Neurodevelopmental outcomes in children and adults with Fetal Valproate Spectrum Disorder: A contribution from the ConcePTION project.

AIM: To describe the neurodevelopmental phenotype of older children and adults with a diagnosis of Fetal Valproate Spectrum Disorder (FVSD). METHODS: In this cross-sectional study, 90 caregivers were recruited and completed a series of questionnaires regarding the neurodevelopmental outcomes of 146 individuals aged 7-37 years (M = 18.1), including individuals with a formal diagnosis of FVSD (n = 99), individuals exposed to Valproate but without an FVSD diagnosis (n = 24), and individuals not exposed to Valproate (N = 23). The mean dose of valproate exposure for individuals with an FVSD diagnosis was 1470 mg/day. RESULTS: Individuals with a diagnosis of FVSD showed significantly higher levels of moderate (43.4%) and severe (14.4%) cognitive impairment than other groups (p = 0.003), high levels of required formal educational support (77.6%), and poorer academic competence than individuals not exposed to Valproate (p = 0.001). Overall psychosocial problems (p = 0.02), internalising problems (p = 0.05) and attention problems (p = 0.001), but not externalising problems, were elevated in individuals with a diagnosis of FVSD. Rates of neurodevelopmental disorders, particularly autistic spectrum disorders (62.9%) and sensory problems (80.6%) are particularly central to the FVSD phenotype. There was no evidence of a statistical dose-dependent effect, possibly due to the high mean dose of exposure having a uniformly negative impact across the sample. Individuals with FVSD had required a significant number of health and child development services. INTERPRETATION: Children and young adults with a diagnosis of FVSD are at an increased risk of a range of altered neurodevelopmental outcomes, highlighting the need for a multidisciplinary approach to clinical management across the lifespan.

Multicomponent telerehabilitation programme for older veterans with multimorbidity: a programme evaluation.

INTRODUCTION: Older veterans with multimorbidity experience physical, mental and social factors which may negatively impact health and healthcare access. Physical function, behaviour change skills and loneliness may not be addressed during traditional physical rehabilitation. Thus, a multicomponent telerehabilitation programme could address these unmet needs. This programme evaluation assessed the safety, feasibility and change in patient outcomes for a multicomponent telerehabilitation programme. METHODS: Individuals were eligible if they were a veteran/spouse, age ≥50 years and had ≥3 comorbidities. The telerehabilitation programme included four core components: (1) High-intensity rehabilitation, (2) Coaching interventions, (3) Social support and (4) Technology. Physical therapists delivered the 12-week programme and collected patient outcomes at baseline, 4 weeks, 8 weeks and 12 weeks. Programme evaluation measures included safety events (occurrence and type), feasibility (adherence) and patient outcomes (physical function). Safety and feasibility outcomes were analysed using descriptive statistics. The mean pre-post programme difference and 95% CI for patient outcomes were generated using paired t-tests. RESULTS: Twenty-one participants enrolled in the telerehabilitation programme; most were male (81%), white (72%) and non-Hispanic (76%), with an average of 5.7 (3.0) comorbidities. Prevalence of insession safety events was 3.2% (0.03 events/session). Fifteen (71.4%) participants adhered to the programme (attended ≥80% of sessions). Mean (95% CI) improvements for physical function are as follows: 4.7 (2.4 to 7.0) repetitions for 30 s sit to stand, 6.0 (4.0 to 9.0) and 5.0 (2.0 to 9.0) repetitions for right arm curl and left arm curl, respectively, and 31.8 (15.9 to 47.7) repetitions for the 2 min step test. CONCLUSION: The telerehabilitation programme was safe, feasible and demonstrated preprogramme to postprogramme improvements in physical function measures while addressing unmet needs in a vulnerable population. These results support a randomised clinical trial while informing programme and process adaptations.

Pulmonary inflammation promoted by type-2 dendritic cells is a feature of human and murine schistosomiasis.

Schistosomiasis is a parasitic disease affecting over 200 million people in multiple organs, including the lungs. Despite this, there is little understanding of pulmonary immune responses during schistosomiasis. Here, we show type-2 dominated lung immune responses in both patent (egg producing) and pre-patent (larval lung migration) murine Schistosoma mansoni (S. mansoni) infection. Human pre-patent S. mansoni infection pulmonary (sputum) samples revealed a mixed type-1/type-2 inflammatory cytokine profile, whilst a case-control study showed no significant pulmonary cytokine changes in endemic patent infection. However, schistosomiasis induced expansion of pulmonary type-2 conventional dendritic cells (cDC2s) in human and murine hosts, at both infection stages. Further, cDC2s were required for type-2 pulmonary inflammation in murine pre-patent or patent infection. These data elevate our fundamental understanding of pulmonary immune responses during schistosomiasis, which may be important for future vaccine design, as well as for understanding links between schistosomiasis and other lung diseases.

