Fibroblast Activation Protein Is Expressed by Altered Osteoprogenitors and Associated to Disease Burden in Fibrous Dysplasia.

Fibrous dysplasia (FD) is a mosaic skeletal disorder involving the development of benign, expansile fibro-osseous lesions during childhood that cause deformity, fractures, pain, and disability. There are no well-established treatments for FD. Fibroblast activation protein (FAPα) is a serine protease expressed in pathological fibrotic tissues that has promising clinical applications as a biomarker and local pro-drug activator in several pathological conditions. In this study, we explored the expression of FAP in FD tissue and cells through published genetic expression datasets and measured circulating FAPα in plasma samples from patients with FD and healthy donors. We found that FAP genetic expression was increased in FD tissue and cells, and present at higher concentrations in plasma from patients with FD compared to healthy donors. Moreover, FAPα levels were correlated with skeletal disease burden in patients with FD. These findings support further investigation of FAPα as a potential imaging and/or biomarker of FD, as well as a pro-drug activator specific to FD tissue.

A resolvable controversy in avian conservation.

Twenty years of squandering an opportunity to save an iconic species from extinction are summarized. In 2005, an article that was featured on the cover of Science announced the rediscovery of the Ivory-billed Woodpecker (Campephilus principalis) in Arkansas. Despite a subsequent report of sightings in Florida by another group of ornithologists, the persistence of this elusive species became controversial when nobody managed to obtain a clear photo. Video footage that was obtained in Louisiana and Florida between 2006 and 2008 should have resolved the issue, but there was a breakdown in rational discourse after critics became entrenched in the position that the species is extinct. After openly and aggressively attacking relatively weak evidence that was presented in the original article, critics used specious arguments behind the scenes to delay the publication of the strongest evidence for a decade. The bulk of this material was finally published in Heliyon in 2017, but the critics have never addressed it. In 2021, the U.S. Fish & Wildlife Service announced a decision to declare the Ivory-billed Woodpecker extinct without addressing the strongest evidence for persistence.

A multi-center evaluation of a novel IVF cryostorage device in an active clinical setting.

The objective of this study was to evaluate the function, and usability of a novel automated software-guided cryostorage system in an active IVF laboratory setting. The investigational device (ID) was installed at 3 IVF laboratories (sites: α, ß, and γ). A total of 15 embryologists were trained to use the ID. Mock patient specimens containing mirrored live patient data were handled using the ID. Temperature readings were recorded every minute. Successful identification, storage, and retrieval of mock patient specimens by the ID were evaluated. To assess an LN2 pressure builder, the frequency of use and events of workflow interruption were logged. Student's t-test was used to determine statistical significance. The ID was in active use for 164 days total. During this time, 329 mock patient egg and embryo cohorts were handled by the ID. The mean ± SD temperatures during active use were: α, - 176.57 ± 1.83 °C; ß, - 178.21 ± 2.75 °C; γ, - 178.98 ± 1.74 and did not differ significantly. The highest recorded temperatures were: α, - 165.14 °C; ß, - 157.41 °C; γ, - 164.45 °C. A total of 1064 automation transactions on 409 specimen vessels were performed. Data was managed on 1501 eggs and embryos. The ID did not lose or misplace any specimen data or vessels, and no mock specimen was exposed to a detrimental (> - 150 °C) temperature excursion. Over the 25 LN2 pressure builder usages during 99 total days, there was 1 occurrence where usage interrupted workflow due to a lack of LN2 pressure. The ID has advantages over the current manual-based cryostorage systems, including radio frequency identification (RFID) tracking, automation of manual tasks, and software guidance to ensure accurate specimen storage and retrieval. The results of this study indicate that the ID can be integrated into active IVF laboratories.

The central and peripheral corneal response to short-term hypoxia.

PURPOSE: To quantify the magnitude and recovery of central and limbal corneal oedema induced by short-term unilateral eyelid closure without contact lens wear. METHODS: The left eye of 10 adults with healthy corneas was patched using a folded eye pad for 30 min. High-resolution optical coherence tomography images (which captured the limbal and central corneal regions simultaneously) were obtained before patching, immediately after eye opening and again at 1, 2, 5, 6, 9, 10, 14 and 15 mins after eyelid opening. Oedema was measured from the limbus (scleral spur) to the central cornea (thinnest corneal location) along the horizontal meridian. RESULTS: A greater amount of limbal oedema was noted (mean [SD] 3.84 [1.79] %) compared to the central cornea (2.48 [0.61] %; p = 0.04) after 30 mins of unilateral eyelid closure. Both central and limbal corneal oedema recovered rapidly following eyelid opening, with no significant differences in the rate of corneal recovery between corneal locations (p = 0.90). CONCLUSIONS: Short-term unilateral eyelid closure resulted in ~55% more relative oedema in the limbal region compared to the central cornea. Rapid recovery of oedema and corneal overshoot (thinning beyond the baseline corneal thickness) was observed within 1-2 min of eyelid opening for both central and peripheral regions.

