Increase in choroidal thickness after blue light stimulation of the blind spot in young adults.

BACKGROUND: Blue light activates melanopsin, a photopigment that is expressed in intrinsically photosensitive retinal ganglion cells (ipRGCs). The axons of ipRGCs converge on the optic disc, which corresponds to the physiological blind spot in the visual field. Thus, a blue light stimulus aligned with the blind spot captures the ipRGCs axons at the optic disc. This study examined the potential changes in choroidal thickness and axial length associated with blue light stimulation of melanopsin-expressing ipRGCs at the blind spot. It was hypothesized that blue light stimulation at the blind spot in adults increases choroidal thickness. METHODS: The blind spots of both eyes of 10 emmetropes and 10 myopes, with a mean age of 28 ± 6 years (SD), were stimulated locally for 1-minute with blue flickering light with a 460 nm peak wavelength. Measurements of choroidal thickness and axial length were collected from the left eye before stimulation and over a 60-minute poststimulation period. At a similar time of day, choroidal thickness and axial length were measured under sham control condition in all participants, while a subset of 3 emmetropes and 3 myopes were measured after 1-minute of red flickering light stimulation of the blind spot with a peak wavelength of 620 nm. Linear mixed model analyses were performed to examine the light-induced changes in choroidal thickness and axial length over time and between refractive groups. RESULTS: Compared with sham control (2 ± 1 µm, n = 20) and red light (-1 ± 2 µm, n = 6) stimulation, subfoveal choroidal thickness increased within 60 min after blue light stimulation of the blind spot (7 ± 1 µm, n = 20; main effect of light, p < 0.001). Significant choroidal thickening after blue light stimulation occurred in emmetropes (10 ± 2 µm, p < 0.001) but not in myopes (4 ± 2 µm, p > 0.05). Choroidal thickening after blue light stimulation was greater in the fovea, diminishing in the parafoveal and perifoveal regions. There was no significant main effect of light, or light by refractive error interaction on the axial length after blind spot stimulation. CONCLUSIONS: These findings demonstrate that stimulating melanopsin-expressing axons of ipRGCs at the blind spot with blue light increases choroidal thickness in young adults. This has potential implications for regulating eye growth.

Discovery of N-X anomeric amides as electrophilic halogenation reagents.

Electrophilic halogenation is a widely used tool employed by medicinal chemists to either pre-functionalize molecules for further diversity or incorporate a halogen atom into drugs or drug-like compounds to solve metabolic problems or modulate off-target effects. Current methods to increase the power of halogenation rely on either the invention of new reagents or activating commercially available reagents with various additives such as Lewis or Brønsted acids, Lewis bases and hydrogen-bonding activators. There is a high demand for new reagents that can halogenate otherwise unreactive compounds under mild conditions. Here we report the invention of a class of halogenating reagents based on anomeric amides, taking advantage of the energy stored in the pyramidalized nitrogen of N-X anomeric amides as a driving force. These robust halogenating methods are compatible with a variety of functional groups and heterocycles, as exemplified on over 50 compounds (including 13 gram-scale examples and 1 flow chemistry scale-up).

Transcriptomic Signature and Pro-Osteoclastic Secreted Factors of Abnormal Bone-Marrow Stromal Cells in Fibrous Dysplasia.

Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants of GNAS encoding for Gαs and leading to excessive cyclic adenosine monophosphate signaling in bone-marrow stromal cells (BMSCs). The effect of Gαs activation in the BMSC transcriptome and how it influences FD lesion microenvironment are unclear. We analyzed changes induced by Gαs activation in the BMSC transcriptome and secretome. RNAseq analysis of differential gene expression of cultured BMSCs from patients with FD and healthy volunteers, and from an inducible mouse model of FD, was performed, and the transcriptomic profiles of both models were combined to build a robust FD BMSC genetic signature. Pathways related to Gαs activation, cytokine signaling, and extracellular matrix deposition were identified. To assess the modulation of several key secreted factors in FD pathogenesis, cytokines and other factors were measured in culture media. Cytokines were also screened in a collection of plasma samples from patients with FD, and positive correlations of several cytokines to their disease burden score, as well as to one another and bone turnover markers, were found. These data support the pro-inflammatory, pro-osteoclastic behavior of FD BMSCs and point to several cytokines and other secreted factors as possible therapeutic targets and/or circulating biomarkers for FD.