Patient-Reported Outcomes Are Similar in the First 2 Years After Staged Versus Combined Hip Arthroscopy and Periacetabular Osteotomy for Hip Dysplasia.

PURPOSE: To compare early patient-reported outcomes after staged versus combined hip arthroscopy and periacetabular osteotomy for hip dysplasia. METHODS: A prospective database was retrospectively reviewed to identify patients that underwent combined or staged hip arthroscopy and periacetabular osteotomy (PAO) from 2012 to 2020. Patients were excluded if they were >40 years of age, had prior ipsilateral hip surgery, or did not have at least 12-24 months of postoperative patient-reported outcome (PRO) data. PROs included the Hip Outcomes Score (HOS) Activities of Daily Living (ADL) and Sports Subscale (SS), Non-Arthritic Hip Score (NAHS), and the Modified Harris Hip Score (mHHS). Paired t-tests were used to compare preoperative to postoperative scores for both groups. Outcomes were compared using linear regression adjusted for baseline characteristics, including age, obesity, cartilage damage, acetabular index, and procedure timing (early vs late practice). RESULTS: Sixty-two hips were included in this analysis (39 combined, 23 staged). The average length of follow-up was similar between the combined and staged groups (20.8 vs 19.6 months; P = .192). Both groups reported significant improvements in PROs at final follow up compared to preoperative scores (P < .05 for all). There were no significant differences in HOS-ADL, HOS-SS, NAHS, or mHHS scores between groups preoperatively or at 3, 6, or 12 months postoperatively (P > .05 for all). There was no significant difference in PROs between the combined and staged groups at the final postoperative time point: HOS-ADL (84.5 vs 84.3; P = .77), HOS-SS (76.0 vs 79.2; P = .68), NAHS (82.2 vs 84.5; P = .79), and mHHS (71.0 vs 71.0, P = .75), respectively. CONCLUSIONS: Staged hip arthroscopy and PAO for hip dysplasia leads to similar PROs at 12-24 months compared to combined procedures. This suggests that with careful and informed patient selection, staging these procedures is an acceptable option for these patients and does not change early outcomes. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Complex small-world regulatory networks emerge from the 3D organisation of the human genome.

The discovery that overexpressing one or a few critical transcription factors can switch cell state suggests that gene regulatory networks are relatively simple. In contrast, genome-wide association studies (GWAS) point to complex phenotypes being determined by hundreds of loci that rarely encode transcription factors and which individually have small effects. Here, we use computer simulations and a simple fitting-free polymer model of chromosomes to show that spatial correlations arising from 3D genome organisation naturally lead to stochastic and bursty transcription as well as complex small-world regulatory networks (where the transcriptional activity of each genomic region subtly affects almost all others). These effects require factors to be present at sub-saturating levels; increasing levels dramatically simplifies networks as more transcription units are pressed into use. Consequently, results from GWAS can be reconciled with those involving overexpression. We apply this pan-genomic model to predict patterns of transcriptional activity in whole human chromosomes, and, as an example, the effects of the deletion causing the diGeorge syndrome.

Congenital Absence of the Patellar Tendon: A Report of 2 Cases.

CASE: Isolated unilateral congenital patellar tendon absence is a rare condition that has not been well described. We report on 2 patients with congenital patellar tendon absence that underwent soft-tissue reconstruction of their patellar tendon. We present the clinical and radiographic features, surgical management with both single-stage and multistage approaches, and postoperative outcomes for the treatment of this condition. CONCLUSION: Soft-tissue reconstruction of the patellar tendon led to satisfactory outcomes, providing active knee extension and improved ambulation in both cases. In cases of significant superior migration, multiple procedures may be required to mobilize the patella to an appropriate position.

What patient factors and Patient-Reported Outcomes Measurement Information System domains are associated with worse pain coping in pediatric orthopaedic patients in the United States?

