High-throughput Oligopaint screen identifies druggable 3D genome regulators.

The human genome functions as a three-dimensional chromatin polymer, driven by a complex collection of chromosome interactions1-3. Although the molecular rules governing these interactions are being quickly elucidated, relatively few proteins regulating this process have been identified. Here, to address this gap, we developed high-throughput DNA or RNA labelling with optimized Oligopaints (HiDRO)-an automated imaging pipeline that enables the quantitative measurement of chromatin interactions in single cells across thousands of samples. By screening the human druggable genome, we identified more than 300 factors that influence genome folding during interphase. Among these, 43 genes were validated as either increasing or decreasing interactions between topologically associating domains. Our findings show that genetic or chemical inhibition of the ubiquitous kinase GSK3A leads to increased long-range chromatin looping interactions in a genome-wide and cohesin-dependent manner. These results demonstrate the importance of GSK3A signalling in nuclear architecture and the use of HiDRO for identifying mechanisms of spatial genome organization.

Reproductive outcome in 326 women with unicornuate uterus.

OBJECTIVES: To study the reproductive outcomes of women with a unicornuate uterus and compare them to those of women with no congenital uterine anomaly. METHODS: This was a single-center, retrospective cohort study. Cases were women aged at least 16 years who were diagnosed with a unicornuate uterus on transvaginal/transrectal ultrasound between January 2008 and September 2021. Controls were women with no congenital uterine anomaly matched 1:1 by age and body mass index. The primary outcome was live-birth rate. Secondary outcomes were pregnancy loss (miscarriage, ectopic pregnancy, termination of pregnancy), preterm delivery, mode of delivery and concomitant gynecological abnormalities (endometriosis, adenomyosis, fibroids). RESULTS: Included in the study were 326 cases and 326 controls. Women with a unicornuate uterus had a significantly lower live-birth rate (184/388 (47.4%) vs 229/396 (57.8%); P = 0.004) and higher rates of overall miscarriage (178/424 (42.0%) vs 155/465 (33.3%); adjusted odds ratio (aOR), 2.21 (95% CI, 1.42-3.42), P < 0.001), ectopic pregnancy (26/424 (6.1%) vs 11/465 (2.4%); aOR, 2.52 (95% CI, 1.22-5.22), P = 0.01), preterm delivery (45/184 (24.5%) vs 17/229 (7.4%); aOR, 3.04 (95% CI, 1.52-5.97), P = 0.001) and Cesarean delivery (116/184 (63.0%) vs 70/229 (30.6%); aOR, 2.54 (95% CI, 1.67-3.88), P < 0.001). Rudimentary-horn pregnancies accounted for 7/26 (26.9%) ectopic pregnancies in the study group. Women with a unicornuate uterus were more likely to have endometriosis (17.5% vs 10.7%; P = 0.018) and adenomyosis (26.7% vs 15.6%; P = 0.001), but were not more likely to have fibroids compared with controls. Women with a functional rudimentary horn were more likely to have pelvic endometriosis compared to those without (odds ratio, 2.4 (95% CI, 1.4-4.1), P = 0.002). CONCLUSIONS: Pregnant women with a unicornuate uterus should be classified as high risk. Removal of a functional rudimentary horn should be discussed with the patient to prevent a rudimentary-horn ectopic pregnancy. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

The Family Level Assessment of Screen Use-Mobile Approach: Development of an Approach to Measure Children's Mobile Device Use.

