Analytical Sensitivity Analysis and Clinical Impact Modeling of Rapigen Rapid Diagnostic Tests for Malaria.

Laboratory benchmarking allows objective analysis of the analytical performance of malaria rapid diagnostic tests (RDTs). We present the analytical detection limits of the Rapigen BIOCREDIT Malaria Ag Pf/Pv (pLDH/pLDH), the Rapigen BIOCREDIT Malaria Ag Pf (pLDH/HRPII), and two best-in-class WHO-prequalified comparator RDTs, generated using standardized panels containing recombinant antigen, in vitro cultured parasites, international standards, and clinical samples. Detection limit antigen concentrations of HRP2, PfLDH, and PvLDH were determined for the Rapigen and comparator RDTs. Detection of antigens in international units (IU)/mL was also evaluated. The Rapigen Ag Pf (pLDH/HRPII) detected 3.9 and 3.9 IU/mL for PfLDH and HRP2, respectively, and the Ag Pf/Pv (pLDH/pLDH) detected 3.9 and 5.0 IU/mL for PfLDH and PvLDH, respectively. The comparator HRP2/PfLDH and HRP2/PvLDH detected 15.6 and 31.3 IU/mL for HRP2 and PfLDH and 15.6 and 50.0 IU/mL for HRP2 and PvLDH, respectively. The RDT clinical sensitivity was predicted through application of analytical detection limits to antigen concentration distributions from clinical symptomatic and asymptomatic cases. Febrile cases would be detected in a majority by both standard and Rapigen RDTs, but incremental increases in sensitivity in the Rapigen RDTs may be important for clinical cases currently missed by microscopy. Rapigen RDTs were predicted to have improved detection of asymptomatic cases and infections with parasites carrying hrp2 deletions through more sensitive PfLDH detection. Through the benchmarking and simulation of clinical sensitivity, a method for rapidly assessing the ability of new RDTs to meet clinical needs using high-sensitivity antigen distribution data is presented.

Perioperative Regional Anesthesia on Persistent Opioid Use and Chronic Pain after Noncardiac Surgery: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Whether regional anesthesia impacts the development of chronic postsurgical pain is currently debateable, and few studies have evaluated an effect on prolonged opioid use. We sought to systematically review the effect of regional anesthesia for adults undergoing noncardiac elective surgery on these outcomes. METHODS: A systematic search was conducted in MEDLINE, EMBASE, CENTRAL, and CINHAL for randomized controlled trials (from inception to April 2022) of adult patients undergoing elective noncardiac surgeries that evaluated any regional technique and included one of our primary outcomes: (1) prolonged opioid use after surgery (continued opioid use ≥2 months postsurgery) and (2) chronic postsurgical pain (pain ≥3 months postsurgery). We conducted a random-effects meta-analysis on the specified outcomes and used the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach to rate the quality of evidence. RESULTS: Thirty-seven studies were included in the review. Pooled estimates indicated that regional anesthesia had a significant effect on reducing prolonged opioid use (relative risk [RR] 0.48, 95% CI, 0.24-0.96, P = .04, I2 0%, 5 trials, n = 348 patients, GRADE low quality). Pooled estimates for chronic pain also indicated a significant effect favoring regional anesthesia at 3 (RR, 0.74, 95% CI, 0.59-0.93, P = .01, I2 77%, 15 trials, n = 1489 patients, GRADE moderate quality) and 6 months (RR, 0.72, 95% CI, 0.61-0.85, P < .001, I2 54%, 19 trials, n = 3457 patients, GRADE moderate quality) after surgery. No effect was found in the pooled analysis at 12 months postsurgery (RR, 0.44, 95% CI, 0.16-1.17, P = .10). CONCLUSIONS: The results of this study suggest that regional anesthesia potentially reduces chronic postsurgical pain up to 6 months after surgery. Our findings also suggest a potential decrease in the development of persistent opioid use.

The dorsal thalamic lateral geniculate nucleus is required for visual control of head direction cell firing direction in rats.

