A Prospective Study of the Diagnostic Performance of Photon-Counting CT Compared With MRI in the Characterization of Renal Masses.

OBJECTIVES: The aim of this study was to assess the interreader reliability and per-RCC sensitivity of high-resolution photon-counting computed tomography (PCCT) in the detection and characterization of renal masses in comparison to MRI. MATERIALS AND METHODS: This prospective study included 24 adult patients (mean age, 52 ± 14 years; 14 females) who underwent PCCT (using an investigational whole-body CT scanner) and abdominal MRI within a 3-month time interval and underwent surgical resection (partial or radical nephrectomy) with histopathology (n = 70 lesions). Of the 24 patients, 17 had a germline mutation and the remainder were sporadic cases. Two radiologists (R1 and R2) assessed the PCCT and corresponding MRI studies with a 3-week washout period between reviews. Readers recorded the number of lesions in each patient and graded each targeted lesion's characteristic features, dimensions, and location. Data were analyzed using a 2-sample t test, Fisher exact test, and weighted kappa. RESULTS: In patients with von Hippel-Lindau mutation, R1 identified a similar number of lesions suspicious for neoplasm on both modalities (51 vs 50, P = 0.94), whereas R2 identified more suspicious lesions on PCCT scans as compared with MRI studies (80 vs 56, P = 0.12). R1 and R2 characterized more lesions as predominantly solid in MRIs (R1: 58/70 in MRI vs 52/70 in PCCT, P < 0.001; R2: 60/70 in MRI vs 55/70 in PCCT, P < 0.001). R1 and R2 performed similarly in detecting neoplastic lesions on PCCT and MRI studies (R1: 94% vs 90%, P = 0.5; R2: 73% vs 79%, P = 0.13). CONCLUSIONS: The interreader reliability and per-RCC sensitivity of PCCT scans acquired on an investigational whole-body PCCT were comparable to MRI scans in detecting and characterizing renal masses. CLINICAL RELEVANCE STATEMENT: PCCT scans have comparable performance to MRI studies while allowing for improved characterization of the internal composition of lesions due to material decomposition analysis. Future generations of this imaging modality may reveal additional advantages of PCCT over MRI.

Recommendations for measuring and standardizing light for laboratory mammals to improve welfare and reproducibility in animal research.

Light enables vision and exerts widespread effects on physiology and behavior, including regulating circadian rhythms, sleep, hormone synthesis, affective state, and cognitive processes. Appropriate lighting in animal facilities may support welfare and ensure that animals enter experiments in an appropriate physiological and behavioral state. Furthermore, proper consideration of light during experimentation is important both when it is explicitly employed as an independent variable and as a general feature of the environment. This Consensus View discusses metrics to use for the quantification of light appropriate for nonhuman mammals and their application to improve animal welfare and the quality of animal research. It provides methods for measuring these metrics, practical guidance for their implementation in husbandry and experimentation, and quantitative guidance on appropriate light exposure for laboratory mammals. The guidance provided has the potential to improve data quality and contribute to reduction and refinement, helping to ensure more ethical animal use.

The Multistable Melanopsins of Mammals.

Melanopsin is a light-activated G protein coupled receptor that is expressed widely across phylogeny. In mammals, melanopsin is found in intrinsically photosensitive retinal ganglion cells (ipRGCs), which are especially important for "non-image" visual functions that include the regulation of circadian rhythms, sleep, and mood. Photochemical and electrophysiological experiments have provided evidence that melanopsin has at least two stable conformations and is thus multistable, unlike the monostable photopigments of the classic rod and cone photoreceptors. Estimates of melanopsin's properties vary, challenging efforts to understand how the molecule influences vision. This article seeks to reconcile disparate views of melanopsin and offer a practical guide to melanopsin's complexities.

Quantitative CT Metrics Associated with Variability in the Diffusion Capacity of the Lung of Post-COVID-19 Patients with Minimal Residual Lung Lesions.