BACKGROUND: There is a strong association between increased mobile device use and worse dietary habits, worse sleep outcomes, and poor academic performance in children. Self-report or parent-proxy report of children's screen time has been the most common method of measuring screen time, which may be imprecise or biased. OBJECTIVE: The objective of this study was to assess the feasibility of measuring the screen time of children on mobile devices using the Family Level Assessment of Screen Use (FLASH)-mobile approach, an innovative method that leverages the existing features of the Android platform. METHODS: This pilot study consisted of 2 laboratory-based observational feasibility studies and 2 home-based feasibility studies in the United States. A total of 48 parent-child dyads consisting of a parent and child aged 6 to 11 years participated in the pilot study. The children had to have their own or shared Android device. The laboratory-based studies included a standardized series of tasks while using the mobile device or watching television, which were video recorded. Video recordings were coded by staff for a gold standard comparison. The home-based studies instructed the parent-child dyads to use their mobile device as they typically use it over 3 days. Parents received a copy of the use logs at the end of the study and completed an exit interview in which they were asked to review their logs and share their perceptions and suggestions for the improvement of the FLASH-mobile approach. RESULTS: The final version of the FLASH-mobile approach resulted in user identification compliance rates of >90% for smartphones and >80% for tablets. For laboratory-based studies, a mean agreement of 73.6% (SD 16.15%) was achieved compared with the gold standard (human coding of video recordings) in capturing the target child's mobile use. Qualitative feedback from parents and children revealed that parents found the FLASH-mobile approach useful for tracking how much time their child spends using the mobile device as well as tracking the apps they used. Some parents revealed concerns over privacy and provided suggestions for improving the FLASH-mobile approach. CONCLUSIONS: The FLASH-mobile approach offers an important new research approach to measure children's use of mobile devices more accurately across several days, even when the child shares the device with other family members. With additional enhancement and validation studies, this approach can significantly advance the measurement of mobile device use among young children.

3D genome, on repeat: Higher-order folding principles of the heterochromatinized repetitive genome.

Nearly half of the human genome is comprised of diverse repetitive sequences ranging from satellite repeats to retrotransposable elements. Such sequences are susceptible to stepwise expansions, duplications, inversions, and recombination events which can compromise genome function. In this review, we discuss the higher-order folding mechanisms of compartmentalization and loop extrusion and how they shape, and are shaped by, heterochromatin. Using primarily mammalian model systems, we contrast mechanisms governing H3K9me3-mediated heterochromatinization of the repetitive genome and highlight emerging links between repetitive elements and chromatin folding.

Cohesin-mediated loop anchors confine the locations of human replication origins.

DNA replication occurs through an intricately regulated series of molecular events and is fundamental for genome stability1,2. At present, it is unknown how the locations of replication origins are determined in the human genome. Here we dissect the role of topologically associating domains (TADs)3-6, subTADs7 and loops8 in the positioning of replication initiation zones (IZs). We stratify TADs and subTADs by the presence of corner-dots indicative of loops and the orientation of CTCF motifs. We find that high-efficiency, early replicating IZs localize to boundaries between adjacent corner-dot TADs anchored by high-density arrays of divergently and convergently oriented CTCF motifs. By contrast, low-efficiency IZs localize to weaker dotless boundaries. Following ablation of cohesin-mediated loop extrusion during G1, high-efficiency IZs become diffuse and delocalized at boundaries with complex CTCF motif orientations. Moreover, G1 knockdown of the cohesin unloading factor WAPL results in gained long-range loops and narrowed localization of IZs at the same boundaries. Finally, targeted deletion or insertion of specific boundaries causes local replication timing shifts consistent with IZ loss or gain, respectively. Our data support a model in which cohesin-mediated loop extrusion and stalling at a subset of genetically encoded TAD and subTAD boundaries is an essential determinant of the locations of replication origins in human S phase.

Laryngopharyngeal reflux: is laparoscopic fundoplication an effective treatment?

