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BackgroundActivity in neurons drives afferent competition that is critical for the refinement of nascent neural circuits. In ferrets, when an eye is lost in early development, surviving retinogeniculate afferents from the spared eye spread across the thalamus in a manner that is dependent on spontaneous retinal activity. However, how this spontaneous activity, also known as retinal waves, might dynamically regulate afferent terminal targeting remains unknown.MethodsWe recorded retinal waves from retinae ex vivo using multi-electrode arrays. Retinae came from ferrets who were binocular or who had one eye surgically removed at birth. Linear mixed effects models were used to investigate the effects of early monocular enucleation on retinal wave activity.ResultsWhen an eye is removed at birth, spontaneous bursts of action potentials by retinal ganglion cells (RGCs) in the surviving eye are shorter in duration. The shortening of RGC burst duration results in decreased pairwise RGC correlations across the retina and is associated with the retinal wave-dependent spread of retinogeniculate afferents previously reported in enucleates.ConclusionOur findings show that removal of the competing eye modulates retinal waves and could underlie the dynamic regulation of competition-based refinement during retinogeniculate development.

The retina extracts relevant features from the visual scene and transmits these features to the brain through separate pathways that will eventually result in the perception of sight. The retinal ganglion cells (RGCs) are the only retinal cell type to send an axonal projection to the brain. This indicates that the signals generated by the RGCs are the end result of retinal processing, and the features detected by the RGCs are all that will be transmitted to the brain about the visual environment. Each RGC type represents a unique pathway that detects specific visual features. RGCs of the same type tile the retina so that the entire visual field is sampled. Different types of RGCs overlap so that each pixel in the visual field gets sampled by each pathway. To understand the different retinal pathways and what gets sent to the brain, it is necessary to know what types of RGCs are in the retina. Current classifications have used morphologies and physiology to describe the different RGC types. It is estimated that 20 different types of RGCs are present in the mammalian retina. However, very little is known about how these morphological features affect functional properties due to the inability to perturb the morphology and observe changes in physiology in many mammals. In order to overcome this limitation, I utilized a large-scale multielectrode array (MEA) approach to record and characterize responses from hundreds of RGCs in the mouse retina. The mouse model is advantageous due to the ease of genetic manipulation, allowing me to disrupt morphology and relate the changes to function. I first characterized and classified RGCs in the wild-type retina to develop a reference for mutant comparisons. I was able to classify up to 8 types of RGCs along with functional properties of the classes, such as tiling arrangements of the RGC receptive fields (RFs). Using a mutant mouse that has defects in dendritic and cell body spacing, I show that the dendritic structure is important for RF tiling and direction selective responses thus showing how morphology affects function. Finally, I used a transgenic mouse, in which RGCs expressing a particular gene was ablated, to show that these eliminated RGCs were a distinct functional subset that responded to light offset. The work that I performed will contribute to a complete classification of RGCs by linking the morphological types to the functional types, as well as the genetic programs that establish their properties. This will be necessary to determine what features are detected by the retina and how they ultimately lead to behavior.

Literature review suggests that studies on biomedical waste generation and disposal behaviors in North America are limited. Given the infectious nature of the materials, effective biomedical waste management is vital to the public health and safety of the residents. This study explicitly examines seasonal variations of treated biomedical waste (TBMW) disposal rates in the City of Regina, Canada, from 2013 to 2022. Immediately before the onset of COVID-19, the City exhibited a steady pattern of TBMW disposal rate at about 6.6 kg∙capita −1 ∙year −1 . However, the COVID-19 pandemic and its associated lockdowns brought about an abrupt and persistent decline in TBMW disposal rates. Inconsistent fluctuations in both magnitude and variability of the monthly TBMW load weights were also observed. The TBMW load weight became particularly variable in 2020, with an interquartile range 4 times higher than 2019. The average TBMW load weight was also the lowest (5.1 tonnes∙month −1 ∙truckload −1 ) in 2020, possibly due to an overall decline in non-COVID-19 medical emergencies, cancellation of elective surgeries, and availability of telehealth options to residents. In general, the TBMW disposal rates peaked during the summer and fall seasons. The day-to-day TBMW disposal contribution patterns between the pre-pandemic and post-pandemic are similar, with 97.5% of total TBMW being disposed of on fixed days. Results from this Canadian case study indicate that there were observable temporal changes in TBMW disposal behaviors during and after the COVID-19 lockdowns.