(1) Background: A reduction in the diffusion capacity of the lung for carbon monoxide is a prevalent longer-term consequence of COVID-19 infection. In patients who have zero or minimal residual radiological abnormalities in the lungs, it has been debated whether the cause was mainly due to a reduced alveolar volume or involved diffuse interstitial or vascular abnormalities. (2) Methods: We performed a cross-sectional study of 45 patients with either zero or minimal residual lesions in the lungs (total volume < 7 cc) at two months to one year post COVID-19 infection. There was considerable variability in the diffusion capacity of the lung for carbon monoxide, with 27% of the patients at less than 80% of the predicted reference. We investigated a set of independent variables that may affect the diffusion capacity of the lung, including demographic, pulmonary physiology and CT (computed tomography)-derived variables of vascular volume, parenchymal density and residual lesion volume. (3) Results: The leading three variables that contributed to the variability in the diffusion capacity of the lung for carbon monoxide were the alveolar volume, determined via pulmonary function tests, the blood vessel volume fraction, determined via CT, and the parenchymal radiodensity, also determined via CT. These factors explained 49% of the variance of the diffusion capacity, with p values of 0.031, 0.005 and 0.018, respectively, after adjusting for confounders. A multiple-regression model combining these three variables fit the measured values of the diffusion capacity, with R = 0.70 and p < 0.001. (4) Conclusions: The results are consistent with the notion that in some post-COVID-19 patients, after their pulmonary lesions resolve, diffuse changes in the vascular and parenchymal structures, in addition to a low alveolar volume, could be contributors to a lingering low diffusion capacity.

A systematic review of the neurobiological effects of theta-burst stimulation (TBS) as measured using functional magnetic resonance imaging (fMRI).

Theta burst stimulation (TBS) is associated with the modulation of a range of clinical, cognitive, and behavioural outcomes, but specific neurobiological effects remain somewhat unclear. This systematic literature review investigated resting-state and task-based functional magnetic resonance imaging (fMRI) outcomes post-TBS in healthy human adults. Fifty studies that applied either continuous-or intermittent-(c/i) TBS, and adopted a pretest-posttest or sham-controlled design, were included. For resting-state outcomes following stimulation applied to motor, temporal, parietal, occipital, or cerebellar regions, functional connectivity generally decreased in response to cTBS and increased in response to iTBS, though there were some exceptions to this pattern of response. These findings are mostly consistent with the assumed long-term depression (LTD)/long-term potentiation (LTP)-like plasticity effects of cTBS and iTBS, respectively. Task-related outcomes following TBS were more variable. TBS applied to the prefrontal cortex, irrespective of task or state, also produced more variable responses, with no consistent patterns emerging. Individual participant and methodological factors are likely to contribute to the variability in responses to TBS. Future studies assessing the effects of TBS via fMRI must account for factors known to affect the TBS outcomes, both at the level of individual participants and of research methodology.

Encoding of environmental illumination by primate melanopsin neurons.

Light regulates physiology, mood, and behavior through signals sent to the brain by intrinsically photosensitive retinal ganglion cells (ipRGCs). How primate ipRGCs sense light is unclear, as they are rare and challenging to target for electrophysiological recording. We developed a method of acute identification within the live, ex vivo retina. Using it, we found that ipRGCs of the macaque monkey are highly specialized to encode irradiance (the overall intensity of illumination) by blurring spatial, temporal, and chromatic features of the visual scene. We describe mechanisms at the molecular, cellular, and population scales that support irradiance encoding across orders-of-magnitude changes in light intensity. These mechanisms are conserved quantitatively across the ~70 million years of evolution that separate macaques from mice.

How do pre-operative intra-articular injections impact periprosthetic joint infection risk following primary total hip arthroplasty? A systematic review and meta-analysis.