Head direction (HD) neurons, signalling facing direction, generate a signal that is primarily anchored to the outside world by visual inputs. We investigated the route for visual landmark information into the HD system in rats. There are two candidates: an evolutionarily older, larger subcortical retino-tectal pathway and a more recently evolved, smaller cortical retino-geniculo-striate pathway. We disrupted the cortical pathway by lesioning the dorsal lateral geniculate thalamic nuclei bilaterally, and recorded HD cells in the postsubicular cortex as rats foraged in a visual-cue-controlled enclosure. In lesioned rats we found the expected number of postsubicular HD cells. Although directional tuning curves were broader across a trial, this was attributable to the increased instability of otherwise normal-width tuning curves. Tuning curves were also poorly responsive to polarizing visual landmarks and did not distinguish cues based on their visual pattern. Thus, the retino-geniculo-striate pathway is not crucial for the generation of an underlying, tightly tuned directional signal but does provide the main route for vision-based anchoring of the signal to the outside world, even when visual cues are high in contrast and low in detail. KEY POINTS: Head direction (HD) cells indicate the facing direction of the head, using visual landmarks to distinguish directions. In rats, we investigated whether this visual information is routed through the thalamus to the visual cortex or arrives via the superior colliculus, which is a phylogenetically older and (in rodents) larger pathway. We lesioned the thalamic dorsal lateral geniculate nucleus (dLGN) in rats and recorded the responsiveness of cortical HD cells to visual cues. We found that cortical HD cells had normal tuning curves, but these were slightly more unstable during a trial. Most notably, HD cells in dLGN-lesioned animals showed little ability to distinguish highly distinct cues and none to distinguish more similar cues. These results suggest that directional processing of visual landmarks in mammals requires the geniculo-cortical pathway, which raises questions about when and how visual directional landmark processing appeared during evolution.

Agrobiodiversity conservation enables sustainable and equitable land sparing.

Intensifying agriculture to spare land for nature could help meet competing food security and biodiversity conservation goals. However, this approach neglects and undervalues agrobiodiversity, currently maintained by millions of smallholder farmers. For intensification to be sustainable and land sparing to be achieved equitably, we must conserve high-agrobiodiversity landscapes.

The clinical impact of contact lens wear on neural structure and function of the cornea.

Contact lens (CL) use is growing rapidly, with a current estimate of over 100 million wearers worldwide. Vast improvements in materials and designs have occurred over the past decades with advancements in the understanding of ocular surface health with CL wear. However, the potential impact of CL on neural structures and function of the ocular surface, particularly in relation to the richly innervated cornea, remain poorly understood. Problems with sensation such as CL discomfort and conditions that may be associated with lens wear including dry eye disease also remain pervasive. This narrative review discusses the findings from studies involving soft or rigid CL wearers, assessed with c linical techniques designed for examining the neural integrity of the cornea, namely in vivo confocal microscopy and esthesiometry. While the collective findings remain equivocal in terms of the changes in corneal nerve morphology and function with conventional CL wear, more specialised CLs, namely orthokeratology lenses, which mechanically manipulates the structure of the cornea seem to produce more prominent changes in nerve distribution and sensitivity reduction. Given the intricate relationship between neural and immune mechanisms in maintaining balanced ocular surface health, the potential links between these structural and functional findings with parainflammation and neuroinflammation, as well as clinical issues including CL discomfort and dry eye disease, are also explored.

Periaqueductal gray connectivity in spinal cord injury-induced neuropathic pain.