Acclimation to warming but not hypoxia alters thermal tolerance and metabolic sensitivity in an estuarine crustacean.

Coastal species are challenged by multiple anthropogenic stressors. Plasticity may buffer the effects of environmental change, but investigation has largely been restricted to single-stressor performance. Multistressor studies have often been short-term and relatively less is known about the consequences of plasticity under one stressor for performance under another. Here, we aimed to test for the effects of thermal or hypoxic acclimation on thermal tolerance in the amphipod Gammarus chevreuxi. Animals were chronically exposed to raised temperature or hypoxia prior to determination of upper thermal limits and routine metabolic rate (RMR). Warm acclimation increased all metrics of thermal tolerance, but hypoxic acclimation had no effect. Different responses to the two stressors was also observed for the thermal sensitivity of RMR. Consequently, this species possesses the ability to increase thermal tolerance via plasticity in response to chronic warming but increasing duration of hypoxic episodes will not confer cross-tolerance to a warming environment.

Bone Anchor Fixation in the Repair of Blunt Traumatic Abdominal Wall Hernias: A Western Trauma Association Multicenter Study.

BACKGROUND: Blunt traumatic abdominal wall hernias (TAWHs) are rare but require a variety of operative techniques to repair including bone anchor fixation (BAF) when tissue tears off bony structures. This study aimed to provide a descriptive analysis of BAF technique for blunt TAWH repair. Bone anchor fixation and no BAF repairs were compared, hypothesizing increased hernia recurrence with BAF repair. METHODS: A secondary analysis of the WTA blunt TAWH multicenter study was performed including all patients who underwent repair of their TAWH. Patients with BAF were compared to those with no BAF with bivariate analyses. RESULTS: 176 patients underwent repair of their TAWH with 41 (23.3%) undergoing BAF. 26 (63.4%) patients had tissue fixed to bone, with 7 of those reinforced with mesh. The remaining 15 (36.6%) patients had bridging mesh anchored to bone. The BAF group had a similar age, sex, body mass index, and injury severity score compared to the no BAF group. The time to repair (1 vs 1 days, P = .158), rate of hernia recurrence (9.8% vs 12.7%, P = .786), and surgical site infection (SSI) (12.5% vs 15.6%, P = .823) were all similar between cohorts. CONCLUSIONS: This largest series to date found nearly one-quarter of TAWH repairs required BAF. Bone anchor fixation repairs had a similar rate of hernia recurrence and SSI compared to no BAF repairs, suggesting this is a reasonable option for repair of TAWH. However, future prospective studies are needed to compare specific BAF techniques and evaluate long-term outcomes including patient-centered outcomes such as pain and quality of life.

The effect of landing zone toricity on scleral lens fitting characteristics and optics.

PURPOSE: The fit and optical performance of a scleral lens is affected by the alignment of the landing zone with the underlying ocular surface. The aim of this research was to quantify the effect of landing zone toricity upon scleral lens fitting characteristics (rotation and decentration) and optics (lens flexure) during short-term wear. METHODS: Scleral lenses with nominal landing zone toricities of 0, 100, 150 and 200 µm were worn in a randomised order by 10 young healthy participants (mean [SD] 24 [7] years) for 30 min, with other lens parameters held constant. Scleral toricity was quantified using a corneo-scleral profilometer, and lens flexure, rotation, and decentration were quantified using over-topography during lens wear. Repeated measures analyses were conducted as a function of landing zone toricity and residual scleral toricity (the difference between scleral and lens toricity) for eyes with 'low' magnitude scleral toricity (mean: 96 µm) and 'high' magnitude scleral toricity (mean: 319 µm). RESULTS: Toric landing zones significantly reduced lens flexure (by 0.37 [0.21] D, p < 0.05) and lens rotation (by 20 [24]°, p < 0.05) compared with a spherical landing zone. Horizontal and vertical lens decentration did not vary significantly with landing zone toricity. These trends for flexure, rotation, and decentration were also observed for eyes with 'low' and 'high' magnitude scleral toricity as a function of residual scleral toricity. CONCLUSION: Landing zones with 100-200 µm toricity significantly reduced lens flexure (by ~62%) and rotation (by ~77%) but not horizontal or vertical lens decentration, compared with a spherical landing zone, when controlling for other confounding variables. The incorporation of a toric landing zone, even for eyes with lower magnitude scleral toricity (~100 µm), may be beneficial, particularly for front surface optical designs.