INTRODUCTION: Laryngopharyngeal reflux (LPR) is difficult to diagnose and treat owing to uncertainty relating to the underlying pathology. The initial management of LPR includes lifestyle modifications and oral medications. In patients who have failed to respond to proton pump inhibitor (PPI) therapy, anti-reflux surgery is considered; laparoscopic fundoplication is the surgery of choice. The primary aim of this review is to identify whether fundoplication is effective in improving signs and symptoms of LPR. The secondary aim is to identify whether patients who have had a poor response to PPIs are likely to have symptom improvement with surgery. The objective of the study is to establish the effect of laparoscopic fundoplication on the reflux symptom index score (RSI). METHODS: PubMed, Embase, Medline and Cochrane databases were used to search according to the PRISMA guidelines. Original articles assessing the efficacy of fundoplication in relieving symptoms of LPR were included. For each study, the efficacy endpoints and safety outcomes were recorded. FINDINGS: Nine studies from 844 initial records met the inclusion criteria: one prospective case control study, one retrospective case-control study, four prospective case series and three retrospective case series involving 287 fundoplications. All nine studies found fundoplication to be effective in improving symptoms of LPR (p < 0.05). CONCLUSION: Current evidence suggests laparoscopic fundoplication is an effective treatment for LPR and should be considered if medical management is unsuccessful.

Laryngopharyngeal reflux: is laparoscopic fundoplication an effective treatment?

INTRODUCTION: Laryngopharyngeal reflux (LPR) is difficult to diagnose and treat owing to uncertainty relating to the underlying pathology. The initial management of LPR includes lifestyle modifications and oral medications. In patients who have failed to respond to proton pump inhibitor (PPI) therapy, anti-reflux surgery is considered; laparoscopic fundoplication is the surgery of choice. The primary aim of this review is to identify whether fundoplication is effective in improving signs and symptoms of LPR. The secondary aim is to identify whether patients who have had a poor response to PPIs are likely to have symptom improvement with surgery. The objective of the study is to establish the effect of laparoscopic fundoplication on the reflux symptom index score (RSI). METHODS: PubMed, Embase, Medline and Cochrane databases were used to search according to the PRISMA guidelines. Original articles assessing the efficacy of fundoplication in relieving symptoms of LPR were included. For each study, the efficacy endpoints and safety outcomes were recorded. FINDINGS: Nine studies from 844 initial records met the inclusion criteria: one prospective case control study, one retrospective case-control study, four prospective case series and three retrospective case series involving 287 fundoplications. All nine studies found fundoplication to be effective in improving symptoms of LPR (p < 0.05). CONCLUSION: Current evidence suggests laparoscopic fundoplication is an effective treatment for LPR and should be considered if medical management is unsuccessful.

COVID-19 testing in outbreak-free care homes: what are the public health benefits?

BACKGROUND: COVID-19 care home outbreaks represent a significant proportion of COVID-19 morbidity and mortality in the UK. National testing initially focused on symptomatic care home residents, before extending to asymptomatic cohorts. AIM: The aim was to describe the epidemiology and transmission of COVID-19 in outbreak free care homes. METHODS: A two-point prevalence survey of COVID-19, in 34 Liverpool care homes, was performed in April and May 2020. Changes in prevalence were analysed. Associations between care home characteristics, reported infection, prevention and control interventions, and COVID-19 status were described and analysed. FINDINGS: No resident developed COVID-19 symptoms during the study. There was no significant difference between: the number of care homes containing at least one test positive resident between the first (17.6%, 95% confidence interval (CI) 6.8-34.5) and second round (14.7%, 95% CI 5.0-31.1) of testing (p>0.99); and the number of residents testing positive between the first (2.1%, 95% CI 1.2-3.4) and second round (1.0%, 95% CI 0.5-2.1) of testing (P=0.11). Care homes providing nursing care (risk ratio (RR) 7.99, 95% CI 1.1-57.3) and employing agency staff (RR 8.4, 95% CI 1.2-60.8) were more likely to contain test positive residents. Closing residents shared space was not associated with residents testing positive (RR 2.63, 95% CI 0.4-18.5). CONCLUSIONS: Asymptomatic COVID-19 care homes showed no evidence of disease transmission or development of outbreaks; suggesting that current infection prevention and control measures are effective in preventing transmission. Repeat testing at two to three weeks had limited or no public health benefits over regular daily monitoring of staff and residents for symptoms. These results should inform policies calling for regular testing of asymptomatic residents.