BACKGROUND AND PURPOSE: Neuropathic pain (NP) is a debilitating condition following spinal cord injury (SCI). The role of periaqueductal gray (PAG) in NP development following SCI remains underexplored. Using resting-state functional MRI (rsfMRI), our study aimed to demonstrate the alterations in functional connectivity (FC) of PAG in NP following SCI. METHODS: Ten SCI patients (SCI + NP, n = 7, and SCI - NP, n = 3), alongside 10 healthy controls (HCs), were enrolled. rsfMRI was conducted followed by seed-to-voxel analysis using PAG as the seed region and then group-based analysis comprising three groups (SCI + NP, SCI - NP, and HC). Age and gender were considered as confounding variables. RESULTS: Compared to HCs, SCI + NP demonstrated decreased FC between PAG and right insula, right frontal orbital cortex, right pallidum, dorsal raphe nucleus (DRN), red nuclei (RN), substantia nigra (SN), and ventral posterolateral (VPL) thalamic nuclei. Compared to SCI - NP, SCI + NP demonstrated increased FC between PAG and posterior cingulate cortex (PCC), hippocampus, cerebellar vermis lobules IV and V, and thalamic structures (posterior and lateral pulvinar, the mediodorsal nuclei, and the ventral lateral nuclei). Additionally, decreased FC between the PAG and VPL, geniculate bodies, intralaminar nuclei of thalamus, DRN, RN, SN, and prefrontal cortex was observed in this comparison. CONCLUSIONS: Altered FC between PAG and right anterior insula, VPL, DRN, RN, SN, cerebellar vermis lobules IV and V, frontal cortex, and PCC was associated with NP sequelae of SCI. Additionally, SCI was independently associated with decreased FC between PAG and right posterior insula, cerebellar lobules IV and V, and cerebellar vermis lobules III, IV, and V.

AcrIF11 is a potent CRISPR-specific ADP-ribosyltransferase encoded by phage and plasmid.

Phage-encoded anti-CRISPR (Acr) proteins inhibit CRISPR-Cas systems to allow phage replication and lysogeny maintenance. Most of the Acrs characterized to date are stable stoichiometric inhibitors, and while enzymatic Acrs have been characterized biochemically, little is known about their potency, specificity, and reversibility. Here, we examine AcrIF11, a widespread phage and plasmid-encoded ADP-ribosyltransferase (ART) that inhibits the Type I-F CRISPR-Cas system. We present an NMR structure of an AcrIF11 homolog that reveals chemical shift perturbations consistent with NAD (cofactor) binding. In experiments that model both lytic phage replication and MGE/lysogen stability under high targeting pressure, AcrIF11 is a highly potent CRISPR-Cas inhibitor and more robust to Cas protein level fluctuations than stoichiometric inhibitors. Furthermore, we demonstrate that AcrIF11 is remarkably specific, predominantly ADP-ribosylating Csy1 when expressed in P. aeruginosa . Given the reversible nature of ADP-ribosylation, we hypothesized that ADPr eraser enzymes (macrodomains) could remove ADPr from Csy1, a potential limitation of PTM-based CRISPR inhibition. We demonstrate that diverse macrodomains can indeed remove the modification from Csy1 in P. aeruginosa lysate. Together, these experiments connect the in vitro observations of AcrIF11's enzymatic activity to its potent and specific effects in vivo , clarifying the advantages and drawbacks of enzymatic Acrs in the evolutionary arms race between phages and bacteria.

Extensive exploration of structure activity relationships for the SARS-CoV-2 macrodomain from shape-based fragment merging and active learning.

The macrodomain contained in the SARS-CoV-2 non-structural protein 3 (NSP3) is required for viral pathogenesis and lethality. Inhibitors that block the macrodomain could be a new therapeutic strategy for viral suppression. We previously performed a large-scale X-ray crystallography-based fragment screen and discovered a sub-micromolar inhibitor by fragment linking. However, this carboxylic acid-containing lead had poor membrane permeability and other liabilities that made optimization difficult. Here, we developed a shape- based virtual screening pipeline - FrankenROCS - to identify new macrodomain inhibitors using fragment X-ray crystal structures. We used FrankenROCS to exhaustively screen the Enamine high-throughput screening (HTS) collection of 2.1 million compounds and selected 39 compounds for testing, with the most potent compound having an IC 50 value equal to 130 µM. We then paired FrankenROCS with an active learning algorithm (Thompson sampling) to efficiently search the Enamine REAL database of 22 billion molecules, testing 32 compounds with the most potent having an IC 50 equal to 220 µM. Further optimization led to analogs with IC 50 values better than 10 µM, with X-ray crystal structures revealing diverse binding modes despite conserved chemical features. These analogs represent a new lead series with improved membrane permeability that is poised for optimization. In addition, the collection of 137 X-ray crystal structures with associated binding data will serve as a resource for the development of structure-based drug discovery methods. FrankenROCS may be a scalable method for fragment linking to exploit ever-growing synthesis-on- demand libraries.