Fatigue is prevalent in immune-mediated inflammatory and neurodegenerative diseases, yet its assessment relies largely on patient-reported outcomes, which capture perception but not fluctuations over time. Wearable sensors, like inertial measurement units (IMUs), offer a way to monitor daily activities and evaluate functional capacity. This study investigates the relationship between sit-to-stand and stand-to-sit transitions and self-reported physical and mental fatigue in participants with Parkinson’s, Huntington’s, rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren’s syndrome and inflammatory bowel disease. Over 4 weeks, participants wore an IMU and reported fatigue levels four times daily. Using mixed-effects models, associations were identified between fatigue and specific kinematic features, such as 5th and 95th percentiles of sit-to-stand performance, suggesting that fatigue alters the control and effort of movement. These kinematic features show promise as indicators for fatigue in these patient populations.

Congenital heart defects can be caused by mutations in genes that guide cardiac lineage formation. Here, we show deletion of NKX2-5 , a critical component of the cardiac gene regulatory network, in human embryonic stem cells (hESCs), results in impaired cardiomyogenesis, failure to activate VCAM1 and to downregulate the progenitor marker PDGFRα. Furthermore, NKX2-5 null cardiomyocytes have abnormal physiology, with asynchronous contractions and altered action potentials. Molecular profiling and genetic rescue experiments demonstrate that the bHLH protein HEY2 is a key mediator of NKX2-5 function during human cardiomyogenesis. These findings identify HEY2 as a novel component of the NKX2-5 cardiac transcriptional network, providing tangible evidence that hESC models can decipher the complex pathways that regulate early stage human heart development. These data provide a human context for the evaluation of pathogenic mutations in congenital heart disease. A gene regulatory network, including the transcription factor Nkx2-5 , regulates cardiac development. Here, the authors show that on deletion of NKX2-5 from human embryonic stem cells, there is impaired cardiomyogenesis and changes in action potentials, and that this is regulated via HEY2 .

Previous research on the effect of replacing sources of animal protein with plant protein on glycemic control has been inconsistent. We therefore conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the effect of this replacement on glycemic control in individuals with diabetes. We searched MEDLINE, EMBASE, and Cochrane databases through 26 August 2015. We included RCTs ≥ 3-weeks comparing the effect of replacing animal with plant protein on HbA1c, fasting glucose (FG), and fasting insulin (FI). Two independent reviewers extracted relevant data, assessed study quality and risk of bias. Data were pooled by the generic inverse variance method and expressed as mean differences (MD) with 95% confidence intervals (CIs). Heterogeneity was assessed (Cochran Q-statistic) and quantified (I2-statistic). Thirteen RCTs (n = 280) met the eligibility criteria. Diets emphasizing a replacement of animal with plant protein at a median level of ~35% of total protein per day significantly lowered HbA1c (MD = −0.15%; 95%-CI: −0.26, −0.05%), FG (MD = −0.53 mmol/L; 95%-CI: −0.92, −0.13 mmol/L) and FI (MD = −10.09 pmol/L; 95%-CI: −17.31, −2.86 pmol/L) compared with control arms. Overall, the results indicate that replacing sources of animal with plant protein leads to modest improvements in glycemic control in individuals with diabetes. Owing to uncertainties in our analyses there is a need for larger, longer, higher quality trials. Trial Registration: ClinicalTrials.gov registration number: NCT02037321.

The heart rhythm disorder long QT syndrome (LQTS) can result in sudden death in the young or remain asymptomatic into adulthood. The features of the surface electrocardiogram (ECG), a measure of the electrical activity of the heart, can be equally variable in LQTS patients, posing well-described diagnostic dilemmas. Here we report a correlation between QT interval prolongation and T-wave notching in LQTS2 patients and use a novel computational framework to investigate how individual ionic currents, as well as cellular and tissue level factors, contribute to notched T waves. Furthermore, we show that variable expressivity of ECG features observed in LQTS2 patients can be explained by as little as 20% variation in the levels of ionic conductances that contribute to repolarization reserve. This has significant implications for interpretation of whole-genome sequencing data and underlies the importance of interpreting the entire molecular signature of disease in any given individual. Patients with the Long QT Syndrome type 2 have abnormal cardiac electrical activity, which is diagnosed by an electrocardiogram (ECG) that shows a prolonged QT interval and a notched T wave. Here the authors uncover the origins of this signature ECG phenotype by using a multi-scale cardiac modelling.

