliver huge negative ion currents, thanks to their multi-beamlet configuration. As the single-beamlet optics defines the transmission losses along the beamline, the extraction of a similar current for all beamlets is extremely desirable, in order to facilitate the beam source operation (i.e., around perveance match). This Review investigates the correlation between the vertical profile of beam intensity and the vertical profiles of plasma properties at the extraction region of the source, focusing on the influence of increasing cesium injection. Only by the combined use of all available source diagnostics, described in this Review, can beam features on the scale of the non-uniformities be investigated with a sufficient space resolution. At RF power of 50 kW/driver, with intermediate bias currents and a filter field of 2.4 mT, it is found that the central part of the four vertical beam segments exhibits comparable plasma density and beamlet currents; at the edges of the central segments, both the beam and electron density appear to decrease (probably maintaining fixed electron-to-ion ratio); at the bottom of the source, an increase of cesium injection can compensate for the vertical drifts that cause a much higher presence of electrons and a lower amount of negative ions.

Safety of thoracic radiotherapy in patients with prior immune-related adverse events from immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) and thoracic radiotherapy are increasingly used to treat advanced cancers. Despite data indicating exaggerated radiation toxicities in patients with autoimmune disease, the safety of thoracic radiotherapy in patients with prior ICI-associated immune-related adverse events (irAEs) is undefined. PATIENTS AND METHODS: Patients treated from 2014 to 2020 with ICIs were queried for receipt of corticosteroids and radiotherapy. Patients who received thoracic radiation after symptomatic irAEs were assessed for ≥grade 2 radiation pneumonitis (RP). Characteristics predictive of RP were assessed using logistic regression and response relationships were modeled. RESULTS: Among 496 assessed patients, 41 with irAE history subsequently treated with thoracic radiotherapy were analyzed. Most irAEs were grade 2 (n = 21) and 3 (n = 19). Median time from irAE onset to radiotherapy was 8.1 months. Most patients received stereotactic body radiation therapy (n = 20) or hypofractionated radiotherapy (n = 18). In total, 25 patients (61%) developed ≥grade 2 RP at a median of 4 months from radiotherapy and 11 months from onset of irAEs. Three months from RP onset, 16 of 24 (67%) assessable patients had persistent symptoms. Among patients with prior ICI pneumonitis (n = 6), five patients (83%) developed ≥grade 2 RP (grade 2, n = 3; grade ≥3, n = 2). The mean lung radiation dose (MLD) predicted for RP (odds ratio: 1.60, P = 0.00002). The relationship between MLD and RP was strong (area under the receiver-operating characteristic curve: 0.85) and showed an exaggerated dose-response. Among patients with an MLD >5 Gy (n = 26), 21 patients (81%) developed ≥grade 2 RP. CONCLUSION: This is the first study assessing the toxicity of radiotherapy among patients with prior irAEs from ICIs. Patients with prior irAEs were found to be at very high risk for clinically significant and persistent RP from thoracic radiotherapy. Careful consideration should be given to the possibility of an increased risk of RP, and close monitoring is recommended in these patients.

Tracking the Migraine Cycle Using Visual Tasks.

There are a number of reports that perceptual, electrophysiological and imaging measures can track migraine periodicity. As the electrophysiological and imaging research requires specialist equipment, it has few practical applications. This study sought to track changes in performance on four visual tasks over the migraine cycle. Coherence thresholds were measured for two motion and two orientation tasks. The first part of the study confirmed that the data obtained from an online study produced comparable results to those obtained under controlled laboratory conditions. Thirteen migraine with aura, 12 without aura, and 12 healthy controls participated. The second part of the study showed that thresholds for discriminating vertical coherent motion varied with the migraine cycle for a majority of the participants who tested themselves multiple times (four with aura, seven without). Performance improved two days prior to a migraine attack and remained improved for two days afterwards. This outcome is as expected from an extrapolation of earlier electrophysiological research. This research points to the possibility of developing sensitive visual tests that patients can use at home to predict an impending migraine attack and so take steps to try to abort it or, if it is inevitable, to plan their lives around it.