Symptoms across the phases of the migraine cycle from the patient's perspective: Results of the MiCOAS qualitative study.

OBJECTIVE: To better understand the breadth and frequency of symptoms across the phases of the migraine cycle using data captured from qualitative patient interviews conducted through the Migraine Clinical Outcome Assessment System (MiCOAS) project. BACKGROUND: People living with migraine experience a range of symptoms across the pre-headache, headache, post-headache, and interictal phases of the migraine cycle. Although clinical diagnostic criteria and clinical trial endpoints focus largely on cardinal symptoms or monthly migraine days, migraine symptom profiles are far more complex. As a part of the MiCOAS project, semi-structured qualitative interviews were undertaken to better understand the migraine-related symptomology from the patient's viewpoint. METHODS: This concept elicitation study used iterative purposeful sampling to select 40 people with self-reported medical diagnosis of migraine for interviews that were conducted via audio-only web conferencing. Key topics related to migraine symptoms, including mood/emotion symptoms, were identified using content analysis. Interview transcripts were also coded to reflect the phase of migraine under discussion, so that patient experiences could be compared by phase. RESULTS: Forty participants (50%, n = 20 episodic migraine; 50%, n = 20 chronic migraine), aged from 21 to 70 years old reported a total of 60 unique symptoms, which were categorized into 30 broader symptom categories. Participants reported between 7 and 22 unique symptom categories across all phases. During pre-headache and headache, participants reported a median of 7.5 (interquartile range [IQR] = 5.5) and 8 (IQR = 4.0) different symptom categories compared to 4 (IQR = 3.0) and 1.5 (IQR = 2.5) for the post-headache and interictal periods, respectively. Head pain during the headache phase was the only universally reported symptom (100%, n = 40). Pooling across all phases, the next most reported symptoms were light sensitivity (93%, n = 37), nausea (88%, n = 35), irritability/impatience (83%, n = 24), sound sensitivity (80%, n = 32), and fatigue/exhaustion (80%, n = 32). One or more interictal symptoms were reported by 73% (n = 29) of participants and included mood/emotion symptoms, such as anxiety (30%, n = 12), depression (18%, n = 7), and anger (15%, n = 6), as well as cardinal symptoms, such as light sensitivity (13%, n = 5) and nausea (13%, n = 5). CONCLUSIONS: Patients experience a range of symptoms across the phases of the migraine cycle. Results often aligned with clinical expectations, but non-cardinal migraine-related symptoms were reported both inside and outside the headache phase, including between attacks. These discoveries highlight the importance of assessing a range of symptoms and timing when developing patient-reported outcome measures for migraine clinical trials.

Prior exposure to pathogens augments host heterogeneity in susceptibility and has key epidemiological consequences.

Pathogen epidemics are key threats to human and wildlife health. Across systems, host protection from pathogens following initial exposure is often incomplete, resulting in recurrent epidemics through partially-immune hosts. Variation in population-level protection has important consequences for epidemic dynamics, but how acquired protection influences inter-individual heterogeneity in susceptibility and its epidemiological consequences remains understudied. We experimentally investigated whether prior exposure (none, low-dose, or high-dose) to a bacterial pathogen alters host heterogeneity in susceptibility among songbirds. Hosts with no prior pathogen exposure had little variation in protection, but heterogeneity in susceptibility was significantly augmented by prior pathogen exposure, with the highest variability detected in hosts given high-dose prior exposure. An epidemiological model parameterized with experimental data found that heterogeneity in susceptibility from prior exposure more than halved epidemic sizes compared with a homogeneous population with identical mean protection. However, because infection-induced mortality was also greatly reduced in hosts with prior pathogen exposure, reductions in epidemic size were smaller than expected in hosts with prior exposure. These results highlight the importance of variable protection from prior exposure and/or vaccination in driving population-level heterogeneity and epidemiological dynamics.

Dietary protein defends lean mass and maintains the metabolic benefits of glucagon receptor agonism in mice.