Background Accurate whole-body staging following biochemical relapse in prostate cancer is vital in determining the optimum disease management. Current imaging guidelines recommend various imaging platforms such as computed tomography (CT), Technetium 99 m ( 99m Tc) bone scan and 18 F-choline and recently 68 Ga-PSMA positron emission tomography (PET) for the evaluation of the extent of disease. Such approach requires multiple hospital attendances and can be time and resource intensive. Recently, whole-body magnetic resonance imaging (WB-MRI) has been used in a single visit scanning session for several malignancies, including prostate cancer, with promising results, providing similar accuracy compared to the combined conventional imaging techniques. The LOCATE trial aims to investigate the application of WB-MRI for re-staging of patients with biochemical relapse (BCR) following external beam radiotherapy and brachytherapy in patients with prostate cancer. Methods/design The LOCATE trial is a prospective cohort, multi-centre, non-randomised, diagnostic accuracy study comparing WB-MRI and conventional imaging. Eligible patients will undergo WB-MRI in addition to conventional imaging investigations at the time of BCR and will be asked to attend a second WB-MRI exam, 12-months following the initial scan. WB-MRI results will be compared to an enhanced reference standard comprising all the initial, follow-up imaging and non-imaging investigations. The diagnostic performance (sensitivity and specificity analysis) of WB-MRI for re-staging of BCR will be investigated against the enhanced reference standard on a per-patient basis. An economic analysis of WB-MRI compared to conventional imaging pathways will be performed to inform the cost-effectiveness of the WB-MRI imaging pathway. Additionally, an exploratory sub-study will be performed on blood samples and exosome-derived human epidermal growth factor receptor (HER) dimer measurements will be taken to investigate its significance in this cohort. Discussion The LOCATE trial will compare WB-MRI versus the conventional imaging pathway including its cost-effectiveness, therefore informing the most accurate and efficient imaging pathway. Trial registration LOCATE trial was registered on ClinicalTrial.gov on 18th of October 2016 with registration reference number NCT02935816 .

In this study, the authors propose an optical microwave (MW) radio-over-fibre system in which an integrated dual-parallel Mach–Zehnder modulator (DP-MZM) is biased at the maximum transmission biasing point. A single drive Mach–Zehnder modulator, in series with the DP-MZM, is used to modulate the 1 GHz radio frequency data onto the optical carrier. They characterise the efficiency of the practical system in terms of power penalty and error vector magnitude. Two modulation schemes are investigated, namely binary phase shift keying (BPSK) and quadrature phase shift keying (QPSK) over fibre spans of 10 and 25 km of standard single mode fibre. The results show that the second-order sideband of MW has the potential to provide error free transmission for BPSK and QPSK. The error free communication system is achieved for BPSK at 10 and 25 km fibre spans at optical launch power (OLP) of 7 dBm, whereas for QPSK, the OLP is ∼11 and ∼12 dBm for 10 and 25 km fibre spans, respectively.

Objectives: To assess the clinical outcomes of mpMRI before biopsy and evaluate the space remaining for novel biomarkers. Methods: The INNOVATE study was set up to evaluate the validity of novel fluidic biomarkers in men with suspected prostate cancer who undergo pre-biopsy mpMRI. We report the characteristics of this clinical cohort, the distribution of clinical serum biomarkers, PSA and PSA density (PSAD), and compare the mpMRI Likert scoring system to the Prostate Imaging–Reporting and Data System v2.1 (PI-RADS) in men undergoing biopsy. Results: 340 men underwent mpMRI to evaluate suspected prostate cancer. 193/340 (57%) men had subsequent MRI-targeted prostate biopsy. Clinically significant prostate cancer (csigPCa), i.e., overall Gleason ≥ 3 + 4 of any length OR maximum cancer core length (MCCL) ≥4 mm of any grade including any 3 + 3, was found in 96/195 (49%) of biopsied patients. Median PSA (and PSAD) was 4.7 (0.20), 8.0 (0.17), and 9.7 (0.31) ng/mL (ng/mL/mL) in mpMRI scored Likert 3,4,5 respectively for men with csigPCa on biopsy. The space for novel biomarkers was shown to be within the group of men with mpMRI scored Likert3 (178/340) and 4 (70/350), in whom an additional of 40% (70/178) men with mpMRI-scored Likert3, and 37% (26/70) Likert4 could have been spared biopsy. PSAD is already considered clinically in this cohort to risk stratify patients for biopsy, despite this 67% (55/82) of men with mpMRI-scored Likert3, and 55% (36/65) Likert4, who underwent prostate biopsy had a PSAD below a clinical threshold of 0.15 (or 0.12 for men aged <50 years). Different thresholds of PSA and PSAD were assessed in mpMRI-scored Likert4 to predict csigPCa on biopsy, to achieve false negative levels of ≤5% the proportion of patients whom who test as above the threshold were unsuitably high at 86 and 92% of patients for PSAD and PSA respectively. When PSA was re tested in a sub cohort of men repeated PSAD showed its poor reproducibility with 43% (41/95) of patients being reclassified. After PI-RADS rescoring of the biopsied lesions, 66% (54/82) of the Likert3 lesions received a different PI-RADS score. Conclusions: The addition of simple biochemical and radiological markers (Likert and PSAD) facilitate the streamlining of the mpMRI-diagnostic pathway for suspected prostate cancer but there remains scope for improvement, in the introduction of novel biomarkers for risk assessment in Likert3 and 4 patients, future application of novel biomarkers tested in a Likert cohort would also require re-optimization around Likert3/PI-RADS2, as well as reproducibility testing.