Carbon quaternization of redox active esters and olefins by decarboxylative coupling.

The synthesis of quaternary carbons often requires numerous steps and complex conditions or harsh reagents that act on heavily engineered substrates. This is largely a consequence of conventional polar-bond retrosynthetic disconnections that in turn require multiple functional group interconversions, redox manipulations, and protecting group chemistry. Here, we report a simple catalyst and reductant combination that converts two types of feedstock chemicals, carboxylic acids and olefins, into tetrasubstituted carbons through quaternization of radical intermediates. An iron porphyrin catalyst activates each substrate by electron transfer or hydrogen atom transfer, and then combines the fragments using a bimolecular homolytic substitution (SH2) reaction. This cross-coupling reduces the synthetic burden to procure numerous quaternary carbon---containing products from simple chemical feedstocks.

Laminectomy for acute transverse sacral fractures with compression of the cauda equina: A neurosurgical perspective.

Introduction: Optimal management of transverse sacral fractures (TSF) remains inconclusive. These injuries may present with neurological deficits including cauda equina syndrome. We present our series of laminectomy for acute TSF with cauda equina compression. Methods: This was a retrospective chart review of all patients that underwent sacral laminectomy for treatment of cauda equina compression in acute TSF at our institution between 2007 through 2023. Results: A total of 9 patients (5 male and 4 female) underwent sacral laminectomy to decompress the cauda equina in the setting of acute high impact trauma. Surgeries were done early within a mean time of 5.9 days. All but one patient had symptomatic cauda equina syndrome. In one instance surgery was applied due to significant canal stenosis present on imaging in a patient with diminished mental status not allowing proper neurological examination. Torn sacral nerve roots were repaired directly when possible. All patients regained their neurological function related to the sacral cauda equina on follow up. The rate of surgical site infection (SSI) was 33%. Conclusion: Acute early sacral laminectomy and nerve root repair as needed was effective in recovering bowel and bladder function in patients after high impact trauma and TSF with cauda equina compression. A high SSI rate may be reduced by delaying surgery past 1 week from trauma, but little data exists at this time for clear recommendations.

Human papillomavirus associated oropharyngeal cancer now the most common mucosal head and neck cancer in Queensland.

INTRODUCTION: The profile and outcomes of head and neck cancer throughout Australia has changed over the past decade. The aim of this study was to perform a population-based analysis of incidence, demographics, stage, treatments and outcomes of patients diagnosed with oropharyngeal squamous cell carcinoma (OPSCC), with a particular focus on HPV-associated disease. METHODS: This was a retrospective analysis of prospectively collected data within the Queensland Oncology Repository (QOR) and analysed by the Queensland Cancer Control Analysis Team. The cohort included patients diagnosed in Queensland between 1 January 2015 and 31 December 2019. Outcome measures included incidence of new OPSCC cases, age-standardised rates (ASR) (3-year average), demographics, p16 status, stage (8th Edition American Joint Commission on Cancer), treatments, and 2- and 5-year overall survival. RESULTS: There were 1527 newly diagnosed OPSCC, representing 96% (1527/1584) of all oropharyngeal cancers. It was the most common head and neck cancer diagnosed, with oral cavity cancer being the second most common (n = 1171). Seventy-seven percent were p16 positive (1170/1527), of which 87% (1019/1170) were male. The median age was 61 years and 49% (568/1170) presented with Stage I disease. The ASR was 6.3/100,000, representing a 144% incidence increase since 1982 (2.6/100,000). Radiotherapy was utilised in 91% of p16+ cases with 2- and 5- year overall survival of 89% and 79%, respectively. CONCLUSION: OPSCC is now the most common mucosal head and neck cancer diagnosed in Queensland, having surpassed oral cavity cancer. The majority are HPV-associated (p16+), presenting with early-stage disease with a favourable prognosis.

Spatial Atlas for Mapping Vascular Microcalcification Using 18F-NaF PET/CT: Application in Hyperphosphatemic Familial Tumoral Calcinosis.