INTRODUCTION: Although intra-articular injections (IAIs) serve as the first-line non-surgical management for severe osteoarthritis (OA), recent analyses have suggested they are associated with an increased infection risk following primary total hip arthroplasty (THA). Therefore, our systematic review and meta-analysis explored the relationship between IAIs and periprosthetic joint infection (PJI) following THA reported in the current literature. METHODS: Five online databases were queried for analyses published from January 1st, 2000-May 1st, 2021 reporting on PJI rates between patients undergoing primary THA who did and did not preoperatively receive an IAI. The overall pooled effect of injection status on PJI incidence was determined using Mantel-Haenszel (M-H) models. This was similarly conducted for segregated preoperative intervals: 0-3 months, > 3-6 months, > 6 + months. RESULTS: A total of 11 articles were included in our analysis reporting on 278,782 THAs (IAI: n = 41,138; no IAI: n = 237,644). Patients receiving pre-operative injections had a significantly higher risk of PJI (OR: 1.31, 95% CI 1.07-1.62; p = 0.009). However, this finding was not robust. IAI receipt within 3-months of THA was associated with significantly higher PJI rates (OR: 1.68, 95% CI 1.48-1.90; p < 0.001). However, no significant difference was demonstrated in the > 3-6 month (OR: 1.19, 95% CI 0.94-1.52; p = 0.16) and > 6 + month sub-analyses (OR: 1.20, 95% CI 0.96-1.50; p = 0.11). The results of all sub-analyses remained were robust. DISCUSSION: Our findings suggest that patients requiring THA should wait at least 3-months following IAI to reduce post-operative infection risk. This information can help inform patients considering OA management options, as well as adult reconstruction surgeons during preoperative optimization.

A cross-sectional study of quantitative CT measurements associated with the diffusion capacity of the lung in recovered COVID-19 patients with normalised chest CT.

Impairment of the diffusion capacity of the lung for carbon monoxide (DLco) is commonly reported in convalescent and recovered COVID-19 patients, although the cause is not fully understood especially in patients with no radiological sequelae. In a group of 47 patients at 7 - 51 weeks post infection with either none or minimal scarring or atelectasis on chest CT scans (total < 0.1% of lung volume), dispersions in DLco-adj % and total lung capacity (TLC) % of predicted were observed, with median(quartiles) of 87(78, 99)% and 84(78, 92)%, respectively. Thirteen(27.1%) patients had DLco-adj% < 80%. Although the DLco-adj% did not significantly correlate with the severity of the illness in the acute phase, time since the onset of symptoms, the volume of residual lesions on CT, age or sex, DLco-adj/alveolar volume (Kco-adj) % predicted was correlated with the measurements of small blood vessel volume fraction (diameter <= 5mm) and parenchyma density on CT. Multivariate analysis revealed that these two CT metrics significantly contributed to the variance in DLco-adj% independent of TLC%. Comparing to between-subject variability of DLco-adj in healthy individuals, patients in this cohort with DLco-adj% < 80% were likely abnormal with a degree of disease not visually detectable on CT. However, it is not clear whether the associated variance of parenchyma density and small vessel volume fraction were a consequence of the COVID-19 disease or a pre-existing background variance.

Light links neonatal neurons for learning.

The newborn mouse's retina senses light even before the eye opens, informing the developing brain of the visual world. Without this information, the brain forms fewer connections and the adult mouse learns sluggishly.

α-Crystallin chaperone mimetic drugs inhibit lens γ-crystallin aggregation: Potential role for cataract prevention.

Γ-Crystallins play a major role in age-related lens transparency. Their destabilization by mutations and physical chemical insults are associated with cataract formation. Therefore, drugs that increase their stability should have anticataract properties. To this end, we screened 2560 Federal Drug Agency-approved drugs and natural compounds for their ability to suppress or worsen H2O2 and/or heat-mediated aggregation of bovine γ-crystallins. The top two drugs, closantel (C), an antihelminthic drug, and gambogic acid (G), a xanthonoid, attenuated thermal-induced protein unfolding and aggregation as shown by turbidimetry fluorescence spectroscopy dynamic light scattering and electron microscopy of human or mouse recombinant crystallins. Furthermore, binding studies using fluorescence inhibition and hydrophobic pocket-binding molecule bis-8-anilino-1-naphthalene sulfonic acid revealed static binding of C and G to hydrophobic sites with medium-to-low affinity. Molecular docking to HγD and other γ-crystallins revealed two binding sites, one in the "NC pocket" (residues 50-150) of HγD and one spanning the "NC tail" (residues 56-61 to 168-174 in the C-terminal domain). Multiple binding sites overlap with those of the protective mini αA-crystallin chaperone MAC peptide. Mechanistic studies using bis-8-anilino-1-naphthalene sulfonic acid as a proxy drug showed that it bound to MAC sites, improved Tm of both H2O2 oxidized and native human gamma D, and suppressed turbidity of oxidized HγD, most likely by trapping exposed hydrophobic sites. The extent to which these drugs act as α-crystallin mimetics and reduce cataract progression remains to be demonstrated. This study provides initial insights into binding properties of C and G to γ-crystallins.

