Examining the Use of VR as a Study Aid for University Students with ADHD.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition characterized by patterns of inattention and impulsivity, which lead to difficulties maintaining concentration and motivation while completing academic tasks. University settings, characterized by a high student-to-staff ratio, make treatments relying on human monitoring challenging. One potential replacement is Virtual Reality (VR) technology, which has shown potential to enhance learning outcomes and promote flow experience. In this study, we investigate the usage of VR with 27 university students with ADHD in an effort to improve their performance in ctableompleting homework, including an exploration of automated feedback via a technology probe. Quantitative results show significant increases in concentration, motivation, and effort levels during these VR sessions and qualitative data offers insight into considerations like comfort and deployment. Together, the results suggest that VR can be a valuable tool in leveling the playing field for university students with ADHD.

Lack of Consensus on the Definition of Aseptic Loosening in Total Ankle Replacement: A Narrative Systematic Review.

Background: Aseptic loosening is one of the most common modes of failure of total ankle replacement (TAR). However, a precise definition of aseptic loosening is still lacking. This systematic review aimed to identify the variations of applied definitions and offer insights into the lack of consensus. Methods: Human studies reporting aseptic loosening of TAR published in peer-reviewed journals within the last decade were considered. The search strategy involved specific terms in Embase, MEDLINE ALL, and the Cochrane Library. Variations in aseptic loosening definitions were analysed. Results: Of 767 studies, 88 were included in this study. Only nine studies precisely defined aseptic loosening with significant variations. Twenty-two studies referenced the term and fifty-seven reported it as a complication but neither defined nor referenced it. Conclusions: Significant uncertainty exists regarding the universal definition of aseptic loosening of TAR, and many variations occur in terms of the assessment approach and criteria.

Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease.

Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Here, we use electronic health records to undertake a genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identify 158 novel genetic associations, more than doubling the number of known associations with TSH, and implicate 112 putative causal genes, of which 76 are not previously implicated. A polygenic score for TSH is associated with TSH levels in African, South Asian, East Asian, Middle Eastern and admixed American ancestries, and associated with hypothyroidism and other thyroid disease in South Asians. In Europeans, the TSH polygenic score is associated with thyroid disease, including thyroid cancer and age-of-onset of hypothyroidism and hyperthyroidism. We develop pathway-specific genetic risk scores for TSH levels and use these in phenome-wide association studies to identify potential consequences of pathway perturbation. Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases.

Single-cell type analysis of wing premotor circuits in the ventral nerve cord of Drosophila melanogaster.

To perform most behaviors, animals must send commands from higher-order processing centers in the brain to premotor circuits that reside in ganglia distinct from the brain, such as the mammalian spinal cord or insect ventral nerve cord. How these circuits are functionally organized to generate the great diversity of animal behavior remains unclear. An important first step in unraveling the organization of premotor circuits is to identify their constituent cell types and create tools to monitor and manipulate these with high specificity to assess their function. This is possible in the tractable ventral nerve cord of the fly. To generate such a toolkit, we used a combinatorial genetic technique (split-GAL4) to create 195 sparse driver lines targeting 198 individual cell types in the ventral nerve cord. These included wing and haltere motoneurons, modulatory neurons, and interneurons. Using a combination of behavioral, developmental, and anatomical analyses, we systematically characterized the cell types targeted in our collection. Taken together, the resources and results presented here form a powerful toolkit for future investigations of neural circuits and connectivity of premotor circuits while linking them to behavioral outputs.

Dynamic syndesmotic stabilisation and reinforcement of the antero-inferior tibiofibular ligament with internal brace.

PURPOSE: Syndesmotic injuries are associated with long recovery times and high morbidity. Systematic reviews show a trend toward better outcomes of suture buttons compared to screw fixation. The anteroinferior tibiofibular ligament (AITFL) confers the most significant component of translational and rotatory stability. Techniques have developed which reinforce the AITFL. This study aimed to assess results of syndesmotic stabilisation with dynamic stabilisation and reinforcement of the AITFL, with an early mobilisation program. MATERIALS AND METHODS: Retrospective case series of 30 patients (mean age 31 years). Syndesmotic instability was confirmed with clinical examination, MRI and weightbearing-CT. Dynamic syndesmotic stabilisation with a single suture button was performed followed by the placement of an Internal Brace over the AITFL. A standardised postoperative rehabilitation protocol was established. Foot and Ankle Ability Measure (FAAM) scores were collected postoperatively. RESULTS: The average follow-up was 13 months. The total FAAM score for ADL was 95 ± 4.9 % (range, 83 - 100 %) and for sport activities 87 ± 13.6 % (range, 50 - 100 %). The rating of mean postoperative function for ADL was 94 ± 5.5 % (range, 80 - 100 %) and 90 ± 13 % (range, 35 - 100 %) for sportv. The difference between acute and chronic injuries was statistically higher (p < 0.05) for daily activities and sport, but the rating of current level of sport activites as well as for daily activites did not show a significant difference (p = 0.9296 and p = 0.1615, respectively). Twenty-seven patients (90 %) rated their overall current level of function as normal or nearly normal. CONCLUSION: This technique aims to directly stabilise the AITFL and the interosseous components of the syndesmosis, and allow early mobilisation and return to sport at 10 weeks. Early results show the procedure is safe, with comparable results to the literature. Acute injuries showed better results of the FAAM score than chronic injuries.