BACKGROUND: Vascular calcification causes significant morbidity and occurs frequently in diseases of calcium/phosphate imbalance. Radiolabeled sodium fluoride positron emission tomography/computed tomography has emerged as a sensitive and specific method for detecting and quantifying active microcalcifications. We developed a novel technique to quantify and map total vasculature microcalcification to a common space, allowing simultaneous assessment of global disease burden and precise tracking of site-specific microcalcifications across time and individuals. METHODS: To develop this technique, 4 patients with hyperphosphatemic familial tumoral calcinosis, a monogenic disorder of FGF23 (fibroblast growth factor-23) deficiency with a high prevalence of vascular calcification, underwent radiolabeled sodium fluoride positron emission tomography/computed tomography imaging. One patient received serial imaging 1 year after treatment with an IL-1 (interleukin-1) antagonist. A radiolabeled sodium fluoride-based microcalcification score, as well as calcification volume, was computed at all perpendicular slices, which were then mapped onto a standardized vascular atlas. Segment-wise mCSmean and mCSmax were computed to compare microcalcification score levels at predefined vascular segments within subjects. RESULTS: Patients with hyperphosphatemic familial tumoral calcinosis had notable peaks in microcalcification score near the aortic bifurcation and distal femoral arteries, compared with a control subject who had uniform distribution of vascular radiolabeled sodium fluoride uptake. This technique also identified microcalcification in a 17-year-old patient, who had no computed tomography-defined calcification. This technique could not only detect a decrease in microcalcification score throughout the patient treated with an IL-1 antagonist but it also identified anatomic areas that had increased responsiveness while there was no change in computed tomography-defined macrocalcification after treatment. CONCLUSIONS: This technique affords the ability to visualize spatial patterns of the active microcalcification process in the peripheral vasculature. Further, this technique affords the ability to track microcalcifications at precise locations not only across time but also across subjects. This technique is readily adaptable to other diseases of vascular calcification and may represent a significant advance in the field of vascular biology.

Organismal Superposition and Death.

Organismal superposition holds that the same individual both is and is not an organism, as a consequence of organismal pluralism. When coupled with the assumption that death is the cessation of an organism, this entails that there is no unique answer as to whether brain death is biological death. This essay argues that concerns about organismal pluralism and superposition do not undermine a theory of biological death, nor entail any metaphysical indeterminacy about the biological vital status of a brain-dead individual.

Loss of the glycosyltransferase Galnt11 affects vitamin D homeostasis and bone composition.

O-glycosylation is a conserved posttranslational modification that impacts many aspects of organismal viability and function. Recent studies examining the glycosyltransferase Galnt11 demonstrated that it glycosylates the endocytic receptor megalin in the kidneys, enabling proper binding and reabsorption of ligands, including vitamin D-binding protein (DBP). Galnt11-deficient mice were unable to properly reabsorb DBP from the urine. Vitamin D plays an essential role in mineral homeostasis and its deficiency is associated with bone diseases such as rickets, osteomalacia, and osteoporosis. We therefore set out to examine the effects of the loss of Galnt11 on vitamin D homeostasis and bone composition. We found significantly decreased levels of serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, consistent with decreased reabsorption of DBP. This was accompanied by a significant reduction in blood calcium levels and a physiologic increase in parathyroid hormone (PTH) in Galnt11-deficient mice. Bones in Galnt11-deficient mice were smaller and displayed a decrease in cortical bone accompanied by an increase in trabecular bone and an increase in a marker of bone formation, consistent with PTH-mediated effects on bone. These results support a unified model for the role of Galnt11 in bone and mineral homeostasis, wherein loss of Galnt11 leads to decreased reabsorption of DBP by megalin, resulting in a cascade of disrupted mineral and bone homeostasis including decreased circulating vitamin D and calcium levels, a physiological increase in PTH, an overall loss of cortical bone, and an increase in trabecular bone. Our study elucidates how defects in O-glycosylation can influence vitamin D and mineral homeostasis and the integrity of the skeletal system.

RNA-based bone histomorphometry: method and its application to explaining postpubertal bone gain in a G610C mouse model of osteogenesis imperfecta.