OBJECTIVE: Glucagon has long been proposed as a component of multi-agonist obesity therapeutics due to its ability to induce energy expenditure and cause weight loss. However, chronic glucagon-receptor agonism has been associated with a reduction in circulating amino acids and loss of lean mass. Importantly, it is currently not known whether the metabolic benefits of glucagon can be maintained under contexts that allow the defence of lean mass. METHODS: We investigate the metabolic effects of the long-acting glucagon receptor agonist, G108, when administered to obese mice at low-doses, and with dietary protein supplementation. RESULTS: Dietary protein supplementation can only fully defend lean mass at a low dose of G108 that is sub-anorectic and does not reduce fat mass. However, in this context, G108 is still highly effective at improving glucose tolerance and reducing liver fat in obese mice. Mechanistically, liver RNA-Seq analysis reveals that dietary protein supplementation defends anabolic processes in low-dose G108-treated mice, and its effects on treatment-relevant glucose and lipid pathways are preserved. CONCLUSION: Glucagon-mediated energy expenditure and weight loss may be mechanistically coupled to hypoaminocidemia and lean mass loss. However, our data suggest that glucagon can treat MAFLD at doses which allow full defence of lean mass given sufficient dietary protein intake. Therefore, proportionate glucagon therapy may be safe and effective in targeting hepatocytes and improving in glycaemia and liver fat.

"But some were more equal than others:" Exploring inequality at Neolithic Çatalhöyük.

We explore the ways in which residents of Neolithic Çatalhöyük in Anatolia differentiated themselves as well as the ways in which they did not. We integrate numerous data sets in order to assess patterns of inequality (A) across buildings with contemporaneous occupations, (B) between buildings that did or did not burn at abandonment, and (C) through time. We use Gini coefficients so as to maximize comparability with other studies of inequality in the ancient and modern worlds, discussing the underlying data and our results to clarify and enhance the value of the quantitative analyses. We evaluate whether or not trajectories of inequality align across data sets in order to determine how far success in one realm correlated with success in another. Our results indicate no unified trajectory of inequality through time. We perceive broadly similar access to staple foods, but not to goods less directly related to survival; relatively elevated income inequality during the middle portion of the site's occupation, plausibly deliberately tamped down; and no evidence for institutionalized or lasting economic or social inequality. These findings shed light on Neolithic social dynamics and also contribute to broader discussions of inequality and the social ramifications of early agropastoralism.

Cascaded Multi-path Shortcut Diffusion Model for Medical Image Translation.

Image-to-image translation is a vital component in medical imaging processing, with many uses in a wide range of imaging modalities and clinical scenarios. Previous methods include Generative Adversarial Networks (GANs) and Diffusion Models (DMs), which offer realism but suffer from instability and lack uncertainty estimation. Even though both GAN and DM methods have individually exhibited their capability in medical image translation tasks, the potential of combining a GAN and DM to further improve translation performance and to enable uncertainty estimation remains largely unexplored. In this work, we address these challenges by proposing a Cascade Multi-path Shortcut Diffusion Model (CMDM) for high-quality medical image translation and uncertainty estimation. To reduce the required number of iterations and ensure robust performance, our method first obtains a conditional GAN-generated prior image that will be used for the efficient reverse translation with a DM in the subsequent step. Additionally, a multi-path shortcut diffusion strategy is employed to refine translation results and estimate uncertainty. A cascaded pipeline further enhances translation quality, incorporating residual averaging between cascades. We collected three different medical image datasets with two sub-tasks for each dataset to test the generalizability of our approach. Our experimental results found that CMDM can produce high-quality translations comparable to state-of-the-art methods while providing reasonable uncertainty estimations that correlate well with the translation error.

Context-specific inhibition of mitochondrial ribosomes by phenicol and oxazolidinone antibiotics.

