Compensation of inner retina to early-stage photoreceptor degeneration in a RhoP23H/+ mouse model of retinitis pigmentosa.

Retinitis pigmentosa (RP) is an inherited retinal disorder characterized by the degeneration of photoreceptors. RhoP23H/+ mice, which carry a Pro23His mutation in the RHODOPSIN (Rho) gene, are one of the most studied animal models for RP. However, except for the photoreceptors, other retinal neural cells have not been fully investigated in this model. Here, we record the temporal changes of the retina by optical coherence tomography (OCT) imaging of the RhoP23H/+ mice, from early to mid-phase of retinal degeneration. Based on thickness analysis, we identified a natural retinal thickness adaption in wild-type mice during early adulthood and observed morphological compensation of the inner retina layer to photoreceptor degeneration in the RhoP23H/+ mice, primarily on the inner nuclear layer (INL). RhoP23H/+ mice findings were further validated via: histology showing the negative correlation of INL and ONL thicknesses; as well as electroretinogram (ERG) showing an increased b-wave to a-wave ratio. These results unravel the sequential morphologic events in this model and suggest a better understanding of retinal degeneration of RP for future studies.

Laser Applications in Wound and Scar Management Post-Mohs Micrographic Surgery: A Systematic Review.

Mohs micrographic surgery (MMS) can lead to complications such as scarring and delayed wound healing, particularly in sensitive areas such as the face, neck, and chest. This study aims to assess the evidence regarding the use of lasers post-MMS for wound healing and scar revision. A comprehensive systematic review of the literature was performed using databases including MEDLINE, PubMed, EMBASE, Web of Science, Cochrane Library, and CINAHL from inception until July 25, 2022. A total of 2147 unique studies were identified, from which 17 were included in the analysis. A total of 17 studies reported applications of lasers with favourable efficacy including wound healing (n = 1), resurfacing of full-thickness skin grafts and split-thickness skin grafts (n = 4), periscar telangiectasias (n = 1), functional scar contractures (n = 2), and scar texture (n = 9). Minimal adverse effects were reported with the use of lasers post-MMS. Overall, the use of lasers post-MMS is a safe and well-tolerated option for scar revision with high patient satisfaction and is less invasive than surgical interventions.

Probing the Limits to Near-Field Heat Transfer Enhancements in Phonon-Polaritonic Materials.

Near-field radiative heat transfer (NFRHT) arises between objects separated by nanoscale gaps and leads to dramatic enhancements in heat transfer rates compared to the far-field. Recent experiments have provided first insights into these enhancements, especially using silicon dioxide (SiO2) surfaces, which support surface phonon polaritons (SPhP). Yet, theoretical analysis suggests that SPhPs in SiO2 occur at frequencies far higher than optimal. Here, we first show theoretically that SPhP-mediated NFRHT, at room temperature, can be 5-fold larger than that of SiO2, for materials that support SPhPs closer to an optimal frequency of 67 meV. Next, we experimentally demonstrate that MgF2 and Al2O3 closely approach this limit. Specifically, we demonstrate that near-field thermal conductance between MgF2 plates separated by 50 nm approaches within nearly 50% of the global SPhP bound. These findings lay the foundation for exploring the limits to radiative heat transfer rates at the nanoscale.

Phoresy and Mites: More Than Just a Free Ride.

Mites are masters at attaching to larger animals, often insects, in a temporary symbiosis called phoresy that allows these tiny animals to exploit patchy resources. In this article, we examine phoresy in the Acari, including those that feed on their carriers in transit, from a broad perspective. From a phylogenetic perspective, phoresy has evolved several times from free-living ancestors but also has been lost frequently. Rotting logs appear to be the first patchy resource exploited by phoretic mites, but the evolution of rapid life cycles later permitted exploitation of short-lived resources. As phoresy is a temporary symbiosis, most species have off-host interactions with their carrier. These relationships can be highly complex and context dependent but often are exploitative of the carrier's resources or progeny. Transitions from phoresy to parasitism seem widespread, but evidence for transitions from obligate phoretic parasitism to permanent parasitism is weak.