We sought to better understand the relationship between Patient-Reported Outcomes Measurement Information System (PROMIS) mobility, pain interference (PI) and depressive symptoms scores, as well as determine what patient factors and PROMIS domains were associated with worse pain coping (PROMIS PI), in a pediatric orthopaedic population. Between 27 August 2015 and 30 April 2019, new pediatric orthopaedic patients 18 years or younger (or their guardians as a proxy) were asked to complete PROMIS mobility, PI and depressive symptoms domains at an academic medical center pediatric orthopaedic clinic. Pearson correlation coefficients (r) were calculated between each PROMIS domain. Linear multivariate regression analysis was used to determine patient characteristics and PROMIS domains associated with presenting PROMIS PI scores. There was a strong-moderate correlation between PROMIS mobility and PI (r = -0.66, P < 0.001), while the correlation between PROMIS mobility and depressive symptoms was moderate-poor (r = -0.38, P < 0.001). There was a moderate correlation between PROMIS depressive symptoms and PI (r = 0.54, P < 0.001). In multivariate linear regression analysis, female gender (ß = 0.82, P < 0.001), self-reported black race (ß = 0.94, P < 0.001), Medicaid insurance (ß = 0.82, P < 0.001) and worsening depressive symptoms (ß = 0.33, P < 0.001) were associated with worse pain coping mechanisms, while increasing mobility (ß = -0.47, P < 0.001) was associated with better pain coping mechanisms. Poor mobility and worse depressive symptoms are associated with worse pain coping mechanisms. Additionally, Medicaid insurance status, black race and female gender are also associated with worse physical limitations secondary to pain.

Radiation furnace for synchrotron dark-field x-ray microscopy experiments.

We present a multi-purpose radiation furnace designed for x-ray experiments at synchrotrons. The furnace is optimized specifically for dark-field x-ray microscopy (DFXM) of crystalline materials at beamline ID06 of the European Synchrotron Radiation Facility. The furnace can reach temperatures above 1200 °C with a thermal stability better than 10 °C, with heating and cooling rates up to 30 K/s. The non-contact heating design enables samples to be heated either in air or in a controlled atmosphere contained within a capillary tube. The temperature was calibrated via the thermal expansion of an α-iron grain. Temperature profiles in the y and z axes were measured by scanning a thermocouple through the focal spot of the radiation furnace. In the current configuration of the beamline, this furnace can be used for DFXM, near-field x-ray topography, bright-field x-ray nanotomography, high-resolution reciprocal space mapping, and limited powder diffraction experiments. As a first application, we present a DFXM case study on isothermal heating of a commercially pure single crystal of aluminum.

Using e-cigarettes for smoking cessation: evaluation of a pilot project in the North West of England.

AIMS: E-cigarettes have been advocated as an effective smoking cessation intervention, with evidence indicating that they are substantially less harmful than conventional cigarettes. As a result, a pilot to encourage people to swap from conventional cigarettes to e-cigarettes was conducted in 2018 in a socially deprived area in the North West of England. This evaluation highlights the key findings from the pilot. METHODS: An analysis of secondary data at 4 weeks (n = 1022) was undertaken to predict those who used solely used e-cigarettes (i.e. had quit tobacco, as confirmed by a carbon monoxide test, CO < 10 ppm) from baseline characteristics, using chi-square tests and logistic regression. Baseline data were demographics, smoking levels and service provider type. RESULTS: Of the 1022 participants who engaged with the pilot 614 were still engaged at 4 weeks, of whom 62% had quit; quitting was more likely in younger participants (aged 18-24) and less likely in those who were sick and disabled. Of those who still smoked tobacco at week 4 (n = 226), smoking had reduced from a baseline of 19.1 cigarettes/day to 8.7. Overall, 37% (381) of those initially enrolled were confirmed to be using an e-cigarette on its own at follow-up. Successful quit was associated with occupation (unemployed, 33% vs intermediate, 47%, p = .023) and residing in the less deprived quintiles of deprivation (50% vs 34% in the most deprived quintile, p = .016). CONCLUSIONS: Making the conservative assumption that all those not in contact at 4 weeks were still smoking tobacco, for every five people entering the scheme, three people stayed on the programme and reduced their cigarette smoking and one person cut out tobacco altogether. E-cigarettes appear to be an effective nicotine replacement therapy; however, further research is required to determine whether e-cigarette users are more likely to reduce their overall nicotine consumption in the longer term.

A nonmyeloablative chimeric mouse model accurately defines microglia and macrophage contribution in glioma.