Bone histomorphometry is a well-established approach to assessing skeletal pathology, providing a standard evaluation of the cellular components, architecture, mineralization, and growth of bone tissue. However, it depends in part on the subjective interpretation of cellular morphology by an expert, which introduces bias. In addition, diseases like osteogenesis imperfecta (OI) and fibrous dysplasia are accompanied by changes in the morphology and function of skeletal tissue and cells, hindering consistent evaluation of some morphometric parameters and interpretation of the results. For instance, traditional histomorphometry combined with collagen turnover markers suggested that reduced bone formation in classical OI is accompanied by increased bone resorption. In contrast, the well-documented postpubertal reduction in fractures would be easier to explain by reduced bone resorption after puberty, highlighting the need for less ambiguous measurements. Here we propose an approach to histomorphometry based on in situ mRNA hybridization, which uses Col1a1 as osteoblast and Ctsk as osteoclast markers. This approach can be fully automated and eliminates subjective identification of bone surface cells. We validate these markers based on the expression of Bglap, Ibsp, and Acp5. Comparison with traditional histological and tartrate-resistant acid phosphatase staining of the same sections suggests that mRNA-based analysis is more reliable. Unlike inconclusive traditional histomorphometry of mice with α2(I)-Gly610 to Cys substitution in the collagen triple helix, mRNA-based measurements reveal reduced osteoclastogenesis in 11-wk-old animals consistent with the postpubertal catch-up osteogenesis observed by microCT. We optimize the technique for cryosections of mineralized bone and sections of paraffin-embedded decalcified tissue, simplifying and broadening its applications. We illustrate the application of the mRNA-based approach to human samples using the example of a McCune-Albright syndrome patient. By eliminating confounding effects of altered cellular morphology and the need for subjective morphological evaluation, this approach may provide a more reproducible and accessible evaluation of bone pathology.

Transcriptomic signature and pro-osteoclastic secreted factors of abnormal bone marrow stromal cells in fibrous dysplasia.

Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants in GNAS, encoding for Gαs, which leads to excessive cAMP signaling in bone marrow stromal cells (BMSCs). Despite advancements in our understanding of FD pathophysiology, the effect of Gαs activation in the BMSC transcriptome remains unclear, as well as how this translates into their local influence in the lesional microenvironment. In this study, we analyzed changes induced by Gαs activation in BMSC transcriptome and performed a comprehensive analysis of their production of cytokines and other secreted factors. We performed RNAseq of cultured BMSCs from patients with FD and healthy volunteers, and from an inducible mouse model of FD, and combined their transcriptomic profiles to build a robust FD BMSC genetic signature. Pathways related to Gαs activation, cytokine signaling, and extracellular matrix deposition were identified. In addition, a comprehensive profile of their secreted cytokines and other factors was performed to identify modulation of several key factors we hypothesized to be involved in FD pathogenesis. We also screened circulating cytokines in a collection of plasma samples from patients with FD, finding positive correlations of several cytokines to their disease burden score, as well as to one another and bone turnover markers. Overall, these data support a pro-inflammatory, pro-osteoclastic behavior of BMSCs bearing hyperactive Gαs variants, and point to several cytokines and other secreted factors as possible therapeutic targets and/or circulating biomarkers for FD.

Presence and Relevance of Myocardial Bridge in LAD-PCI of CTO and Non-CTO Lesions.

BACKGROUND: Intravascular ultrasound (IVUS) studies show that one-quarter of left anterior descending (LAD) arteries have a myocardial bridge. An MB may be associated with stent failure when the stent extends into the MB. OBJECTIVES: The aim of this study was to investigate: 1) the association between an MB and chronic total occlusion (CTO) in any LAD lesions; and 2) the association between an MB and subsequent clinical outcomes after percutaneous coronary intervention in LAD CTOs. METHODS: A total of 3,342 LAD lesions with IVUS-guided percutaneous coronary intervention (280 CTO and 3,062 non-CTO lesions) were included. The primary outcome was target lesion failure (cardiac death, target vessel myocardial infarction, definite stent thrombosis, and ischemic-driven target lesion revascularization). RESULTS: An MB by IVUS was significantly more prevalent in LAD CTOs than LAD non-CTOs (40.4% [113/280] vs 25.8% [789/3,062]; P < 0.0001). The discrepancy in CTO length between angiography and IVUS was greater in 113 LAD CTOs with an MB than 167 LAD CTOs without an MB (6.0 [Q1, Q3: 0.1, 12.2] mm vs 0.2 [Q1, Q3: -1.4, 8.4] mm; P < 0.0001). Overall, 48.7% (55/113) of LAD CTOs had a stent that extended into an MB after which target lesion failure was significantly higher compared to a stent that did not extend into an MB (26.3% vs 0%; P = 0.0004) or compared to an LAD CTO without an MB (26.3% vs 9.6%; P = 0.02). CONCLUSIONS: An MB was more common in LAD CTO than non-CTO LAD lesions. If present, approximately one-half of LAD CTOs had a stent extending into an MB that, in turn, was associated with worse outcomes.