The antibiotics chloramphenicol (CHL) and oxazolidinones including linezolid (LZD) are known to inhibit mitochondrial translation. This can result in serious, potentially deadly, side effects when used therapeutically. Although the mechanism by which CHL and LZD inhibit bacterial ribosomes has been elucidated in detail, their mechanism of action against mitochondrial ribosomes has yet to be explored. CHL and oxazolidinones bind to the ribosomal peptidyl transfer center (PTC) of the bacterial ribosome and prevent incorporation of incoming amino acids under specific sequence contexts, causing ribosomes to stall only at certain sequences. Through mitoribosome profiling, we show that inhibition of mitochondrial ribosomes is similarly context-specific - CHL and LZD lead to mitoribosome stalling primarily when there is an alanine, serine, or threonine in the penultimate position of the nascent peptide chain. We further validate context-specific stalling through in vitro translation assays. A high resolution cryo-EM structure of LZD bound to the PTC of the human mitoribosome shows extensive similarity to the mode of bacterial inhibition and also suggests potential avenues for altering selectivity. Our findings could help inform the rational development of future, less mitotoxic, antibiotics, which are critically needed in the current era of increasing antimicrobial resistance.

Deep mutational scanning of EccD3 reveals the molecular basis of its essentiality in the mycobacterium ESX secretion system.

Tuberculosis remains the deadliest infectious disease in the world and requires novel therapeutic targets. The ESX-3 secretion system, which is essential for iron and zinc homeostasis and thus M. tuberculosis survival, is a promising target. In this study, we perform a deep mutational scan on the ESX-3 core protein EccD3 in the model organism M. smegmatis. We systematically investigated the functional roles of 145 residues across the soluble ubiquitin-like domain, the conformationally distinct flexible linker, and selected transmembrane helices of EccD3. Our data combined with structural comparisons to ESX-5 complexes support a model where EccD3 stabilizes the complex, with the hinge motif within the linker being particularly sensitive to disruption. Our study is the first deep mutational scan in mycobacteria, which could help guide drug development toward novel treatment of tuberculosis. This study underscores the importance of context-specific mutational analyses for discovering essential protein interactions within mycobacterial systems.

Streamlining LC-MS Characterization of Pharmaceutical Polymers by Fourier-Transform-Based Deconvolution and Macromolecular Mass Defect Analysis.

Polymer conjugation has risen in importance over the past three decades as a means of increasing the in vivo half-life of biotherapeutics, with benefits including better stability, greater drug efficacy, and lower toxicity. However, the intrinsic variability of polymer synthesis results in products with broad distributions in chain length and branching structure, complicating quality control for successful functionalization and downstream conjugation. Frequently, a combination of several analytical techniques is required for comprehensive characterization. While liquid chromatography-mass spectrometry (LC-MS) is a powerful platform that can provide detailed molecular features of polymers, the mass spectra are inherently challenging to interpret due to high mass polydispersity and overlapping charge distributions. Here, by leveraging Fourier transform-based deconvolution and macromolecular mass defect analysis, we demonstrate a new way to streamline pharmaceutical polymer analysis, shedding light on polymer size, composition, branching, and end-group functionalization with the capability for reaction monitoring.

Fentanyl-positive urine drug screens in the emergency department: Association with intentional opioid misuse and racial disparities.

Background: An increase in opioid-related overdoses, notably from potent synthetic opioids like fentanyl, prompted this consideration of characteristics of emergency department (ED) patients with evidence for illicit fentanyl use or exposure, the correlation with intentional opioid misuse, and subsequent ED management. Methods: A retrospective review was performed of patients presenting to an urban academic medical center ED with evidence for illicit fentanyl use, determined by positive urine drug screens (UDS), from 6/2021 through 11/2021. Participant demographics, comorbidities, ED chief complaint and disposition, and evidence of intentional opioid misuse were considered. Secondary outcomes included provision of buprenorphine/naloxone and/or naloxone kits at discharge, ED recidivism, and six-month mortality. Bivariate comparisons and logistic regression models were performed. Results: Among 409 unique patients, most were white and male with a mean age of 39.4. Approximately half presented with opioid-related complaints. Evidence of intentional opioid misuse was identified in 72.6 % of patients. Black patients had 79 % lower odds of intentional opioid misuse compared to white patients. Regarding ED management, 28.8 % were discharged with buprenorphine/naloxone and 14.0 % with a naloxone kit. Black patients had 63 % lower odds of receiving buprenorphine/naloxone compared to white patients after controlling for covariates. Nearly 6 % of the study population died within six months of the initial ED visit. Conclusion: This fentanyl-focused review describes patient characteristics which largely mirror the epidemiology of the current opioid epidemic; however, despite evidence of objective exposure, it also suggests that Black patients may be less likely to use fentanyl intentionally. It also highlights potential disparities related to ED-based opioid misuse patient management.