AIMS: Resident and peripherally derived glioma associated microglia/macrophages (GAMM) play a key role in driving tumour progression, angiogenesis, invasion and attenuating host immune responses. Differentiating these cells' origins is challenging and current preclinical models such as irradiation-based adoptive transfer, parabiosis and transgenic mice have limitations. We aimed to develop a novel nonmyeloablative transplantation (NMT) mouse model that permits high levels of peripheral chimerism without blood-brain barrier (BBB) damage or brain infiltration prior to tumour implantation. METHODS: NMT dosing was determined in C57BL/6J or Pep3/CD45.1 mice conditioned with concentrations of busulfan ranging from 25 mg/kg to 125 mg/kg. Donor haematopoietic cells labelled with eGFP or CD45.2 were injected via tail vein. Donor chimerism was measured in peripheral blood, bone marrow and spleen using flow cytometry. BBB integrity was assessed with anti-IgG and anti-fibrinogen antibodies. Immunocompetent chimerised animals were orthotopically implanted with murine glioma GL-261 cells. Central and peripheral cell contributions were assessed using immunohistochemistry and flow cytometry. GAMM subpopulation analysis of peripheral cells was performed using Ly6C/MHCII/MerTK/CD64. RESULTS: NMT achieves >80% haematopoietic chimerism by 12 weeks without BBB damage and normal life span. Bone marrow derived cells (BMDC) and peripheral macrophages accounted for approximately 45% of the GAMM population in GL-261 implanted tumours. Existing markers such as CD45 high/low proved inaccurate to determine central and peripheral populations while Ly6C/MHCII/MerTK/CD64 reliably differentiated GAMM subpopulations in chimerised and unchimerised mice. CONCLUSION: NMT is a powerful method for dissecting tumour microglia and macrophage subpopulations and can guide further investigation of BMDC subsets in glioma and neuro-inflammatory diseases.

Extrusion without a motor: a new take on the loop extrusion model of genome organization.

Chromatin loop extrusion is a popular model for the formation of CTCF loops and topological domains. Recent HiC data have revealed a strong bias in favour of a particular arrangement of the CTCF binding motifs that stabilize loops, and extrusion is the only model to date which can explain this. However, the model requires a motor to generate the loops, and although cohesin is a strong candidate for the extruding factor, a suitable motor protein (or a motor activity in cohesin itself) has yet to be found. Here we explore a new hypothesis: that there is no motor, and thermal motion within the nucleus drives extrusion. Using theoretical modelling and computer simulations we ask whether such diffusive extrusion could feasibly generate loops. Our simulations uncover an interesting ratchet effect (where an osmotic pressure promotes loop growth), and suggest, by comparison to recent in vitro and in vivo measurements, that diffusive extrusion can in principle generate loops of the size observed in the data. Extra View on : C. A. Brackley, J. Johnson, D. Michieletto, A. N. Morozov, M. Nicodemi, P. R. Cook, and D. Marenduzzo "Non-equilibrium chromosome looping via molecular slip-links", Physical Review Letters 119 138101 (2017).

Using biological-physical modelling for informing sea lice dispersal in Loch Linnhe, Scotland.

Sea lice are a constraint on the sustainable growth of Scottish marine salmonid aquaculture. As part of an integrated pest management approach, farms coordinate procedures within spatial units. We present observations of copepodids being at relatively greater density than nauplii in upper waters, which informs the development of surface layer sea lice transmission modelling of Loch Linnhe, Scotland, for informing farm parasite management. A hydrodynamic model is coupled with a biological particle-tracking model, with characteristics of plankton sea lice. Simulations are undertaken for May and October 2011-2013, forced by local wind data collected for those periods. Particles are continually released from positions representing farm locations, weighted by relative farm counts, over a 2-week period and tracked for a further 5 days. A comparison is made between modelled relative concentrations against physical and biological surveys to provide confidence in model outputs. Connectivity between farm locations is determined in order to propose potential coordination areas. Generally, connectivity depends on flow patterns in the loch and decreases with increased farm separation. The connectivity indices are used to estimate the origins of the sea lice population composition at each site, which may influence medicinal regimens to avoid loss of efficacy.

An inductively coupled plasma mass spectrometry method for relative free copper determination and generation of a paediatric reference interval.

Background Diagnosis of Wilson's disease is currently performed using caeruloplasmin as a first-line screening test; however, this test has well-described limitations. Monitoring of known Wilson's disease patients often uses 24-h urine collection; however, this is inaccurate in children. Methods for directly measuring plasma free copper have been described, but no reference interval data exist for a paediatric population. Methods An inductively coupled plasma mass spectrometry method for measuring free copper was developed and validated, using ultracentrifugation. A paediatric reference interval was generated using 85 plasma samples from children attending outpatient clinics at University Hospital Southampton. Results Results showed no significant contamination of copper using the ultracentrifugation technique, and validation showed the method was accurate and precise with an analytical coefficient of variation between 5 and 7% depending on the concentration of free copper. Conclusions We describe the use and validation of an ultrafiltration inductively coupled plasma mass spectrometry method for plasma free copper with the first published paediatric reference interval. Free copper could provide much needed assistance for the monitoring of Wilson's disease in children and also for adults.

