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.

Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina.

High-acuity vision in primates, including humans, is mediated by a small central retinal region called the fovea. As more accessible organisms lack a fovea, its specialized function and its dysfunction in ocular diseases remain poorly understood. We used 165,000 single-cell RNA-seq profiles to generate comprehensive cellular taxonomies of macaque fovea and peripheral retina. More than 80% of >60 cell types match between the two regions but exhibit substantial differences in proportions and gene expression, some of which we relate to functional differences. Comparison of macaque retinal types with those of mice reveals that interneuron types are tightly conserved. In contrast, projection neuron types and programs diverge, despite exhibiting conserved transcription factor codes. Key macaque types are conserved in humans, allowing mapping of cell-type and region-specific expression of >190 genes associated with 7 human retinal diseases. Our work provides a framework for comparative single-cell analysis across tissue regions and species.

Mixed Palettes of Melanopsin Phototransduction.

Animal photoreceptors divide into two fundamental classes, ciliary and rhabdomeric. Jiang and colleagues demonstrate that this boundary is disregarded by the intrinsically photosensitive retinal ganglion cells of mammals. These neurons draw from phototransduction mechanisms of both classes, enriching the signals that they produce to drive a diversity of visual functions.

A Population Representation of Absolute Light Intensity in the Mammalian Retina.

Environmental illumination spans many log units of intensity and is tracked for essential functions that include regulation of the circadian clock, arousal state, and hormone levels. Little is known about the neural representation of light intensity and how it covers the necessary range. This question became accessible with the discovery of mammalian photoreceptors that are required for intensity-driven functions, the M1 ipRGCs. The spike outputs of M1s are thought to uniformly track intensity over a wide range. We provide a different understanding: individual cells operate over a narrow range, but the population covers irradiances from moonlight to full daylight. The range of most M1s is limited by depolarization block, which is generally considered pathological but is produced intrinsically by these cells. The dynamics of block allow the population to code stimulus intensity with flexibility and efficiency. Moreover, although spikes are distorted by block, they are regularized during axonal propagation.

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.

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.

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.

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.

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.

An anatomical study defining the safe range of angles in percutaneous iliosacral and transsacral screw fixation.

Percutaneous iliosacral screw fixation and transsacral fixation are challenging procedures requiring extensive knowledge of sacral anatomy to avoid damaging nearby neurovascular structures. Greater knowledge of anatomical screw trajectory and size allowances would be helpful to guide surgical placement. An anatomical study of 40 cadaveric sacra in specimens ages 18-65 was performed. Three-dimensional surface scans were obtained, and computer modeling software was used to simulate a 7.3 mm diameter screw with 1 mm buffer inserted orthogonal to the sacroiliac joint in the pelvic inlet and outlet views. Transsacral screws were also inserted into S1 and S2 vertebrae. For screws orthogonal to the sacroiliac joint, the overall mean screw insertion angle was 4.1° ± 7.5° (range, -18.3° to 22.0°) in the inlet view in the posterior to anterior direction, and 21.7° ± 5.1° (range, 8.2°-36.3°) in the outlet view in the caudal to cranial direction. Before breaching the sacrum, the range of sacral tunnel lengths was between 31.1 and 70.1 mm with a range of diameters between 9.3 and 13.3 mm. Transsacral screws inserted into either the S1 or S2 vertebrae did not breach the sacrum in 40% (16/40) at each level. 30% (12/40) of sacra could not safely accommodate both S1 and S2 transsacral screws. There is an initial screw insertion angle range of -4° to 12° in the inlet view and 16°-27° in the outlet view. There was always adequate size to accept a 7.3 mm or larger screw.

Periprosthetic joint infection rates across primary total hip arthroplasty surgical approaches: a systematic review and meta-analysis of 653,633 procedures.

INTRODUCTION: Evidence demonstrates comparable clinical outcomes across the various surgical approaches to primary total hip arthroplasty (THA). However, high-quality contemporary data regarding periprosthetic joint infection (PJI) risk between direct anterior approach (DAA) and other (THA) approaches is lacking. This systematic review and meta-analysis evaluated PJI rates reported in the literature between the DAA and other approaches. MATERIALS AND METHODS: Five online databases were queried for all studies published from January 1st, 2000 through February 17th, 2021 that reported PJI rates between DAA and other surgical approaches. Studies reporting on primary THAs for osteoarthritis (OA) and that included PJI rates segregated by surgical approach were included. Articles reporting on revision THA, alternative THA etiologies, or minimally invasive techniques were excluded. Mantel-Haenszel (M-H) models were utilized to evaluate the pooled effect of surgical approach on infection rates. Validated risk of bias and methodological quality assessment tools were applied to each study. Multiple sensitivity analyses were conducted to evaluate the robustness of analyses. RESULTS: 28 articles reporting on 653,633 primary THAs were included. No differences were found between DAA cohorts and combined other approaches (OR: 0.95; 95% CI 0.74-1.21; p = 0.67) as well as segregated anterolateral approach cohorts (OR: 0.82, 95% CI 0.64-1.06; p = 0.13). However, DAA patients had a significantly reduced risk of infection compared to those undergoing posterior (OR: 0.66, 95% CI 0.58-0.74; p < 0.0001) and direct lateral (OR: 0.56, 95% CI 0.48-0.65; p < 0.00001) approaches. CONCLUSION: The DAA to primary THA had comparable or lower PJI risk when compared to other contemporary approaches. The results of the most up-to-date evidence available serve to encourage adult reconstruction surgeons who have already adopted the DAA. Additionally, orthopaedic surgeons considering adoption or use of the direct anterior approach for other reasons should not be dissuaded over theoretical concern for a general increase in the risk of PJI. LEVEL OF EVIDENCE: Level III.