Visual impact of diffusion optic technology lenses for myopia control.

PURPOSE: To assess the visual impact of Diffusion Optics Technology™ 0.2 DOT lenses (SightGlass Vision Inc.) designed for myopia control on primary gaze. DOT spectacle lenses contain light scattering elements that scatter light as it passes through the lens which, in turn, reduces retinal image contrast. METHODS: Fifty-one children (12.2 ± 1.3, range 10-14 years; 51% females) were randomly assigned to wear DOT spectacle (n = 27) or single vision lenses (n = 24) across six investigational sites in North America. Binocular high- and low-contrast distant visual acuities, near visual acuity, reading speed, contrast sensitivity, stereoacuity and glare were assessed in primary gaze after at least 3 years of wear, with the study 95% powered in all metrics to detect significant differences between the groups. RESULTS: Mean binocular distance high-contrast (-0.09 ± 0.02 vs. -0.08 ± 0.02 logMAR, p = 0.81), low-contrast (0.05 ± 0.02 vs. 0.07 ± 0.02 logMAR, p = 0.52) and near visual acuity with glare sources (-0.06 ± 0.03 vs. -0.09 ± 0.03 logMAR, p = 0.32) were similar for DOT and single vision lens wearers, respectively. Contrast sensitivity was similar between children wearing DOT or single vision lenses across 11 of the 16 spatial frequencies (p > 0.05). Mean stereopsis was similar (p = 0.30) with the DOT lenses (33.2 ± 12.5″) and single vision lenses (38.1 ± 14.2″). Functional reading speed metrics were similar in both study groups, as was the objectively measured head tilt during reading (p > 0.05). The mean halo radius was 0.56° ± 0.17° with the DOT lenses compared with 0.50° ± 0.12° with single vision lenses (p = 0.02), but the statistically significant difference was smaller than the non-inferiority bound of 0.4°. CONCLUSION: Diffusion optics technology lenses provide a clinically equivalent visual experience to a standard single vision lens.

Arrhythmic Risk Stratification by Cardiovascular Magnetic Resonance Imaging in Patients With Nonischemic Cardiomyopathy.

BACKGROUND: Myocardial fibrosis (MF) forms part of the arrhythmic substrate for ventricular arrhythmias (VAs). OBJECTIVES: This study sought to determine whether total myocardial fibrosis (TF) and gray zone fibrosis (GZF), assessed using cardiovascular magnetic resonance, are better than left ventricular ejection fraction (LVEF) in predicting ventricular arrhythmias in patients with nonischemic cardiomyopathy (NICM). METHODS: Patients with NICM in a derivation cohort (n = 866) and a validation cohort (n = 848) underwent quantification of TF and GZF. The primary composite endpoint was sudden cardiac death or VAs (ventricular fibrillation or ventricular tachycardia). RESULTS: The primary endpoint was met by 52 of 866 (6.0%) patients in the derivation cohort (median follow-up: 7.5 years; Q1-Q3: 5.2-9.3 years). In competing-risks analyses, MF on visual assessment (MFVA) predicted the primary endpoint (HR: 5.83; 95% CI: 3.15-10.8). Quantified MF measures permitted categorization into 3 risk groups: a TF of >0 g and ≤10 g was associated with an intermediate risk (HR: 4.03; 95% CI: 1.99-8.16), and a TF of >10 g was associated with the highest risk (HR: 9.17; 95% CI: 4.64-18.1) compared to patients with no MFVA (lowest risk). Similar trends were observed in the validation cohort. Categorization into these 3 risk groups was achievable using TF or GZF in combination or in isolation. In contrast, LVEF of <35% was a poor predictor of the primary endpoint (validation cohort HR: 1.99; 95% CI: 0.99-4.01). CONCLUSIONS: MFVA is a strong predictor of sudden cardiac death and VAs in NICM. TF and GZF mass added incremental value to MFVA. In contrast, LVEF was a poor discriminator of arrhythmic risk.