Effects of photobiomodulation therapy on regulation of myogenic regulatory factor mRNA expression in vivo: A systematic review.

Non-invasive promotion of myogenic regulatory factors (MRFs), through photobiomodulation therapy (PBMT), may be a viable method of facilitating skeletal muscle regeneration post-injury, given the importance of MRF in skeletal muscle regeneration. The aim of this systematic review was to collate current evidence, identifying key themes and changes in expression of MRF in in vivo models. Web of Science, PubMed, Scopus and Cochrane databases were systematically searched and identified 1459 studies, of which 10 met the inclusion criteria. Myogenic determination factor was most consistently regulated in response to PBMT treatment, and the expression of remaining MRFs was heterogenous. All studies exhibited a high risk of bias, primarily due to lack of blinding in PBMT application and MRF analysis. Our review suggests that the current evidence base for MRF expression from PBMT is highly variable. Future research should focus on developing a robust methodology for determining the effect of laser therapy on MRF expression, as well as long-term assessment of skeletal muscle regeneration.

Dual high-stroke and high-work capacity artificial muscles inspired by DNA supercoiling.

Powering miniature robots using actuating materials that mimic skeletal muscle is attractive because conventional mechanical drive systems cannot be readily downsized. However, muscle is not the only mechanically active system in nature, and the thousandfold contraction of eukaryotic DNA into the cell nucleus suggests an alternative mechanism for high-stroke artificial muscles. Our analysis reveals that the compaction of DNA generates a mass-normalized mechanical work output exceeding that of skeletal muscle, and this result inspired the development of composite double-helix fibers that reversibly convert twist to DNA-like plectonemic or solenoidal supercoils by simple swelling and deswelling. Our modeling-optimized twisted fibers give contraction strokes as high as 90% with a maximum gravimetric work 36 times higher than skeletal muscle. We found that our supercoiling coiled fibers simultaneously provide high stroke and high work capacity, which is rare in other artificial muscles.

The association of blood pressure variability with adverse outcomes in a primary care chronic kidney disease cohort.

BACKGROUND: Hypertension is common in individuals with chronic kidney disease and both conditions are associated with adverse outcomes including cardiovascular morbidity. Therefore, it is clinically important to identify methods of risk prediction in individuals with chronic kidney disease. Blood pressure variability has recently emerged as a predictor of cardiovascular events and mortality in the general population, with growing evidence indicating that it may play a similar role in individuals with chronic kidney disease. However, there have been no large studies assessing blood pressure variability in individuals with chronic kidney disease in primary care, where the majority of these patients are managed. METHOD: Using a retrospective observational study design, we analyzed routinely collected blood pressure readings from 16 999 individuals in The Leicester and County Chronic Kidney Disease cohort. Standard deviation, coefficient of variation and average real variability of SBP were used to calculate blood pressure variability. RESULTS: During a median follow-up of 5.0 (IQR 3.3--5.0) years, 2053 (12.1%) patients had cardiovascular events, death occurred in 5021 (29.6%) individuals and 156 (0.9%) individuals had endstage kidney disease events. In adjusted models, standard deviation and coefficient of variation were associated with cardiovascular events, all-cause mortality and endstage kidney disease. Average real variability was associated with all-cause mortality and cardiovascular events, but not endstage kidney disease. CONCLUSION: Blood pressure variability may be an accessible, routinely collected, noninvasive measure for stratifying the risk of adverse events in individuals with chronic kidney disease in a primary care setting.

Genetic and clinical characteristics of treatment-resistant depression using primary care records in two UK cohorts.