Obstructive sleep apnea in the patient with atrial fibrillation: current knowledge and remaining uncertainties.

PURPOSE OF REVIEW: Obstructive sleep apnea (OSA) is highly prevalent in patients with atrial fibrillation and plays a causal role for OSA in the pathogenesis of atrial fibrillation. The presence of OSA in atrial fibrillation is associated with increased symptom burden and increased risk of hospitalizations. Furthermore, untreated OSA is associated with an increased risk of atrial fibrillation recurrence post ablation or cardioversion, and observational studies suggest that continuous positive airway pressure (CPAP) therapy can attenuate this risk. This review describes our current understanding of the relationship between OSA and atrial fibrillation with an emphasis on emerging evidence. RECENT FINDINGS: Recent studies have identified novel screening questionnaires, which may be superior to traditional questionnaires in identifying OSA in atrial fibrillation populations. Significant night-to-night variability in OSA severity has been shown in atrial fibrillation patients, which has implications for diagnostic testing. While several small, randomized control trials (RCTs) have not shown CPAP therapy to be effective in reducing atrial fibrillation burden, one RCT did show CPAP can attenuate the atrial substrate with implications for long-term outcomes. SUMMARY: Further RCTs, appropriately powered, and focused on well defined cohorts, are required to guide management decisions regarding screening and treatment of OSA in atrial fibrillation populations.

Outpatient visit trends for internal medicine ambulatory care sensitive conditions after the COVID-19 pandemic: a time-series analysis.

BACKGROUND: The COVID-19 pandemic led to a dramatic shift in the delivery of outpatient medicine with reduced in-person visits and a transition to predominantly virtual visits. We sought to understand trends in visit patterns for ambulatory care sensitive conditions (ACSCs) commonly seen in internal medicine clinics. METHODS: We included adult outpatients seen for an ACSC between March 15th, 2017 and March 14th, 2021 at a single-centre in Ontario, Canada. Monthly visits were assessed by visit type (new consultation, follow-up), diagnosis, and clinic. Time series analyses compared visit volumes pre- and post-pandemic. Proportion of virtual visits were compared before and during the pandemic. Patient and visit factors were compared between in-person and virtual visits. RESULTS: 8274 patients with 34,021 visits were included. Monthly visits increased by 15% during the pandemic (p <  0.0001). New consultations decreased by 10% (p = 0.0053) but follow-up visits increased by 21% (p <  0.0001). Monthly heart failure visits increased by 43% (p <  0.0001) whereas atrial fibrillation visits decreased. Pre- pandemic, < 1% of visits were virtual compared to 82% during the pandemic (p <  0.0001). Less than half of heart failure visits were virtual whereas > 95% of diabetes visits were virtual. CONCLUSIONS: We found a significant increase in overall visits to internal medicine clinics driven by increased volumes of follow-up visits, which more than offset decreased new consultations. There was variability in visit trends and uptake of virtual care by visit diagnosis, which may indicate challenges with delivery of virtual care for certain conditions.

Conservation-Law-Based Global Bounds to Quantum Optimal Control.

Active control of quantum systems enables diverse applications ranging from quantum computation to manipulation of molecular processes. Maximum speeds and related bounds have been identified from uncertainty principles and related inequalities, but such bounds utilize only coarse system information and loosen significantly in the presence of constraints and complex interaction dynamics. We show that an integral-equation-based formulation of conservation laws in quantum dynamics leads to a systematic framework for identifying fundamental limits to any quantum control scenario. We demonstrate the utility of our bounds in three scenarios-three-level driving, decoherence suppression, and maximum-fidelity gate implementations-and show that in each case our bounds are tight or nearly so. Global bounds complement local-optimization-based designs, illuminating performance levels that may be possible, as well as those that cannot be surpassed.

Development and evaluation of stem cell collection procedure diagrams to support the education and recruitment of committed stem cell donors.