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.

Assessing cerebellar-cortical connectivity using concurrent TMS-EEG: a feasibility study.

Combined single-pulse transcranial magnetic stimulation (TMS) and electroencephalography (EEG) has been used to probe the features of local networks in the cerebral cortex. Here, we investigated whether we can use this approach to explore long-range connections between the cerebellum and cerebral cortex. Ten healthy adults received single-pulse suprathreshold TMS to the cerebellum and an occipital/parietal control site with double-cone and figure-of-eight coils while cerebral activity was recorded. A multisensory electrical control condition was used to simulate the sensation of the double-cone coil at the cerebellar site. Two cleaning pipelines were compared, and the spatiotemporal relationships of the EEG output between conditions were examined at sensor and source levels. Cerebellar stimulation with the double-cone coil resulted in large artifact in the EEG trace. The addition of SOUND filtering to the cleaning pipeline improved the signal such that further analyses could be undertaken. The cortical potentials evoked by the active TMS conditions showed strong relationships with the responses to the multisensory control condition after ∼50 ms. A distinct parietal component at ∼42 ms was found following cerebellar double-cone stimulation. Although evoked potentials differed across all conditions at early latencies, it is unclear as to whether these represented TMS-related network activation of the cerebellarthalamocortical tract, or whether components were dominated by sensory contamination and/or coil-driven artifact. This study highlights the need for caution when interpreting outcomes from cerebellar TMS-EEG studies.NEW & NOTEWORTHY This is the first study to systematically assess the feasibility of obtaining TMS-evoked potentials from cerebellar stimulation with concurrent EEG. An innovative control condition using electrical stimulation was modified to mimic the sensory aspects of cerebellar stimulation with a double-cone coil, and a state-of-the art cleaning pipeline was trialled. The extent of artifact contamination in signals from stimulation of a cerebellar and an occipital/parietal control site using two TMS coil types was highlighted.

Is there a relationship between EEG and sTMS neurophysiological markers of the putative human mirror neuron system?

The mirror neuron system (MNS) has been theorized to play a neurobiological role in a number of social cognitive abilities and is commonly indexed putatively in humans via interpersonal motor resonance (IMR) and mu suppression. Although both indices are thought to measure similar neuronal populations (i.e., "mirror neurons"), it has been suggested that these methods are unrelated, and therefore, incompatible. However, prior studies reporting no relationships were typically conducted in small and underpowered samples. Thus, we aimed to investigate this potential association in a large sample of neurotypical adults (N = 116; 72 females). Participants underwent transcranial magnetic stimulation (TMS), electromyography (EMG), and electroencephalography (EEG) during the observation of videos of actors performing grasping actions in order to index IMR and mu suppression (in beta, lower alpha, and upper alpha bandwidths). A series of linear regressions revealed no associations between IMR and each of the mu suppression bandwidths. Supplementary Bayesian analyses provided further evidence in favor of the null (B01  = 8.85-8.93), providing further support for no association between the two indices of MNS activity. Our findings suggest that these two measures may indeed be unrelated indices that perhaps assess different neurophysiological aspects of the MNS. These results have important implications for future studies examining the MNS.

Cerebral Cortical Activity Following Non-invasive Cerebellar Stimulation-a Systematic Review of Combined TMS and EEG Studies.

The cerebellum sends dense projections to both motor and non-motor regions of the cerebral cortex via the cerebellarthalamocortical tract. The integrity of this tract is crucial for healthy motor and cognitive function. This systematic review examines research using transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) to the cerebellum with combined cortical electroencephalography (EEG) to explore the temporal features of cerebellar-cortical connectivity. A detailed discussion of the outcomes and limitations of the studies meeting review criteria is presented. Databases were searched between 1 December 2017 and 6 December 2017, with Scopus alerts current as of 23 July 2019. Of the 407 studies initially identified, 10 met review criteria. Findings suggested that cerebellar-cortical assessment is suited to combined TMS and EEG, although work is required to ensure experimental procedures are optimal for eliciting a reliable cerebellar response from stimulation. A distinct variation in methodologies and outcome measures employed across studies, and small sample sizes limited the conclusions that could be drawn regarding the electrophysiological signatures of cerebellar-cortical communication. This review highlights the need for stringent protocols and methodologies for cerebellar-cortical assessments via combined TMS and EEG. With these in place, combined TMS and EEG will provide a valuable means for exploring cerebellar connectivity with a wide range of cortical sites. Assessments have the potential to aid in the understanding of motor and cognitive function in both healthy and clinical groups, and provide insights into long-range neural communication generally.