Modifications to a Vitis Shoot Tip Cryopreservation Procedure: Effect of Shoot Tip Size and Use of Cryoplates.

BACKGROUND: Cryopreservation has been considered a preferred method for the long-term storage of plant germplasm, especially to efficiently conserve and maintain the genetic integrity of genebank materials. Droplet-vitrification (DV) procedures have been developed to cryopreserve Vitis shoot tips from in vitro-grown plants. OBJECTIVE: This research focused on optimizing shoot tip sizes for DV and the feasibility of using cryo-plates for Vitis cryopreservation. MATERIALS AND METHODS: Uniform shoot tips were obtained from nodal sections cultured from in vitro-grown stock plants of Vitis aestivalis and Vitis jacquemontii (PI 135726). Shoot tips were precultured for 3 days on medium containing 0.3 M sucrose, salicylic acid, glutathione (reduced form), and ascorbic acid. They were cryopreserved using either DV on aluminum foil strips or by placement in calcium alginate gel in the wells of aluminium cryo-plates (V cryo-plate method). Shoot tips were then treated with loading solution followed by PVS2 treatment prior to liquid nitrogen (LN) exposure. Shoot tips were warmed in unloading solution and placed on recovery medium. The effect of extraction or non-extraction of the cryopreserved shoot tips from alginate beads was also tested. RESULTS: The highest regrowth levels of cryopreserved shoot tips were obtained using 1 mm shoot tips and a PVS2 exposure for 90 min at 0°C with the DV method on aluminum foil strips or by using 30 min of PVS2 at 22°C using V cryo-plates. CONCLUSION: Shoot tip size is an important factor in the cryopreservability of Vitis shoot tips; 1 mm shoot tips were the most successful for the DV cryopreservation method that was tested. In addition, the V cryo-plate cryopreservation technique described herein can be easily executed and results in high regrowth levels (≥70%) with quality plants obtained from cryo-exposed shoot tips, making it a practical and promising Vitis cryopreservation methodology.

Effectiveness of fascial closure technique following percutaneous endovascular aneurysm repair.

INTRODUCTION: Percutaneous access and closure is commonly performed for patients undergoing endovascular aneurysm repair (EVAR). It has proven to be a safe and successful method of closure associated with fewer complications when compared with the traditional open technique. Fascial closure is an alternative technique that can be used for closure reducing the risks associated with the open technique. The aim of this study was to assess the safety and durability of fascial closure for failed percutaneous closure device following EVAR. MATERIALS AND METHODS: Over a 12-month period, 49 patients who had undergone EVAR were identified via our EVAR register. Retrospective analysis of the clinical records was undertaken. We identified all the patients who had fascial closure of the groins following a failed percutaneous closure device. Patients had a computed tomography angiogram one month postoperatively, with duplex imaging and clinic follow-up three months later. RESULTS: Fascial closure was performed in 14 groins. It failed in three groins and these patients had traditional open repair. Fascial closure was successful in 11 groins (7 patients). Of these seven patients, one was female (6%). The mean age was 80 years (range 68-92 years). Two patients died and one was lost to follow-up. One pseudoaneurysms were seen on computed tomography angiogram, which was managed conservatively and had resolved on follow-up imaging. CONCLUSIONS: Fascial closure is a very good alternative to open repair after failure of the closure device.

Parathyroid hormone-related peptide activates and modulates TRPV1 channel in human DRG neurons.

Parathyroid hormone-related peptide (PTHrP) is associated with advanced tumor growth and metastasis, especially in breast, prostate and myeloma cancers that metastasize to bones, resulting in debilitating chronic pain conditions. Our recent studies revealed that the receptor for PTHrP, PTH1R, is expressed in mouse DRG sensory neurons, and its activation leads to flow-activation and modulation of TRPV1 channel function, resulting in peripheral heat and mechanical hypersensitivity. In order to verify the translatability of our findings in rodents to humans, we explored whether this signalling axis operates in primary human DRG sensory neurons. Analysis of gene expression data from recently reported RNA deep sequencing experiments performed on mouse and human DRGs reveals that PTH1R is expressed in DRG and tibial nerve. Furthermore, exposure of cultured human DRG neurons to PTHrP leads to slow-sustained activation of TRPV1 and modulation of capsaicin-induced channel activation. Both activation and modulation of TRPV1 by PTHrP were dependent on PKC activity. Our findings suggest that functional PTHrP/PTH1R-TRPV1 signalling exists in human DRG neurons, which could contribute to local nociceptor excitation in the vicinity of metastatic bone tumor microenvironment.