Nonequilibrium Chromosome Looping via Molecular Slip Links.

We propose a model for the formation of chromatin loops based on the diffusive sliding of molecular slip links. These mimic the behavior of molecules like cohesin, which, along with the CTCF protein, stabilize loops which contribute to organizing the genome. By combining 3D Brownian dynamics simulations and 1D exactly solvable nonequilibrium models, we show that diffusive sliding is sufficient to account for the strong bias in favor of convergent CTCF-mediated chromosome loops observed experimentally. We also find that the diffusive motion of multiple slip links along chromatin is rectified by an intriguing ratchet effect that arises if slip links bind to the chromatin at a preferred "loading site." This emergent collective behavior favors the extrusion of loops which are much larger than the ones formed by single slip links.

Predicting Water Resource Impacts of Unconventional Gas Using Simple Analytical Equations.

The rapid expansion in unconventional gas development over the past two decades has led to concerns over the potential impacts on groundwater resources. Although numerical models are invaluable for assessing likelihood of impacts at particular sites, simpler analytical models are also useful because they help develop hydrological understanding. Analytical approaches are also valuable for preliminary assessments and to determine where more complex models are warranted. In this article, we present simple analytical solutions that can be used to predict: (1) the spatial extent of drawdown from horizontal wells drilled into the gas-bearing formation, and rate of recovery after gas production ceases; (2) the potential for upward transport of contaminants from the gas-bearing formation to shallow aquifers during hydraulic fracturing operations when pressures in the gas-bearing formation are greatly increased; and (3) the potential downward leakage of water from shallow aquifers during depressurization of gas-bearing formations. In particular, we show that the recovery of pressure after production ceases from gas-bearing shale formations may take several hundred years, and we present critical hydraulic conductivity values for intervening aquitards, below which the impact on shallow aquifers will be negligible. The simplifying assumptions inherent in these solutions will limit their predictive accuracy for site-specific assessments, compared to numerical models that incorporate knowledge of spatial variations in formation properties and which may include processes not considered in the simpler solutions.

Incidence and Complications of Open Hip Preservation Surgery: An ABOS Database Review.

Hip preservation surgery encompasses various surgical procedures that have the goal of decreasing the progression of osteoarthritis, preserving normal hip function, and delaying the need for arthroplasty. These procedures can encompass arthroscopic, open, and combined techniques. This study investigated the trends and complications associated with open hip preservation surgery performed by candidates undergoing Part II of the American Board of Orthopaedic Surgery examination. The American Board of Orthopaedic Surgery Part II surgeon case database was queried from the years 2003 to 2013 for Current Procedural Terminology (CPT) codes related to open hip preservation surgery in patients 10 years and older. Patient demographics, fellowship training, geographic location, and complications were extracted from the database. These data were analyzed to determine the incidence by year of individual procedures and complications. During the study period, 644 cases (352 male, 292 female; mean age, 29.7 years) and 730 CPT codes were reported. The most commonly reported fellowship was pediatric orthopedics. No trend was observed in the overall incidence of these surgeries, but there was an increase in the number of cases performed in the Midwest. There were 212 reported complications, with a rate of 33% per case, or 29% per CPT code (range, 12.5%-100% per CPT code). Complications reported ranged from infection to death. The incidence of complications over time showed no discernible trend. Based on the results of this study, the yearly incidence and complications associated with open hip preservation surgery performed by surgeons undergoing board certification should continue at a predictable rate. [Orthopedics. 2017; 40(1):e109-e116.].

Simulating topological domains in human chromosomes with a fitting-free model.

We discuss a polymer model for the 3D organization of human chromosomes. A chromosome is represented by a string of beads, with each bead being "colored" according to 1D bioinformatic data (e.g., chromatin state, histone modification, GC content). Individual spheres (representing bi- and multi-valent transcription factors) can bind reversibly and selectively to beads with the appropriate color. During molecular dynamics simulations, the factors bind, and the string spontaneously folds into loops, rosettes, and topologically-associating domains (TADs). This organization occurs in the absence of any specified interactions between distant DNA segments, or between transcription factors. A comparison with Hi-C data shows that simulations predict the location of most boundaries between TADs correctly. The model is "fitting-free" in the sense that it does not use Hi-C data as an input; consequently, one of its strengths is that it can - in principle - be used to predict the 3D organization of any region of interest, or whole chromosome, in a given organism, or cell line, in the absence of existing Hi-C data. We discuss how this simple model might be refined to include more transcription factors and binding sites, and to correctly predict contacts between convergent CTCF binding sites.