Rapid sensing of clinically relevant glutamine concentrations in human serum with metabolically engineered E. coli-based cell-free protein synthesis.

Bioavailable glutamine (Gln) is critical for metabolism, intestinal health, immune function, and cell signaling. Routine measurement of serum Gln concentrations could facilitate improved diagnosis and treatment of severe infections, anorexia nervosa, chronic kidney disease, diabetes, and cancer. Current methods for quantifying tissue Gln concentrations rely mainly on HPLC, which requires extensive sample preparation and expensive equipment. Consequently, patient Gln levels may be clinically underutilized. Cell-free protein synthesis (CFPS) is an emerging sensing platform with promising clinical applications, including detection of hormones, amino acids, nucleic acids, and other biomarkers. In this work, in vitro E. coli amino acid metabolism is engineered with methionine sulfoximine to inhibit glutamine synthetase and create a CFPS Gln sensor. The sensor features a strong signal-to-noise ratio and a detection range ideally suited to physiological Gln concentrations. Furthermore, it quantifies Gln concentration in the presence of human serum. This work demonstrates that CFPS reactions which harness the metabolic power of E. coli lysate may be engineered to detect clinically relevant analytes in human samples. This approach could lead to transformative point-of-care diagnostics and improved treatment regimens for a variety of diseases including cancer, diabetes, anorexia nervosa, chronic kidney disease, and severe infections.

Hydrofoam and oxygen headspace bioreactors improve cell-free therapeutic protein production yields through enhanced oxygen transport.

Protein therapeutics are powerful tools in the fight against diabetes, cancers, growth disorders, and many other debilitating diseases. However, availability is limited due to cost and complications of production from living organisms. To make life-saving protein therapeutics more available to the world, the possibility of magistral or point-of-care protein therapeutic production has gained focus. The recent invention and optimization of lyophilized "cell-free" protein synthesis reagents and its demonstrated ability to produce highly active versions of FDA-approved cancer therapeutics have increased its potential for low-cost, single-batch, magistral medicine. Here we present for the first time the concept of increased oxygen mass transfer in small-batch, cell-free protein synthesis (CFPS) reactions through air-water foams. These "hydrofoam" reactions increased CFPS yields by up to 100%. Contrary to traditional protein synthesis using living organisms, where foam bubbles cause cell-lysis and production losses, hydrofoam CFPS reactions are "cell-free" and better tolerate foaming. Simulation and experimental results suggest that oxygen transfer is limiting in even small volume batch CFPS reactors and that the hydrofoam format improved oxygen transfer. This is further supported by CFPS reactions achieving higher yields when oxygen gas replaces air in the headspace of batch reactions. Improving CFPS yields with hydrofoam reduces the overall cost of biotherapeutic production, increasing availability to the developing world. Beyond protein therapeutic production, hydrofoam CFPS could also be used to enhance other CFPS applications including biosensing, biomanufacturing, and biocatalysis.

Engineering Cell-Free Protein Synthesis for High-Yield Production and Human Serum Activity Assessment of Asparaginase: Toward On-Demand Treatment of Acute Lymphoblastic Leukemia.

Acute lymphocytic leukemia (ALL) is a common childhood cancer in the United States, with over 6000 new cases diagnosed each year. Administration of bacterial asparaginase (ASNase) has improved survival rates to nearly 80%, however these therapeutics have high incidence of immunological neutralization and serum activity must be monitored for most effective treatment regimens. Here, a 72% improvement in cell-free protein synthesis (CFPS) of FDA approved l-asparaginase (crisantaspase) is demonstrated by employing an aspartate-fed-batch reactor format. A CFPS-based ASNase activity assay as a tool for therapeutic regimentation and production quality control is also presented. This work suggests that shelf-stable and low-cost Escherichia coli-based CFPS reactions may be employed on-demand to 1) synthesize biologics on-site for patient administration, 2) verify biologic activity for dosage calculations, and 3) monitor therapeutic activity in human serum during the treatment regimen. The combination of both therapeutic production and activity assessment introduces a concept of synergistic utility for bacterial cell lysates in modern medical treatment. Indeed, recent work with CFPS biosensors supports a not-too-distant future when shelf-stable E. coli CFPS systems are used to diagnose, treat, and monitor treatment of diseases in the clinical setting.