BACKGROUND: Diagrams which allow potential unrelated stem cell donors to visualize the stem cell collection process were hypothesized to support the recruitment and education of committed stem cell donors. STUDY DESIGN AND METHODS: A series of bone marrow and peripheral blood stem cell collection procedure diagrams were developed, featuring young adult male donors of varied ethnic backgrounds. Post-implementation, surveys were conducted to evaluate stakeholder perspective on the diagrams' utility. A quality improvement project was conducted at five stem cell drives from 2017 to 2018 at which recruiters did or did not show the diagrams to potential donors. Following the drives, registrants were invited to complete a survey exploring their experience, knowledge and attitude towards donation. RESULTS: The diagrams were implemented in Canada in 07/2016. Of 293 participating registrants (24·7% non-Caucasian males) recruited at five drives between 2017 and 2018, 76% (n = 197) were shown the diagrams. Participants who were shown the diagrams were significantly more likely to report that the recruiters appeared very knowledgeable (89% vs. 76%, P = 0·019) and to report improved self-reported knowledge of stem cell donation (P = 0·010) compared to participants not shown the diagram. Data are also shown demonstrating that stakeholders in donor recruitment used and valued the diagrams and that use of the diagrams was associated with improved donor recruitment outcomes in Canada. CONCLUSION: This report is the first evaluation of stem cell collection diagrams in the literature. The diagrams are relevant to donor registries, recruitment organizations and transplant centres worldwide, and their use may support efforts to educate and recruit committed, ethnically diverse donors.

Feasibility of function-guided lung treatment planning with parametric response mapping.

PURPOSE: Recent advancements in functional lung imaging have been developed to improve clinicians' knowledge of patient pulmonary condition prior to treatment. Ultimately, it may be possible to employ these functional imaging modalities to tailor radiation treatment plans to optimize patient outcome and mitigate pulmonary complications. Parametric response mapping (PRM) is a computed tomography (CT)-based functional lung imaging method that utilizes a voxel-wise image analysis technique to classify lung abnormality phenotypes, and has previously been shown to be effective at assessing lung complication risk in diagnostic applications. The purpose of this work was to demonstrate the implementation of PRM guidance in radiotherapy treatment planning. METHODS AND MATERIALS: A retrospective study was performed with 18 lung cancer patients to test the incorporation of PRM into a radiotherapy planning workflow. Paired inspiration/expiration pretreatment CT scans were acquired and PRM analysis was utilized to classify each voxel as normal, parenchymal disease, small airway disease, and emphysema. Density maps were generated for each PRM classification to contour high density regions of pulmonary abnormalities. Conventional volumetric-modulated arc therapy and PRM-guided treatment plans were designed for each patient. RESULTS: PRM guidance was successfully implemented into the treatment planning process. The inclusion of PRM priorities resulted in statistically significant (p < 0.05) improvements to the V20Gy within the PRM avoidance contours. On average, reductions of 5.4% in the V20Gy(%) were found. The PRM-guided treatment plans did not significantly increase the dose to the organs at risk or result in insufficient planning target volume coverage, but did increase plan complexity. CONCLUSIONS: PRM guidance was successfully implemented into a treatment planning workflow and shown to be effective for dose redistribution within the lung. This work has provided a framework for the potential clinical implementation of PRM-guided treatment planning.

The Impact of Extreme Heat Events on Emergency Departments in Canadian Hospitals.