An Anatomic Study of the Proximal Tibial Epiphysis With Relevance to Percutaneous Epiphysiodesis Using Transphyseal Screws (PETS).

BACKGROUND: Percutaneous epiphysiodesis using transphyseal screws (PETS) is a common procedure to correct lower extremity limb-length discrepancies in the pediatric population. A potential complication of this procedure is development of tibial valgus deformity, which may occur secondary to decreased screw purchase in the thinner medial proximal tibial epiphysis. The thickness of the proximal tibial epiphysis has not yet been well quantified, which was the aim of this study. METHODS: Three-dimensional surface scans of 32 cadaveric proximal tibial epiphyses in specimens aged 3 to 17 years old were obtained and computer modeling software was utilized to measure the thickness of the proximal tibial epiphysis at 20 standardized potential screw insertion points according to a generated 5×4 map. RESULTS: When normalized to the total width of the proximal tibial epiphysis, the lateral side is thicker compared with the medial side. The positions with the greatest thickness are located at the midline in the sagittal plane and 33% of the total physeal width away from the medial and lateral edges in the coronal plane (0.265 and 0.261 normalized thickness, respectively). The proximal tibial epiphysis is particularly thin 25% from the medial edge (normalized thickness range: 0.196 to 0.221). Multiple regression analysis revealed a significant relationship between increasing age and female sex with thinner normalized medial and lateral heights. CONCLUSIONS: During PETS, areas for greater screw purchase are located centrally in the sagittal plane and 33% of the total width away from the medial and lateral edges of the proximal tibial epiphysis in the coronal plane. Caution should be taken when inserting screws in the medial 25% of the proximal tibial epiphysis as it is thinner relative to the lateral edge, particularly in females. CLINICAL RELEVANCE: This study provides quantitative, anatomic data on the thickness of the proximal tibial epiphysis, which can direct screw placement during PETS for correcting limb-length discrepancies. These data may help lessen the risk of developing tibial valgus deformity although future clinical studies are necessary to fully evaluate this possibility.

Assessment of cortical inhibition depends on inter individual differences in the excitatory neural populations activated by transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is used to probe inhibitory intracortical neurotransmission and has been used to infer the neurobiological dysfunction that may underly several neurological disorders. One technique, short-interval intracortical inhibition (SICI), indexes gamma-aminobutyric acid (GABA) mediated inhibitory activity and is a promising biomarker. However emerging evidence suggests SICI does not exclusively represent GABAergic activity because it may be influenced by inter-individual differences in the specific excitatory neural populations activated by TMS. Here we used the latency of TMS motor evoked potentials (MEPs) to index these inter-individual differences, and found that a significant proportion of the observed variability in SICI magnitude was accounted for by MEP latency, r = - 0.57, r2 = 0.33, p = .014. We conclude that SICI is influenced by inter-individual differences in the excitatory neural populations activated by TMS, reducing the precision of this GABAergic probe. Interpreting SICI measures in the context of MEP latency may facilitate a more precise assessment of GABAergic intracortical inhibition. The reduced cortical inhibition observed in some neuropathologies could be influenced by reduced activity in specific excitatory neural populations. Including MEP latency assessment in research investigating SICI in clinical groups could assist in differentiating the cortical circuits impacted by neurological disorders.