Multidomain Predictors of Protracted Recovery following Concussion Among 5- to 9-Year-Old Patients: A Preliminary Study.

OBJECTIVE: To determine which components from a multidomain assessment best predict protracted recovery in pediatric patients with a concussion. STUDY DESIGN: A prospective cohort of patients aged 5-9 years who presented within 21 days of concussion to a specialty clinic were categorized into normal (≤30 days) and protracted (>30 days) recovery. Participants provided demographic and medical history information, and completed the Child Sport Concussion Assessment Tool-5 symptom report and balance assessment, the Vestibular/Ocular Motor Screen-Child (VOMS-C), and the Pediatric Immediate Post-concussion Assessment and Cognitive Testing. Univariate logistic regressions (LR) were used to inform a follow-up forward stepwise LR to identify the best predictors of protracted recovery. Receiver operating characteristic analysis of the area under the curve (AUC) was used to identify which predictors retained from the LR model best discriminated recovery. RESULTS: The final sample included 68 patients (7.52 ± 2.3 years; 56% male), 36 (52.9%) with normal and 32 (47.1%) with protracted recovery. Results of the LR to identify protracted recovery were significant (P < .001) and accounted for 39% of the variance. The model accurately classified 78% of patients, with days to first clinic visit (OR, 1.2; 95% CI, 1.1-1.4; P = .003) and positive VOMS-C findings (OR, 8.32; 95% CI, 2.4-28.8; P < .001) as significant predictors. A receiver operating characteristic analysis of the AUC of this 2-factor model discriminated protracted from normal recovery (AUC, 0.82; 95% CI, 0.71-0.92; P < .001). CONCLUSIONS: Days to first clinic visit and positive findings on the VOMS-C were the most robust predictors of protracted recovery after concussion in young pediatric patients.

Venoarterial Extracorporeal Life Support Use in Acute Pulmonary Embolism Shows Favorable Outcomes.

BACKGROUND: Differences in outcomes by indication for venoarterial extracorporeal life support (VA-ECLS) are poorly described. We hypothesized that patients on VA-ECLS for acute pulmonary embolism (PE) have fewer complications and better survival than patients on VA-ECLS for other indications. METHODS: All patients ≥18 years on VA-ECLS from the Extracorporeal Life Support Organization global registry (2010-2019) were evaluated (n = 29,842). After excluding patients aged >79 years (n = 729) and those with incomplete indication data (n = 2530), patients were stratified by VA-ECLS indication for PE vs all other indications. The association between being discharged alive and each type of complication with VA-ECLS indication was assessed. RESULTS: Of 26,583 patients included in the analysis, 978 (3.7%) were on VA-ECLS for a primary diagnosis of acute PE. Acute PE patients were younger (53.1 vs 56.7 years, P < .001) and were more likely to be women (52.1% vs 32.3%, P < .001). Patients who underwent VA-ECLS for acute PE were 78% more likely to be discharged alive vs patients supported with VA-ECLS for other reasons (52.8% vs 40.4%; P < .001). Acute PE patients had fewer cardiovascular and renal complications (26.6% vs 38.0% and 31.1% vs 39.4%, respectively; adjusted P < .001). Acute PE patients had higher odds of having clots and mechanical complications (8.7% vs 7.9% and 16.7% vs 14.6%, respectively; adjusted P < .001). CONCLUSIONS: Patients undergoing VA-ECLS for acute PE have higher odds of survival to hospital discharge compared with those supported for other indications. Additionally, VA-ECLS in this population is associated with fewer cardiovascular and renal complications but higher mechanical complications.