INTRODUCTION: Mean daily temperatures in Canada rose 1.7°C between 1948 and 2016, and the frequency, severity, and duration of extreme heat events has increased. These events can exacerbate underlying health conditions, bringing patients to emergency departments (EDs). This retrospective analysis assessed the impact of temperature and humidex on ED volume and length of stay (LOS). METHODS: LOS is an indicator of ED overcrowding and system performance. Using daily maximum temperatures and humidex values, this study investigated the impact of mean 3-d temperatures and humidex preceding ED presentation on the median and maximum ED LOS and patient volume in 2 community hospitals in Montreal, Quebec, during the summer months of 2016 to 2018. Data were analyzed with 1-way analysis of variance with post hoc Fisher least significant difference tests and Spearman correlation tests. RESULTS: The mean maximum temperature and humidex were 26.1°C and 30.4°C, respectively (n=276 d). Mean 3-d temperatures ≥30°C were associated with higher daily ED volumes in both hospitals (138 vs 121, P=0.002 and 132 vs 125, P=0.03) and with increased median LOS at 1 hospital (8.9 vs 7.6 h, P=0.03). Mean 3-d humidex ≥35 was associated with higher daily ED volumes at both hospitals as well (136 vs 123, P=0.01 and 133 vs 125, P=0.009) with an increased median LOS at 1 hospital (8.6 vs 6.9 h, P=0.0001) with humidex values of 25 to 29.9°C. CONCLUSIONS: Heat events were associated with increased ED presentations and LOS. This study suggests that a warming climate can impede emergency service provision by increasing the demand for and delaying timely care.

Tumor Necrosis Factor-α-Mediated Metaplastic Inhibition of LTP Is Constitutively Engaged in an Alzheimer's Disease Model.

LTP, a fundamental mechanism of learning and memory, is a highly regulated process. One form of regulation is metaplasticity (i.e., the activity-dependent and long-lasting changes in neuronal state that orchestrate the direction, magnitude, and persistence of future synaptic plasticity). We have previously described a heterodendritic metaplasticity effect, whereby strong high-frequency priming stimulation in stratum oriens inhibits subsequent LTP in the stratum radiatum of hippocampal area CA1, potentially by engagement of the enmeshed astrocytic network. This effect may occur due to neuron-glia interactions in response to priming stimulation that leads to the release of gliotransmitters. Here we found in male rats that TNFα and associated signal transduction enzymes, but not interleukin-1ß (IL-1ß), were responsible for mediating the metaplasticity effect. Replacing priming stimulation with TNFα incubation reproduced these effects. As TNFα levels are elevated in Alzheimer's disease, we examined whether heterodendritic metaplasticity is dysregulated in a transgenic mouse model of the disease, either before or after amyloid plaque formation. We showed that TNFα and IL-1ß levels were significantly increased in aged but not young transgenic mice. Although control LTP was impaired in the young transgenic mice, it was not TNFα-dependent. In the older transgenic mice, however, LTP was impaired in a way that occluded further reduction by heterosynaptic metaplasticity, whereas LTP was entirely rescued by incubation with a TNFα antibody, but not an IL-1ß antibody. Thus, TNFα mediates a heterodendritic metaplasticity in healthy rodents that becomes constitutively and selectively engaged in a mouse model of Alzheimer's disease.SIGNIFICANCE STATEMENT The proinflammatory cytokine TNFα is known to be capable of inhibiting LTP and is upregulated several-fold in brain tissue, serum, and CSF of Alzheimer's disease (AD) patients. However, the mechanistic roles played by TNFα in plasticity and AD remain poorly understood. Here we show that TNFα and its downstream signaling molecules p38 MAPK, ERK, and JNK contribute fundamentally to a long-range metaplastic inhibition of LTP in rats. Moreover, the impaired LTP in aged APP/PS1 mice is rescued by incubation with a TNFα antibody. Thus, there is an endogenous engagement of the metaplasticity mechanism in this mouse model of AD, supporting the idea that blocking TNFα might be of therapeutic benefit in the disease.

High-NA achromatic metalenses by inverse design.

We use inverse design to discover metalens structures that exhibit broadband, achromatic focusing across low, moderate, and high numerical apertures. We show that standard unit-cell approaches cannot achieve high-efficiency high-NA focusing, even at a single frequency, due to the incompleteness of the unit-cell basis, and we provide computational upper bounds on their maximum efficiencies. At low NA, our devices exhibit the highest theoretical efficiencies to date. At high NA-of 0.9 with translation-invariant films and of 0.99 with "freeform" structures-our designs are the first to exhibit achromatic high-NA focusing.

Approaching the upper limits of the local density of states via optimized metallic cavities.