The role of the primary motor cortex in motor imagery: A theta burst stimulation study.

While mentally simulated actions activate similar neural structures to overt movement, the role of the primary motor cortex (PMC) in motor imagery remains disputed. The aim of the study was to use continuous theta burst stimulation (cTBS) to modulate corticospinal activity to investigate the putative role of the PMC in implicit motor imagery in young adults with typical and atypical motor ability. A randomized, double blind, sham-controlled, crossover, offline cTBS protocol was applied to 35 young adults. During three separate sessions, adults with typical and low motor ability (developmental coordination disorder [DCD]), received active cTBS to the PMC and supplementary motor area (SMA), and sham stimulation to either the PMC or SMA. Following stimulation, participants completed measures of motor imagery (i.e., hand rotation task) and visual imagery (i.e., letter number rotation task). Although active cTBS significantly reduced corticospinal excitability in adults with typical motor ability, neither task performance was altered following active cTBS to the PMC or SMA, compared to performance after sham cTBS. These results did not differ across motor status (i.e., typical motor ability and DCD). These findings are not consistent with our hypothesis that the PMC (and SMA) is directly involved in motor imagery. Instead, previous motor cortical activation observed during motor imagery may be an epiphenomenon of other neurophysiological processes and/or activity within brain regions involved in motor imagery. This study highlights the need to consider multi-session theta burst stimulation application and its neural effects when probing the putative role of motor cortices in motor imagery.

An anatomic and 3D study of the development of the proximal humeral physis.

PURPOSE: During maturation, the ossification centers of the proximal humerus form a characteristic pattern consisting of a metaphyseal peak and corresponding epiphyseal valley. The surface topographies of the metaphyseal peak and epiphyseal valley are not well described and may have variation with age and structural importance to the pathogenesis of proximal humeral epiphysiolysis. METHODS: High-resolution 3-dimensional surface scans of 24 cadaveric proximal humeral epiphyses and metaphyses in specimens aged 3 to 18 years were obtained. Computer modeling software was used to measure the peak height of the metaphysis and maximal depth of the epiphysis relative to a perpendicular line drawn across the proximal humeral physis. RESULTS: The metaphyseal peak had a mean height of 12.7 ± 1.6 mm while the epiphyseal valley had a mean depth of 13.1 ± 2.1 mm, both consistently positioned in the posterolateral quadrant. Both the absolute metaphyseal peak height (R2 = 0.536; p < 0.001) and absolute epiphyseal valley depth (R2 = 0.524; p < 0.001) increase with advancing age. Multiple linear regression analysis demonstrated that normalized metaphyseal peak height + sex (adjusted R2 = 0.408; p < 0.002) correlated more with age than normalized epiphyseal valley depth + sex (adjusted R2 = 0.128; p < 0.091). CONCLUSION: Prominence of the metaphyseal peak and epiphyseal valley both increase with advancing age, with a lower correlation between normalized sizes with age as compared to the absolute sizes, suggesting that these structures stay relatively proportional with growth.

Intra-articular injection receipt within 3 months prior to primary total knee arthroplasty is associated with increased periprosthetic joint infection risk.