Successful Cryopreservation of Vitis Shoot Tips: Novel Pre-treatment Combinations Applied to Nine Species.

BACKGROUND: Secure back-up of Vitis genetic resource collections requires cryopreservation methods that give long-term survival of clonal germplasm having diverse genetic backgrounds. OBJECTIVE: This work sought to increase survival of Vitis shoot tips exposed to liquid nitrogen using combinations of pretreatments and cryoprotection procedures. The new procedure should give high survival of shoot tips from a wide range of Vitis species. MATERIALS AND METHODS: In vitro plants from nine Vitis species were used as source material for nodal sections. Shoot tips were then excised from nodal sections that were grown on medium containing benzyladenine, salicylic acid, glutathione, and ascorbic acid. The shoot tips were treated with loading solution, and then half-strength PVS2 for 30 minutes, prior to full-strength PVS2 treatments for between 60 and 90 minutes prior to liquid nitrogen (LN) exposure. RESULTS: Shoot tip regrowth levels were highest 90 minutes in PVS2+LN and ranged from 24-43% and averaged 35±2% across the nine Vitis species. CONCLUSION: The pretreatment, cryopreservation, and recovery methods yielded successful regrowth for multiple Vitis species using a droplet-vitrification procedure.

Truncal varicose vein diameter and patient-reported outcome measures.

BACKGROUND: Varicose veins and chronic venous disease are common, and some funding bodies ration treatment based on a minimum diameter of the incompetent truncal vein. This study assessed the effect of maximum vein diameter on clinical status and patient symptoms. METHODS: A prospective observational cohort study of patients presenting with symptomatic varicose veins to a tertiary referral public hospital vascular clinic between January 2011 and July 2012. Patients underwent standardized assessment with venous duplex ultrasonography, and completed questionnaires assessing quality of life (QoL) and symptoms (Aberdeen Varicose Vein Questionnaire, EuroQol Five Domain QoL assessment and EuroQol visual analogue scale). Clinical scores (Venous Clinical Severity Score (VCSS) and Clinical Etiologic Anatomic Pathophysiologic (CEAP) class) were also calculated. Regression analysis was used to investigate the relationship between QoL, symptoms and vein diameter. RESULTS: Some 330 patients were assessed before surgery. The median maximum vein diameter was 7·0 (i.q.r. 5·3-9·2) mm overall, 7·9 (6·0-9·8) mm for great saphenous vein and 6·0 (5·2-8·9) mm for small saphenous vein. In linear regression analysis, vein diameter was shown to have a significant association with VCSS (P = 0·041). For every 1-mm increase in vein diameter, there was a 2·75-fold increase in risk of being in CEAP class C4 compared with C2. No other QoL or symptom measures were related to vein diameter. CONCLUSION: Incompetent truncal vein diameter was associated with increasing VCSS, but not a variety of other varicose vein disease-specific and generic patient-reported outcome measures.

Veterans with post-traumatic stress disorder exhibit altered emotional processing and attentional control during an emotional Stroop task.