By computational optimization of air-void cavities in metallic substrates, we show that the local density of states (LDOS) can reach within a factor of ≈10 of recent theoretical upper limits and within a factor ≈4 for the single-polarization LDOS, demonstrating that the theoretical limits are nearly attainable. Optimizing the total LDOS results in a spontaneous symmetry breaking where it is preferable to couple to a specific polarization. Moreover, simple shapes such as optimized cylinders attain nearly the performance of complicated many-parameter optima, suggesting that only one or two key parameters matter in order to approach the theoretical LDOS bounds for metallic resonators.

Limits to surface-enhanced Raman scattering near arbitrary-shape scatterers: erratum.

In this erratum, we correct two minor algebraic errors from our previous published manuscript [Opt. Express 27, 35189 (2019)], which do not affect the main results or conclusions, and make a corresponding small change to one figure.

Computational Bounds to Light-Matter Interactions via Local Conservation Laws.

We develop a computational framework for identifying bounds to light-matter interactions, originating from polarization-current-based formulations of local conservation laws embedded in Maxwell's equations. We propose an iterative method for imposing only the maximally violated constraints, enabling rapid convergence to global bounds. Our framework can identify bounds to the minimum size of any scatterer that encodes a specific linear operator, given only its material properties, as we demonstrate for the optical computation of a discrete Fourier transform. It further resolves bounds on far-field scattering properties over any arbitrary bandwidth, where previous bounds diverge.

Effect of Ultrafiltration on Sleep Apnea and Cardiac Function in End-Stage Renal Disease.

RATIONALE: End-stage renal disease (ESRD) patients have high annual mortality mainly due to cardiovascular causes. The acute effects of obstructive and central sleep apnea on cardiac function in ESRD patients have not been determined. We therefore tested, in patients with ESRD, the hypotheses that (1) sleep apnea induces deterioration in cardiac function overnight and (2) attenuation of sleep apnea severity by ultrafiltration (UF) attenuates this deterioration. METHODS: At baseline, ESRD patients, on conventional hemodialysis, with left ventricular ejection fraction (LVEF) >45% had polysomnography (PSG) performed on a non-dialysis day to determine the apnea-hypopnea index (AHI). Echocardiography was performed at the bedside, before and after sleep. Isovolumetric contraction time divided by left ventricular ejection time (IVCT/ET) and isovolumetric relaxation time divided by ET (IVRT/ET) were measured by tissue doppler imaging. The myocardial performance index (MPI), a composite of systolic and diastolic function was also calculated. One week later, subjects with sleep apnea (AHI ≥15) had fluid removed by UF, followed by repeat PSG and echocardiography. -Results: Fifteen subjects had baseline measurements, of which 7 had an AHI <15 (no-sleep-apnea group) and 8 had an AHI ≥15 (sleep-apnea group). At baseline, there was no overnight change in the LVEF in either the no-sleep-apnea group or the sleep-apnea group. In the no-sleep-apnea group, there was also no overnight change in MPI, IVCT/ET and IVRT/ET. However, in the sleep-apnea group there were overnight increases in MPI, IVCT/ET and IVRT/ET (p = 0.008, 0.007 and 0.031, respectively), indicating deterioration in systolic and diastolic function. Following fluid removal by UF in the sleep-apnea group, the AHI decreased by 48.7% (p = 0.012) and overnight increases in MPI, IVCT/ET and IVRT/ET observed at baseline were abolished. CONCLUSIONS: In ESRD, cardiac function deteriorates overnight in those with sleep apnea, but not in those without sleep apnea. This overnight deterioration in the sleep-apnea group may be at least partially due to sleep apnea, since attenuation of sleep apnea by UF was accompanied by elimination of this deleterious overnight effect.

Changes in pulmonary restrictive parameters by intensive home hemodialysis: a case report.