PURPOSE: This systematic review and meta-analysis analyzed the influence of pre-operative intra-articular injections (IAI) on periprosthetic joint infection (PJI) rates after primary total knee arthroplasty (TKA). METHODS: Studies published between January 1st, 2000 and May 1st, 2021 evaluating PJI rates among TKA patients with and without IAI were identified from PubMed, Cochrane Library, MEDLINE, EBSCO Host, and Google Scholar. The pooled effect of IAI on PJI risk was calculated utilizing Mantel-Haenszel (M-H) models. Sub-analysis comparisons were conducted based on the interval from IAI to TKA: 0-3 months; > 3-6 months; > 6-12 months. The Methodological Index for Non-Randomized Studies (MINORS) and the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) tool were utilized to evaluate the quality of each included study. RESULTS: The present analysis included 12 studies reporting on 349,605 TKAs (IAI: n = 115,122; No IAI: n = 234,483). Patients receiving an IAI at any point prior to TKA (2850/115,122; 2.48%) had statistically significant increased risk of infection compared to patients not receiving IAIs (4479/234,483; 1.91%; OR: 1.14, 95% CI: 1.08-1.20; p < 0.0001). However, this finding was not demonstrated across sensitivity analyses. Receiving injections within 3 months prior to TKA was associated with increased infection risk (OR: 1.23, 95% CI: 1.14-1.31; p < 0.0001). There were no differences in infection rates when injections were given between > 3 and 6 months (OR: 0.82, 95% CI: 0.47-1.43; p = 0.49) and > 6-12 months prior to TKA (OR: 1.26, 95% CI: 0.89-1.78; p = 0.18). CONCLUSIONS: Based on the current literature, the findings of this analysis suggest that patients receiving IAI should wait at least 3 months before undergoing TKA to mitigate infection risk. Orthopaedic surgeons and patients can utilize this information when undergoing shared decision-making regarding osteoarthritis management options and timing. LEVEL OF EVIDENCE: Level III.

Individual variations of visual information.

In this issue of Neuron, Shah et al. reveal that coding of visual space by the primate retina varies across individuals and sexes. A computational model provides insight into themes and variations of coding. Implications for sight restoration are explored.

Retinal ganglion cells expressing CaM kinase II in human and nonhuman primates.

Immunoreactivity for calcium-/calmodulin-dependent protein kinase II (CaMKII) in the primate dorsal lateral geniculate nucleus (dLGN) has been attributed to geniculocortical relay neurons and has also been suggested to arise from terminals of retinal ganglion cells. Here, we combined immunostaining with single-cell injections to investigate the expression of CaMKII in retinal ganglion cells of three primate species: macaque (Macaca fascicularis, M. nemestrina), human, and marmoset (Callithrix jacchus). We found that in all species, about 2%-10% of the total ganglion cell population expressed CaMKII. In all species, CaMKII was expressed by multiple types of wide-field ganglion cell including large sparse, giant sparse (melanopsin-expressing), broad thorny, and narrow thorny cells. Three other ganglion cells types, namely, inner and outer stratifying maze cells in macaque and tufted cells in marmoset were also found. Double labeling experiments showed that CaMKII-expressing cells included inner and outer stratifying melanopsin cells. Nearly all CaMKII-expressing ganglion cell types identified here are known to project to the koniocellular layers of the dLGN as well as to the superior colliculus. The best characterized koniocellular projecting cell type-the small bistratified (blue ON/yellow OFF) cell-was, however, not CaMKII-positive in any species. Our results indicate that the pattern of CaMKII expression in retinal ganglion cells is largely conserved across different species of primate suggesting a common functional role. But the results also show that CaMKII is not a marker for all koniocellular projecting retinal ganglion cells.

Do gaze behaviours during action observation predict interpersonal motor resonance?

Interpersonal motor resonance (IMR) is a common putative index of the mirror neuron system (MNS), a network containing specialised cells that fire during both action execution and observation. Visual content inputs to the MNS, however, it is unclear whether visual behaviours mediate the putative MNS response. We aimed to examine gaze effects on IMR during action observation. Neurotypical adults (N = 99; 60 female) underwent transcranial magnetic stimulation, electromyography, and eye-tracking during the observation of videos of actors performing grasping actions. IMR was measured as a percentage change in motor evoked potentials (MEPs) of the first dorsal interosseous muscle during action observation relative to baseline. MEP facilitation was observed during action observation, indicating IMR (65.43%, SE = 11.26%, P < 0.001). Fixations occurring in biologically relevant areas (face/hand/arm) yielded significantly stronger IMR (81.03%, SE = 14.15%) than non-biological areas (63.92%, SE = 14.60, P = 0.012). This effect, however, was only evident in the first of four experimental blocks. Our results suggest that gaze fixation can modulate IMR, but this may be affected by the salience and novelty of the observed action. These findings have important methodological implications for future studies in both clinical and healthy populations.