Secular changes in functional disability, pain, fatigue and mental well-being in early rheumatoid arthritis. A longitudinal meta-analysis.

OBJECTIVES: To conduct a systematic review and longitudinal meta-analysis of early rheumatoid arthritis (RA) cohorts with long-term data on pain, fatigue or mental well-being. METHODS: Searches using PUBMED, EMBASE and PyscInfo were performed to identify all early RA cohorts with longitudinal measures of pain, fatigue or mental well-being, along with clinical measures. Using longitudinal meta-analyses, the progression of each outcome over the first 60-months was estimated. Cohorts were stratified based on the median recruitment year to investigate secular trends in disease progression. RESULTS: Of 7,319 papers identified, 75 met the inclusion criteria and 46 cohorts from 41 publications provided sufficient data on 18,046 patients for meta-analysis. The Disease Activity Scores (DAS28) and the Short-Form 36 (SF-36) Physical Component Score (PCS) indicated that post-2002 cohorts had statistically significant improvements over the first 60-months compared to pre-2002 cohorts, with standardised mean differences (SMD) of 0.86 (95% Confidence Intervals 0.34 to 1.37) and 0.76 (95% CI 0.25 to 1.27) respectively at month-60. However, post-2002 cohorts indicated statistically non-significant improvements in pain, fatigue, functional disability and SF-36 Mental Component Score (MCS) compared to pre-2002 cohorts, with SMD of 0.24 (95% CI -0.25 to 0.74), 0.38 (95% CI -0.11 to 0.88), 0.34 (95% CI -0.15-0.84) and -0.08 (95% CI -0.41 to 0.58) at month-60 respectively. CONCLUSIONS: Recent cohorts indicate improved levels of disease activity and physical quality of life, however this has not translated into similar improvements in levels of pain, fatigue and functional disability by 60-months.

Using Instrument-Guided Team Reflection and Debriefing to Cultivate Teamwork Knowledge, Skills, and Attitudes in Pre-Clerkship Learning Teams.

Drawing on the science of teamwork and the science of learning, we designed an instrument-guided team reflection and debriefing activity to foster teamwork knowledge, skills, and attitudes (KSAs) in medical students. We then embedded this activity within and between a biweekly series of pre-clerkship Team-Based Learning sessions with the goal of encouraging medical students to cultivate a practical and metacognitive appreciation of eight foundational teamwork KSAs that are applicable to both healthcare teams and classroom learning teams. On evaluations, 144 learners from a class of 156 reported increased appreciation for and team improvement with these teamwork KSAs.

Examining the influence of social-environmental variables on self-injurious behaviour in adolescent boys with fragile X syndrome.

BACKGROUND: Individuals with fragile X syndrome (FXS), the most common known inherited form of intellectual disability, are at increased risk for showing specific forms of self-injurious behaviour (SIB) such as hand biting and head hitting, suggesting that biological factors associated with the syndrome confers increased risk for SIB. Few studies, however, have examined the extent to which social-environmental variables can influence the occurrence of these behaviours in this population. METHOD: Twenty-two adolescent boys with FXS, aged 10 to 18 years were systematically exposed to seven environmental conditions in functional analyses of SIB conducted over 2 days at our research centre. RESULTS: Fourteen (63.6%) boys with FXS engaged in SIB during the functional analyses. Ten (45.5%) boys engaged in SIB that was maintained by social-environmental variables, that is, gaining access to attention/tangibles and/or escaping from social interaction, task demands and/or transition demands. For two boys, SIB was undifferentiated across conditions, and for two boys, SIB appeared to be maintained by automatic reinforcement. CONCLUSIONS: Social-environmental variables appeared to maintain SIB in a significant proportion of boys with FXS. Given that pharmacological treatments for SIB have limited efficacy in this population, the potential role of social-environmental factors on SIB should be examined before pharmacological treatments are implemented for these behaviours.