Treatment-resistant depression (TRD) is a major contributor to the disability caused by major depressive disorder (MDD). Primary care electronic health records provide an easily accessible approach to investigate TRD clinical and genetic characteristics. MDD defined from primary care records in UK Biobank (UKB) and EXCEED studies was compared with other measures of depression and tested for association with MDD polygenic risk score (PRS). Using prescribing records, TRD was defined from at least two switches between antidepressant drugs, each prescribed for at least 6 weeks. Clinical-demographic characteristics, SNP-based heritability (h2SNP) and genetic overlap with psychiatric and non-psychiatric traits were compared in TRD and non-TRD MDD cases. In 230,096 and 8926 UKB and EXCEED participants with primary care data, respectively, the prevalence of MDD was 8.7% and 14.2%, of which 13.2% and 13.5% was TRD, respectively. In both cohorts, MDD defined from primary care records was strongly associated with MDD PRS, and in UKB it showed overlap of 71-88% with other MDD definitions. In UKB, TRD vs healthy controls and non-TRD vs healthy controls h2SNP was comparable (0.25 [SE = 0.04] and 0.19 [SE = 0.02], respectively). TRD vs non-TRD was positively associated with the PRS of attention deficit hyperactivity disorder, with lower socio-economic status, obesity, higher neuroticism and other unfavourable clinical characteristics. This study demonstrated that MDD and TRD can be reliably defined using primary care records and provides the first large scale population assessment of the genetic, clinical and demographic characteristics of TRD.

Comorbidities and outcomes in South Asian individuals with chronic kidney disease: an observational primary care cohort.

BACKGROUND: South Asian (SA) individuals are more likely to develop end-stage renal disease (ESRD), but how chronic kidney disease (CKD) differs in relation to demographics, comorbidities and outcomes has not been studied. We aimed to study differences in SA individuals with CKD compared with White individuals. METHODS: This was an observational CKD cohort comparing SA with White individuals. Inclusion criteria were ≥18 years of age and two or more Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFRs <60 mL/min/1.73 m2 >3 months apart. Individuals with ESRD at baseline were excluded. Baseline characteristics, including eGFR formulae [CKD-EPI and CKD-EPI-Pakistan (CKD-EPI-PK)], were compared. Analysis using competing risk regression for cardiovascular (CV) and ESRD events and Cox proportional hazard model for mortality was performed. RESULTS: From an adult population of 277 248 individuals, 17 248 individuals had CKD, of whom 1990 (11.5%) were of SA ethnicity. Age-adjusted prevalence of CKD was similar between ethnicities. SA individuals were more likely to be male, younger and socioeconomically deprived, and to have diabetes mellitus, CV disease and advanced CKD. Mean CKD-EPI-PK eGFR was 6.5 mL/min/1.73 m2 lower (41.1 versus 47.6, 95% confidence interval for difference 6.47-6.56) than for CKD-EPI. During 5 years of follow-up, 5109 (29.6%) individuals died, 2072 (12.0%) had a CV and 156 (0.90%) an ESRD event. Risk for SA individuals was higher for ESRD, similar to CV events and lower for mortality. Each 1 mL/min/1.73 m2 decrease in CKD-EPI-PK was associated with a 13.1% increased ESRD risk (adjusted subdistribution hazard ratio 0.869, 95% confidence interval 0.841-0.898). CONCLUSIONS: SA individuals with CKD were younger and had more advanced disease than White individuals. Risk of ESRD was higher and CKD-EPI-PK was associated with ESRD risk in SA individuals. Specific CKD interventions, including the use of CKD-EPI-PK, should be considered in SA populations.

Central processing of leg proprioception in Drosophila.

Proprioception, the sense of self-movement and position, is mediated by mechanosensory neurons that detect diverse features of body kinematics. Although proprioceptive feedback is crucial for accurate motor control, little is known about how downstream circuits transform limb sensory information to guide motor output. Here we investigate neural circuits in Drosophila that process proprioceptive information from the fly leg. We identify three cell types from distinct developmental lineages that are positioned to receive input from proprioceptor subtypes encoding tibia position, movement, and vibration. 13Bα neurons encode femur-tibia joint angle and mediate postural changes in tibia position. 9Aα neurons also drive changes in leg posture, but encode a combination of directional movement, high frequency vibration, and joint angle. Activating 10Bα neurons, which encode tibia vibration at specific joint angles, elicits pausing in walking flies. Altogether, our results reveal that central circuits integrate information across proprioceptor subtypes to construct complex sensorimotor representations that mediate diverse behaviors, including reflexive control of limb posture and detection of leg vibration.