Intrinsically photosensitive retinal ganglion cells.

Life on earth is subject to alternating cycles of day and night imposed by the rotation of the earth. Consequently, living things have evolved photodetective systems to synchronize their physiology and behavior with the external light-dark cycle. This form of photodetection is unlike the familiar "image vision," in that the basic information is light or darkness over time, independent of spatial patterns. "Nonimage" vision is probably far more ancient than image vision and is widespread in living species. For mammals, it has long been assumed that the photoreceptors for nonimage vision are also the textbook rods and cones. However, recent years have witnessed the discovery of a small population of retinal ganglion cells in the mammalian eye that express a unique visual pigment called melanopsin. These ganglion cells are intrinsically photosensitive and drive a variety of nonimage visual functions. In addition to being photoreceptors themselves, they also constitute the major conduit for rod and cone signals to the brain for nonimage visual functions such as circadian photoentrainment and the pupillary light reflex. Here we review what is known about these novel mammalian photoreceptors.

Long-term aspirin does not lower risk of stroke and increases bleeding risk in low-risk atrial fibrillation ablation patients.

BACKGROUND: Stroke risk is a significant concern in patients with atrial fibrillation (AF). Low stroke risk patients (CHADS2 VASc 0-2) are often treated long-term with aspirin after catheter ablation. Defining the long-term risks versus benefits of aspirin therapy, after an ablation, is essential to validate this common clinical approach. METHODS: A total of 4,124 AF ablation patients undergoing their index ablation were included in this retrospective observational study. We compared 1- and 3-year outcomes for cerebrovascular accident (CVA), transient ischemic attack (TIA), gastrointestinal (GI) bleeding, genitourinary (GU) bleeding, any bleeding, and AF recurrence among patients receiving: none, aspirin, or warfarin as long-term therapies. RESULTS: Patient distribution by CHADS2 VASc scores was as follows: 0: 1,143 (28%), 1: 1,588 (39%), and 2: 1,393 (34%). Significantly higher incidents of: female gender, hypertension, diabetes mellitus, heart failure, and vascular disease were seen with higher CHADS2 VASc scores (P < 0.0001 for all). At 3 years, 238 (5.9%) patients were on warfarin, 743 (18.6) on aspirin, and 3,013 (75.5%) on no therapy; with occurrences of CVA/TIA (1.4%, 3.0%, 3.9%, P < 0.0001, respectively), GI bleeding (0.8%, 1.9%, 1.1%, P = 0.06, respectively), and GU bleeding (1.7%, 2.8%, 2.1%, P = 0.008, respectively) that increased with advancing CHA2 DS2 VASc score. There was a significantly increased risk for both CVA/TIA with aspirin therapy, when compared to no therapy or warfarin therapy in general, and across all CHA2 DS2 VASc scores. CONCLUSIONS: After catheter ablation, low risk patients do not benefit from long-term aspirin therapy, but are at risk for higher rates of bleeding when compared to no therapy or warfarin.

Adaptation to steady light by intrinsically photosensitive retinal ganglion cells.

Intrinsically photosensitive retinal ganglion cells (ipRGCs) are recently discovered photoreceptors in the mammalian eye. These photoreceptors mediate primarily nonimage visual functions, such as pupillary light reflex and circadian photoentrainment, which are generally expected to respond to the absolute light intensity. The classical rod and cone photoreceptors, on the other hand, mediate image vision by signaling contrast, accomplished by adaptation to light. Experiments by others have indicated that the ipRGCs do, in fact, light-adapt. We found the same but, in addition, have now quantified this light adaptation for the M1 ipRGC subtype. Interestingly, in incremental-flash-on-background experiments, the ipRGC's receptor current showed a flash sensitivity that adapted in background light according to the Weber-Fechner relation, well known to describe the adaptation behavior of rods and cones. Part of this light adaptation by ipRGCs appeared to be triggered by a Ca(2+) influx, in that the flash response elicited in the absence of extracellular Ca(2+) showed a normal rising phase but a slower decay phase, resulting in longer time to peak and higher sensitivity. There is, additionally, a prominent Ca(2+)-independent component of light adaptation not typically seen in rods and cones or in invertebrate rhabdomeric photoreceptors.