BACKGROUND: Post-traumatic stress disorder (PTSD) is often associated with attention allocation and emotional regulation difficulties, but the brain dynamics underlying these deficits are unknown. The emotional Stroop task (EST) is an ideal means to monitor these difficulties, because participants are asked to attend to non-emotional aspects of the stimuli. In this study, we used magnetoencephalography (MEG) and the EST to monitor attention allocation and emotional regulation during the processing of emotionally charged stimuli in combat veterans with and without PTSD. METHOD: A total of 31 veterans with PTSD and 20 without PTSD performed the EST during MEG. Three categories of stimuli were used, including combat-related, generally threatening and neutral words. MEG data were imaged in the time-frequency domain and the network dynamics were probed for differences in processing threatening and non-threatening words. RESULTS: Behaviorally, veterans with PTSD were significantly slower in responding to combat-related relative to neutral and generally threatening words. Veterans without PTSD exhibited no significant differences in responding to the three different word types. Neurophysiologically, we found a significant three-way interaction between group, word type and time period across multiple brain regions. Follow-up testing indicated stronger theta-frequency (4-8 Hz) responses in the right ventral prefrontal (0.4-0.8 s) and superior temporal cortices (0.6-0.8 s) of veterans without PTSD compared with those with PTSD during the processing of combat-related words. CONCLUSIONS: Our data indicated that veterans with PTSD exhibited deficits in attention allocation and emotional regulation when processing trauma cues, while those without PTSD were able to regulate emotion by directing attention away from threat.

A 3 year minimum follow up of Endoprosthetic replacement for distal femoral fractures - An alternative treatment option.

INTRODUCTION: Although the use of an endoprosthesis for distal femoral fractures remains a valid treatment option the widespread use is in its infancy. METHODOLOGY: In this retrospective case series, we review cases of distal femoral fracture treated with endoprosthetic replacement (EPR). The outcomes we assessed were the time to start mobilising, the time to discharge, morbidity and mortality as well as an Oxford knee score to assess pain and function and also the early survivorship. 6 of the 11 from the cohort had existing Total Knee Replacements (TKRs) in situ. RESULTS: There were 11 knees in our cohort with a mean age of 81.5 years (range 52-102 years). The median time to follow up was 3.5 years (range 1.6 to 5.5 years). The median times to theatre was 3 days and to discharge was 16 days. Oxford functional and pain scores were 32/48. DISCUSSION: In the appropriate patient and fracture pattern, Endoprosthetic knee replacement is an excellent option in the treatment of distal femoral fractures whether associated with an existing TKR or not. The implant is more costly than traditional open reduction and internal fixation, but the earlier return to full mobility post-operatively may save on hospital/care home stay and free up hospital space and minimise complications.

The North Wyke Farm Platform: effect of temperate grassland farming systems on soil moisture contents, runoff and associated water quality dynamics.

The North Wyke Farm Platform was established as a United Kingdom national capability for collaborative research, training and knowledge exchange in agro-environmental sciences. Its remit is to research agricultural productivity and ecosystem responses to different management practices for beef and sheep production in lowland grasslands. A system based on permanent pasture was implemented on three 21-ha farmlets to obtain baseline data on hydrology, nutrient cycling and productivity for 2 years. Since then two farmlets have been modified by either (i) planned reseeding with grasses that have been bred for enhanced sugar content or deep-rooting traits or (ii) sowing grass and legume mixtures to reduce nitrogen fertilizer inputs. The quantities of nutrients that enter, cycle within and leave the farmlets were evaluated with data recorded from sensor technologies coupled with more traditional field study methods. We demonstrate the potential of the farm platform approach with a case study in which we investigate the effects of the weather, field topography and farm management activity on surface runoff and associated pollutant or nutrient loss from soil. We have the opportunity to do a full nutrient cycling analysis, taking account of nutrient transformations in soil, and flows to water and losses to air. The NWFP monitoring system is unique in both scale and scope for a managed land-based capability that brings together several technologies that allow the effect of temperate grassland farming systems on soil moisture levels, runoff and associated water quality dynamics to be studied in detail. HIGHLIGHTS: Can meat production systems be developed that are productive yet minimize losses to the environment?The data are from an intensively instrumented capability, which is globally unique and topical.We use sensing technologies and surveys to show the effect of pasture renewal on nutrient losses.Platforms provide evidence of the effect of meteorology, topography and farm activity on nutrient loss.

Translational Assays for Assessment of Cognition in Rodent Models of Alzheimer's Disease and Dementia.