Association between bedtime and self-reported illness among college students: a representative nationwide study of China.

OBJECTIVE: This study was to examine the association between bedtime and self-reported illness among Chinese college students. METHODS: Participants were 11,942 students, who were identified through a multistage survey sampling process. Sleep and illness status were obtained by self report. Both unadjusted and adjusted methods were considered in the analyses. RESULTS: The logistic regression model found that late bedtime was positively associated with self reported short and long-term illness (OR: 3.70 and 1, 79) after adjusting for demographic characteristics, short sleep duration, and mental disorders. CONCLUSIONS: This study is the first to find a positive relationship between late bedtime and self reported illnesses in China or elsewhere. The findings underscore the importance of educating college students about the importance of sleep.

A spinor Bose-Einstein condensate phase-sensitive amplifier for SU(1,1) interferometry.

The SU(1,1) interferometer was originally conceived as a Mach-Zehnder interferometer with the beam-splitters replaced by parametric amplifiers. The parametric amplifiers produce states with correlations that result in enhanced phase sensitivity. F = 1 spinor Bose-Einstein condensates (BECs) can serve as the parametric amplifiers for an atomic version of such an interferometer by collisionally producing entangled pairs of |F = 1, m = ±1〉 atoms. We simulate the effect of single and double-sided seeding of the inputs to the amplifier using the truncated-Wigner approximation. We find that single-sided seeding degrades the performance of the interferometer exactly at the phase the unseeded interferometer should operate the best. Double-sided seeding results in a phase-sensitive amplifier, where the maximal sensitivity is a function of the phase relationship between the input states of the amplifier. In both single and double-sided seeding we find there exists an optimal phase that achieves sensitivity beyond the standard quantum limit. Experimentally, we demonstrate a spinor phase-sensitive amplifier using a BEC of 23Na in an optical dipole trap. This configuration could be used as an input to such an interferometer. We are able to control the initial phase of the double-seeded amplifier, and demonstrate sensitivity to initial population fractions as small as 0.1%.

What's new in atopic eczema? An analysis of systematic reviews published in 2014. Part 2. Treatment and prevention.

This review forms part of a series of annual updates that summarize the evidence base for atopic eczema (AE). It provides a summary of key findings from 12 systematic reviews (SRs) that were published or indexed during 2014, and focuses on the treatment and prevention of AE. For an update of SRs on the epidemiology, mechanisms of disease and methodological issues, see Part 1 of this update. Although phototherapy and various systemic medications (including ciclosporin, azathioprine and methotrexate) are commonly used to treat AE, many of these have not been robustly assessed in head-to-head randomized controlled trials. Educational interventions may improve AE severity and quality of life for children and their families. Intake of probiotics prenatally and postnatally may help prevent AE, but there is little evidence to suggest a role in the treatment of AE. Although no benefit was found for allergen avoidance in preventing AE, the use of immunotherapy to treat AE-associated aeroallergen sensitivity requires further evaluation. There is insufficient evidence for Vitamin D supplementation for the treatment of AE This overview of reviews provides a succinct guide for clinicians and patients wishing to remain up to date with the most recent evidence for the treatment and prevention of AE.

What's new in atopic eczema? An analysis of systematic reviews published in 2014. Part 1. Epidemiology, risk factors and outcomes.