Controllable duration and repetition-rate picosecond pulses from a high-average-power OP-GaAs OPO.

We report an orientation-patterned gallium arsenide (OP-GaAs) optical parametric oscillator (OPO) offering a high degree of temporal flexibility with controllable pulse repetition rates from 100 MHz to 1 GHz and pulse durations from ∼95 ps to ∼1.1 ns. The maximum average power of 9.2-W signal (3.3 µm) and 4.5-W idler (4.9 µm) was obtained at a repetition rate of 100 MHz and a pulse duration of ∼95 ps, with a pump power of 34.3 W and at a slope efficiency of 45.4%. The corresponding total average output power of 13.7 W is the highest power achieved to date from an OP-GaAs OPO, to the best of our knowledge.

A Systematic Nomenclature for the Drosophila Ventral Nerve Cord.

Drosophila melanogaster is an established model for neuroscience research with relevance in biology and medicine. Until recently, research on the Drosophila brain was hindered by the lack of a complete and uniform nomenclature. Recognizing this, Ito et al. (2014) produced an authoritative nomenclature for the adult insect brain, using Drosophila as the reference. Here, we extend this nomenclature to the adult thoracic and abdominal neuromeres, the ventral nerve cord (VNC), to provide an anatomical description of this major component of the Drosophila nervous system. The VNC is the locus for the reception and integration of sensory information and involved in generating most of the locomotor actions that underlie fly behaviors. The aim is to create a nomenclature, definitions, and spatial boundaries for the Drosophila VNC that are consistent with other insects. The work establishes an anatomical framework that provides a powerful tool for analyzing the functional organization of the VNC.

Correction: The Kidney Failure Risk Equation for prediction of end stage renal disease in UK primary care: An external validation and clinical impact projection cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.1002955.].

High-average-power picosecond mid-infrared OP-GaAs OPO.

We report a high-average-power mid-infrared picosecond (ps) optical parametric oscillator (OPO) based on orientation-patterned gallium arsenide (OP-GaAs), with wide wavelength tunability. The OP-GaAs OPO is synchronously pumped by a thulium-doped-fiber (TDF) master oscillator power amplifier (MOPA), seeded by a gain-switched laser diode. At a pump power of 35.3 W and a repetition rate of 100 MHz, a maximum OPO total average output power of 9.7 W (signal 5.7 W (0.60 kW peak power), idler 4.0 W (0.42 kW peak power)) is obtained at signal and idler wavelengths of 3093 nm and 5598 nm, and a thermally induced power roll-off is observed. To mitigate the thermal effects, an optical chopper is placed before the OPO to provide burst mode operation and a reduced thermal load. We achieved a linear growth in OPO output power over the full range of available pump powers in this instance confirming thermal effects as the origin of the roll-off observed under continuous pumping. We estimate the maximum peak powers of the signal and idler are estimated to be over 0.79 kW and 0.58 kW, respectively in this instance. A wide mid-infrared wavelength tuning range of 2895-3342 nm (signal) and 4935-6389 nm (idler) is demonstrated.

The Kidney Failure Risk Equation for prediction of end stage renal disease in UK primary care: An external validation and clinical impact projection cohort study.