Cognitive dysfunction appears as a core feature of dementia, which includes its most prevalent form, Alzheimer's disease (AD), as well as vascular dementia, frontotemporal dementia, and other brain disorders. AD alone affects more than 45 million people worldwide, with growing prevalence in aging populations. There is no cure, and therapeutic options remain limited. Gene-edited and transgenic animal models, expressing disease-specific gene mutations, illuminate pathogenic mechanisms leading to cognitive decline in AD and other forms of dementia. To date, cognitive tests in AD mouse models have not been directly relevant to the clinical presentation of AD, providing challenges for translation of findings to the clinic. Touchscreen testing in mice has enabled the assessment of specific cognitive domains in mice that are directly relevant to impairments described in human AD patients. In this review, we provide context for how cognitive decline is measured in the clinic, describe traditional methods for assessing cognition in mice, and outline novel approaches, including the use of the touchscreen platform for cognitive testing. We highlight the limitations of traditional memory-testing paradigms in mice, particularly their capacity for direct translation into cognitive testing of patients. While it is not possible to expect direct translation in testing methodologies, we can aim to develop tests that engage similar neural substrates in both humans and mice. Ultimately, that would enable us to better predict efficacy across species and therefore improve the chances that a treatment that works in mice will also work in the clinic.

How much do we know about schizophrenia and how well do we know it? Evidence from the Schizophrenia Library.

BACKGROUND: True findings about schizophrenia remain elusive; many findings are not replicated and conflicting results are common. Well-conducted systematic reviews have the ability to make robust, generalizable conclusions, with good meta-analyses potentially providing the closest estimate of the true effect size. In this paper, we undertake a systematic approach to synthesising the available evidence from well-conducted systematic reviews on schizophrenia. METHOD: Reviews were identified by searching Medline, EMBASE, CINAHL, Current Contents and PsycINFO. The decision to include or exclude reviews, data extraction and quality assessments were conducted in duplicate. Evidence was graded as high quality if reviews contained large samples and robust results; and as moderate quality if reviews contained imprecision, inconsistency, smaller samples or study designs that may be prone to bias. RESULTS: High- and moderate-quality evidence shows that numerous psychosocial and biomedical treatments are effective. Patients have relatively poor cognitive functioning, and subtle, but diverse, structural brain alterations, altered electrophysiological functioning and sleep patterns, minor physical anomalies, neurological soft signs, and sensory alterations. There are markers of infection, inflammation or altered immunological parameters; and there is increased mortality from a range of causes. Risk for schizophrenia is increased with cannabis use, pregnancy and birth complications, prenatal exposure to Toxoplasma gondii, childhood central nervous system viral infections, childhood adversities, urbanicity and immigration (first and second generation), particularly in certain ethnic groups. Developmental motor delays and lower intelligence quotient in childhood and adolescence are apparent. CONCLUSIONS: We conclude that while our knowledge of schizophrenia is very substantial, our understanding of it remains limited.

Localization and expression of CaBP1/caldendrin in the mouse brain.

Ca(2+) binding protein 1 (CaBP1) and caldendrin are alternatively spliced variants of a subfamily of CaBPs with high homology to calmodulin. Although CaBP1 and caldendrin regulate effectors including plasma membrane and intracellular Ca(2+) channels in heterologous expression systems, little is known about their functions in vivo. Therefore, we generated mice deficient in CaBP1/caldendrin expression (C-KO) and analyzed the expression and cellular localization of CaBP1 and caldendrin in the mouse brain. Immunoperoxidase labeling with antibodies recognizing both CaBP1 and caldendrin was absent in the brain of C-KO mice, but was intense in multiple brain regions of wild-type mice. By Western blot, the antibodies detected two proteins that were absent in the C-KO mouse and consistent in size with caldendrin variants originating from alternative translation initiation sites. By quantitative PCR, caldendrin transcript levels were far greater than those for CaBP1, particularly in the cerebral cortex and hippocampus. In the frontal cortex but not in the hippocampus, caldendrin expression increased steadily from birth. By double-label immunofluorescence, CaBP1/caldendrin was localized in principal neurons and parvalbumin-positive interneurons. In the cerebellum, CaBP1/caldendrin antibodies labeled interneurons in the molecular layer and in basket cell terminals surrounding the soma and axon initial segment of Purkinje neurons, but immunolabeling was absent in Purkinje neurons. We conclude that CaBP1/caldendrin is localized both pre- and postsynaptically where it may regulate Ca(2+) signaling and excitability in select groups of excitatory and inhibitory neurons.