This review summarizes key findings from nine systematic reviews on atopic eczema (AE) published or first indexed in 2014. It focuses on epidemiology, disease processes and methodological issues. There is reasonable evidence to conclude that high birth weight (> 4000 g) is a risk factor for the development of AE. A lower socioeconomic position is associated with lower prevalence of AE. The effect of exposure to traffic-related air pollution in childhood on the development of AE is uncertain. CD14 polymorphisms do not appear to have an effect in AE. There may be a role for interleukin-18 in AE development. Patients with AE are at decreased risk of brain tumours, but at increased risk of developing attention deficit hyperactivity disorder. Evidence supports the view that normal-appearing skin in AE is in fact structurally abnormal. Lower success rates at inducing remission in AE are associated with increased risk of relapse during long-term follow-up. The Eczema Area Severity Index (EASI) has been agreed as the preferred core instrument to measure clinical signs in future research. There remains a lack of consensus on the definition of an AE flare.

Problem behaviour in adolescent boys with fragile X syndrome: relative prevalence, frequency and severity.

BACKGROUND: A large proportion of boys with fragile X syndrome (FXS), the most common known inherited form of intellectual disability (ID), exhibit problem behaviours (e.g. aggression, self-injury, property destruction and stereotypy) that can negatively impact the health and safety of others as well as the individual concerned. However, data are limited concerning the relative prevalence, frequency and severity of problem behaviours exhibited by boys with FXS compared with those by boys with mixed-aetiology ID who also exhibit problem behaviours. METHOD: As part of a larger study on problem behaviour, we obtained survey data on 85 adolescent boys with FXS and 155 age-matched boys with mixed-aetiology ID who exhibited at least one form of problem behaviour. RESULTS: For boys with FXS, stereotypy was reported to be more prevalent (χ2 = 4.52, P = 0.012), self-injury was reported to more frequent (U = 2525, P = 0.010) and aggression was reported to be less severe (U = 4176, P = 0.029) than for boys with mixed-aetiology ID. Ratings of aggression and property destruction were highly correlated in each group in terms of both frequency and severity (r = 0.60 to 0.71). Examination of the data by age indicated that the relative frequency of self-injury decreased with age in boys with FXS (χ2 = 8.29, P = 0.040). CONCLUSIONS: Taken together, these results refine and extend previous studies concerning the specificity of the behavioural phenotype in FXS and indicate that specific forms of problem behaviour shown by boys with FXS appear to differ from those exhibited by boys with mixed-aetiology ID in terms of prevalence, frequency and severity. Studies employing more objective measures of frequency and severity, including direct observations, are needed to confirm these findings.

Automatic landmark generation for deformable image registration evaluation for 4D CT images of lung.

Deformable image registration (DIR) has become a common tool in medical imaging across both diagnostic and treatment specialties, but the methods used offer varying levels of accuracy. Evaluation of DIR is commonly performed using manually selected landmarks, which is subjective, tedious and time consuming. We propose a semi-automated method that saves time and provides accuracy comparable to manual selection. Three landmarking methods including manual (with two independent observers), scale invariant feature transform (SIFT), and SIFT with manual editing (SIFT-M) were tested on 10 thoracic 4DCT image studies corresponding to the 0% and 50% phases of respiration. Results of each method were evaluated against a gold standard (GS) landmark set comparing both mean and proximal landmark displacements. The proximal method compares the local deformation magnitude between a test landmark pair and the closest GS pair. Statistical analysis was done using an intra class correlation (ICC) between test and GS displacement values. The creation time per landmark pair was 22, 34, 2.3, and 4.3 s for observers 1 and 2, SIFT, and SIFT-M methods respectively. Across 20 lungs from the 10 CT studies, the ICC values between the GS and observer 1 and 2, SIFT, and SIFT-M methods were 0.85, 0.85, 0.84, and 0.82 for mean lung deformation, and 0.97, 0.98, 0.91, and 0.96 for proximal landmark deformation, respectively. SIFT and SIFT-M methods have an accuracy that is comparable to manual methods when tested against a GS landmark set while saving 90% of the time. The number and distribution of landmarks significantly affected the analysis as manifested by the different results for mean deformation and proximal landmark deformation methods. Automatic landmark methods offer a promising alternative to manual landmarking, if the quantity, quality and distribution of landmarks can be optimized for the intended application.