BACKGROUND: Patients with End-Stage Renal Disease (ESRD) are at an increased risk for restrictive lung disease due to accumulation of uremic toxins and volume overload. Hemodialysis is the preferred treatment for improving lung function in dialysis patients. However, the effects of fluid removal and solute clearance by hemodialysis on lung function remain unclear. CASE PRESENTATION: We report a case of restrictive lung disorder in a hemodialysis patient, who showed improvement in both clinical and spirometric lung function after initiation of intensive home hemodialysis (32 h per week). CONCLUSION: Intensive hemodialysis augments fluid removal and solute clearance, which in turn may improve restrictive lung function.

Predicting the knowledge-recklessness distinction in the human brain.

Criminal convictions require proof that a prohibited act was performed in a statutorily specified mental state. Different legal consequences, including greater punishments, are mandated for those who act in a state of knowledge, compared with a state of recklessness. Existing research, however, suggests people have trouble classifying defendants as knowing, rather than reckless, even when instructed on the relevant legal criteria. We used a machine-learning technique on brain imaging data to predict, with high accuracy, which mental state our participants were in. This predictive ability depended on both the magnitude of the risks and the amount of information about those risks possessed by the participants. Our results provide neural evidence of a detectable difference in the mental state of knowledge in contrast to recklessness and suggest, as a proof of principle, the possibility of inferring from brain data in which legally relevant category a person belongs. Some potential legal implications of this result are discussed.

Limits to surface-enhanced Raman scattering near arbitrary-shape scatterers.

The low efficiency of Raman spectroscopy can be overcome by placing the active molecules in the vicinity of scatterers, typically rough surfaces or nanostructures with various shapes. This surface-enhanced Raman scattering (SERS) leads to substantial enhancement that depends on the scatterer that is used. In this work, we find fundamental upper bounds on the Raman enhancement for arbitrary-shaped scatterers, depending only on its material constants and the separation distance from the molecule. According to our metric, silver is optimal in visible wavelengths while aluminum is better in the near-UV region. Our general analytical bound scales as the volume of the scatterer and the inverse sixth power of the distance to the active molecule. Numerical computations show that simple geometries fall short of the bounds, suggesting further design opportunities for future improvement. For periodic scatterers, we use two formulations to discover different bounds, and the tighter of the two always must apply. Comparing these bounds suggests an optimal period depending on the volume of the scatterer.

IFN-stimulated Gene Expression, Type 2 Inflammation, and Endoplasmic Reticulum Stress in Asthma.

RATIONALE: Quantification of type 2 inflammation provided a molecular basis for heterogeneity in asthma. Non-type 2 pathways that contribute to asthma pathogenesis are not well understood. OBJECTIVES: To identify dysregulated pathways beyond type 2 inflammation. METHODS: We applied RNA sequencing to airway epithelial brushings obtained from subjects with stable mild asthma not on corticosteroids (n = 19) and healthy control subjects (n = 16). Sequencing reads were mapped to human and viral genomes. In the same cohort, and in a separate group with severe asthma (n = 301), we profiled blood gene expression with microarrays. MEASUREMENTS AND MAIN RESULTS: In airway brushings from mild asthma on inhaled corticosteroids, RNA sequencing yielded 1,379 differentially expressed genes (false discovery rate < 0.01). Pathway analysis revealed increased expression of type 2 markers, IFN-stimulated genes (ISGs), and endoplasmic reticulum (ER) stress-related genes. Airway epithelial ISG expression was not associated with type 2 inflammation in asthma or with viral transcripts but was associated with reduced lung function by FEV1 (ρ = -0.72; P = 0.0004). ER stress was confirmed by an increase in XBP1 (X-box binding protein 1) splicing in mild asthma and was associated with both type 2 inflammation and ISG expression. ISGs were also the most activated genes in blood cells in asthma and were correlated with airway ISG expression (ρ = 0.55; P = 0.030). High blood ISG expression in severe asthma was similarly unrelated to type 2 inflammation. CONCLUSIONS: ISG activation is prominent in asthma, independent of viral transcripts, orthogonal to type 2 inflammation, and associated with distinct clinical features. ER stress is associated with both type 2 inflammation and ISG expression.