The molecular genetic analysis of the expanding pachyonychia congenita case collection.

BACKGROUND: Pachyonychia congenita (PC) is a rare autosomal dominant keratinizing disorder characterized by severe, painful, palmoplantar keratoderma and nail dystrophy, often accompanied by oral leucokeratosis, cysts and follicular keratosis. It is caused by mutations in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16 or KRT17. OBJECTIVES: To identify mutations in 84 new families with a clinical diagnosis of PC, recruited by the International Pachyonychia Congenita Research Registry during the last few years. METHODS: Genomic DNA isolated from saliva or peripheral blood leucocytes was amplified using primers specific for the PC-associated keratin genes and polymerase chain reaction products were directly sequenced. RESULTS: Mutations were identified in 84 families in the PC-associated keratin genes, comprising 46 distinct keratin mutations. Fourteen were previously unreported mutations, bringing the total number of different keratin mutations associated with PC to 105. CONCLUSIONS: By identifying mutations in KRT6A, KRT6B, KRT6C, KRT16 or KRT17, this study has confirmed, at the molecular level, the clinical diagnosis of PC in these families.

Visual disturbance following sclerotherapy for varicose veins, reticular veins and telangiectasias: a systematic literature review.

The objective of the study was to review the literature reporting visual disturbance (VD)following sclerotherapy for varicose veins. Underlying mechanisms will be discussed. A literature search of the databases Medline and Google Scholar was performed. Original articles including randomized trials, case series and case reports reporting VD in humans following sclerotherapy for varicose veins were included. Additional references were also obtained if they had been referenced in related publications. The search yielded 4948 results of which 25 reports were found to meet the inclusion criteria. In larger series with at least 500 included patients the prevalence of VD following sclerotherapy ranges from 0.09% to 2%. In most reports foam sclerotherapy was associated with VD (19); exclusive use of liquid sclerosant was reported in two cases, some reports included foam and liquid sclerosant (4). There were no persistent visual disorders reported. VD occurred with polidocanol and sodium tetradecyl sulphate in different concentrations (0.25­3%). Various forms of foam preparation including various ways of foam production and the liquid ­air ratio (1 or 2 parts of liquid mixed with 3, 4 or 5 parts of air) were reported in association with the occurrence of VD. VDs following sclerotherapy for varicose veins are rare and all reported events were transient. Bubble embolism or any kind of embolism seems unlikely to be the only underlying mechanism. A systemic inflammatory response following sclerotherapy has been suggested. Further research to clarify the mechanism of action of sclerosants is required.

Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction.

Autism spectrum disorders (ASDs) have been suggested to arise from abnormalities in the canonical and non-canonical Wnt signaling pathways. However, a direct connection between a human variant in a Wnt pathway gene and ASD-relevant brain pathology has not been established. Prickle2 (Pk2) is a post-synaptic non-canonical Wnt signaling protein shown to interact with post-synaptic density 95 (PSD-95). Here, we show that mice with disruption in Prickle2 display behavioral abnormalities including altered social interaction, learning abnormalities and behavioral inflexibility. Prickle2 disruption in mouse hippocampal neurons led to reductions in dendrite branching, synapse number and PSD size. Consistent with these findings, Prickle2 null neurons show decreased frequency and size of spontaneous miniature synaptic currents. These behavioral and physiological abnormalities in Prickle2 disrupted mice are consistent with ASD-like phenotypes present in other mouse models of ASDs. In 384 individuals with autism, we identified two with distinct, heterozygous, rare, non-synonymous PRICKLE2 variants (p.E8Q and p.V153I) that were shared by their affected siblings and inherited paternally. Unlike wild-type PRICKLE2, the PRICKLE2 variants found in ASD patients exhibit deficits in morphological and electrophysiological assays. These data suggest that these PRICKLE2 variants cause a critical loss of PRICKLE2 function. The data presented here provide new insight into the biological roles of Prickle2, its behavioral importance, and suggest disruptions in non-canonical Wnt genes such as PRICKLE2 may contribute to synaptic abnormalities underlying ASDs.