BACKGROUND: The Kidney Failure Risk Equation (KFRE) uses the 4 variables of age, sex, urine albumin-to-creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR) in individuals with chronic kidney disease (CKD) to predict the risk of end stage renal disease (ESRD), i.e., the need for dialysis or a kidney transplant, within 2 and 5 years. Currently, national guideline writers in the UK and other countries are evaluating the role of the KFRE in renal referrals from primary care to secondary care, but the KFRE has had limited external validation in primary care. The study's objectives were therefore to externally validate the KFRE's prediction of ESRD events in primary care, perform model recalibration if necessary, and assess its projected impact on referral rates to secondary care renal services. METHODS AND FINDINGS: Individuals with 2 or more Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR values < 60 ml/min/1.73 m2 more than 90 days apart and a urine ACR or protein-to-creatinine ratio measurement between 1 December 2004 and 1 November 2016 were included in the cohort. The cohort included 35,539 (5.6%) individuals (57.5% female, mean age 75.9 years, median CKD-EPI eGFR 51 ml/min/1.73 m2, median ACR 3.2 mg/mmol) from a total adult practice population of 630,504. Overall, 176 (0.50%) and 429 (1.21%) ESRD events occurred within 2 and 5 years, respectively. Median length of follow-up was 4.7 years (IQR 2.8 to 6.6). Model discrimination was excellent for both 2-year (C-statistic 0.932, 95% CI 0.909 to 0.954) and 5-year (C-statistic 0.924, 95% 0.909 to 0.938) ESRD prediction. The KFRE overpredicted risk in lower (<20%) risk groups. Reducing the model's baseline risk improved calibration for both 2- and 5-year risk for lower risk groups, but led to some underprediction of risk in higher risk groups. Compared to current criteria, using referral criteria based on a KFRE-calculated 5-year ESRD risk of ≥5% and/or an ACR of ≥70 mg/mmol reduced the number of individuals eligible for referral who did not develop ESRD, increased the likelihood of referral eligibility in those who did develop ESRD, and referred the latter at a younger age and with a higher eGFR. The main limitation of the current study is that the cohort is from one region of the UK and therefore may not be representative of primary care CKD care in other countries. CONCLUSIONS: In this cohort, the recalibrated KFRE accurately predicted the risk of ESRD at 2 and 5 years in primary care. Its introduction into primary care for referrals to secondary care renal services may lead to a reduction in unnecessary referrals, and earlier referrals in those who go on to develop ESRD. However, further validation studies in more diverse cohorts of the clinical impact projections and suggested referral criteria are required before the latter can be clinically implemented.

Genome-Wide Transcriptional Analysis Reveals Novel AhR Targets That Regulate Dendritic Cell Function during Influenza A Virus Infection.

Activation of the ligand inducible aryl hydrocarbon receptor (AhR) during primary influenza A virus infection diminishes host responses by negatively regulating the ability of dendritic cells (DC) to prime naive CD8+ T cells, which reduces the generation of CTL. However, AhR-regulated genes and signaling pathways in DCs are not fully known. In this study, we used unbiased gene expression profiling to identify differentially expressed genes and signaling pathways in DCs that are modulated by AhR activation in vivo. Using the prototype AhR agonist TCDD, we identified the lectin receptor Cd209a (DC-SIGN) and chemokine Ccl17 as novel AhR target genes. We further show the percentage of DCs expressing CD209a on their surface was significantly decreased by AhR activation during infection. Whereas influenza A virus infection increased CCL17 protein levels in the lung and lung-draining lymph nodes, this was significantly reduced following AhR activation. Targeted excision of AhR in the hematopoietic compartment confirmed AhR is required for downregulation of CCL17 and CD209a. Loss of AhR's functional DNA-binding domain demonstrates that AhR activation alone is necessary but not sufficient to drive downregulation. AhR activation induced similar changes in gene expression in human monocyte-derived DCs. Analysis of the murine and human upstream regulatory regions of Cd209a and Ccl17 revealed a suite of potential transcription factor partners for AhR, which may coregulate these genes in vivo. This study highlights the breadth of AhR-regulated pathways within DCs, and that AhR likely interacts with other transcription factors to modulate DC functions during infection.

The Primary-Secondary Care Partnership to Improve Outcomes in Chronic Kidney Disease (PSP-CKD) Study: A Cluster Randomized Trial in Primary Care.

BACKGROUND: Most patients with CKD are managed in the community. Whether nurse-led CKD management programs improve outcomes in patients with CKD in primary care is unclear. METHODS: To assess the effect of such a program on the rate of renal function decline in patients with CKD (stages 3-5) in primary care in the United Kingdom, we conducted a cluster randomized trial, the Primary-Secondary Care Partnership to Improve Outcomes in Chronic Kidney Disease study. A software program designed for the study created a data file of patients with CKD in participating practices. In 23 intervention practices (11,651 patients), a CKD nurse practitioner worked with nominated practice leads to interpret the data file and implement guideline-based patient-level CKD management interventions. The 23 control practices (11,706 patients) received a data file but otherwise, continued usual CKD care. The primary outcome was defined at the cluster (practice) level as the change from baseline of the mean eGFR of the patients with CKD at 6-month intervals up to 42 months. Secondary outcomes included numbers of patients coded for CKD, mean BP, numbers of patients achieving National Institute for Health and Care Excellence BP targets for CKD, and proteinuria measurement. RESULTS: After 42 months, eGFR did not differ significantly between control and intervention groups. CKD- and proteinuria-related coding improved significantly along with the number of patients achieving BP targets in the intervention group versus usual care. CONCLUSIONS: CKD management programs in primary care may not slow progression of CKD, but they may significantly improve processes of care and potentially decrease the cardiovascular disease burden in CKD and related costs.