Ocular findings in Jansen metaphyseal chondrodysplasia.

Jansen metaphyseal chondrodysplasia (JMC) is an ultra-rare disorder caused by germline heterozygous PTHR1 variants resulting in constitutive activation of parathyroid hormone type 1 receptor. A description of ocular manifestations of the disease is lacking. Six patients with JMC underwent a detailed ophthalmic evaluation, spectral-domain optical coherence tomography (OCT), visual field testing, and craniofacial CT scans. Five of 6 patients had good visual acuity. All patients had widely spaced eyes; 5/6 had downslanted palpebral fissures. One patient had proptosis, and another had bilateral ptosis. Two patients had incomplete closure of the eyelids (lagophthalmos), one had a history of progressive right facial nerve palsy with profuse epiphora, while the second had advanced optic nerve atrophy with corresponding retinal nerve fiber layer (RNFL) thinning on OCT and significant bilateral optic canal narrowing on CT scan. Additionally, this patient also had central visual field defects and abnormal color vision. A third patient had normal visual acuity, subtle temporal pallor of the optic nerve head, normal average RNFL, but decreased temporal RNFL and retinal ganglion cell layer analysis (GCA) on OCT. GCA was decreased in 4/6 patients indicating a subclinical optic nerve atrophic process. None of the patients had glaucoma or high myopia. These data represent the first comprehensive report of ophthalmic findings in JMC. Patients with JMC have significant eye findings associated with optic canal narrowing due to extensive skull base dysplastic bone overgrowth that appear to be more prevalent and pronounced with age. Progressive optic neuropathy from optic canal narrowing may be a feature of JMC, and OCT GCA can serve as a useful biomarker for progression in the setting of optic canal narrowing. We suggest that patients with JMC should undergo regular ophthalmic examination including color vision, OCT, visual field testing, orbital, and craniofacial imaging.

A nanobody against the V-ATPase c subunit inhibits metastasis of 4T1-12B breast tumor cells to lung in mice.

The vacuolar H+-ATPase (V-ATPase) is an ATP-dependent proton pump that functions to control the pH of intracellular compartments as well as to transport protons across the plasma membrane of various cell types, including cancer cells. We have previously shown that selective inhibition of plasma membrane V-ATPases in breast tumor cells inhibits the invasion of these cells in vitro. We have now developed a nanobody directed against an extracellular epitope of the mouse V-ATPase c subunit. We show that treatment of 4T1-12B mouse breast cancer cells with this nanobody inhibits V-ATPase-dependent acidification of the media and invasion of these cells in vitro. We further find that injection of this nanobody into mice implanted with 4T1-12B cells orthotopically in the mammary fat pad inhibits metastasis of tumor cells to lung. These results suggest that plasma membrane V-ATPases represent a novel therapeutic target to limit breast cancer metastasis.

Comparison of embryologist stress, somatization, and burnout reported by embryologists working in UK HFEA-licensed ART/IVF clinics and USA ART/IVF clinics.

STUDY QUESTION: What is the prevalence of occupational stress, somatization, and burnout reported by UK and US, embryologists and the impact of work conditions on these well-being outcomes? SUMMARY ANSWER: Surveyed UK and US embryologists reported moderate perceived stress, low somatic symptom severity, high levels of burnout, and overall stressful work conditions, but with differences that could be due to country-specific occupational and employment characteristics. WHAT IS KNOWN ALREADY?: Spanish, UK, US, and international surveys have identified high levels of occupational stress, somatization, burnout, and occupational health issues among embryologists. These issues have been attributed to embryologists' occupational challenges and work conditions. STUDY DESIGN, SIZE, DURATION: A cross-sectional web-based survey was sent to 253 embryologists working in UK ART/IVF clinics and 487 embryologists working in US ART/IVF clinics. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants self-reported their stress levels, somatization, burnout, and work conditions. Proportions across the Perceived Stress Scale (PSS), Patient Health Questionnaire (PHQ-15), Maslach Burnout Inventory-General Survey (MBI-GS), a single-item work unit grade (A-F), and customized occupational and sociodemographic questionnaires were calculated using descriptive statistics. Welch's t-test was utilized to compare PSS and PHQ-15 scores between groups. Risk ratios were calculated using log-binomial regression for all models except for levels of anxiety related to performing cryostorage tasks, for which Poisson models were used. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 50.6% (128) of the embryologists in the UK and 50.1% (244) in the US completed the survey. Both groups self-reported moderate PSS and low PHQ-15 scores, although fewer UK embryologists scored high on the MBI cynicism dimension than their US colleagues (43% UK vs 60% US embryologists, P < 0.05). The UK and US embryologists did not differ on the MBI exhaustion dimension with both scoring high for exhaustion (59% UK vs 62% US). Although 81% and 80% of UK and US embryologists, respectively, reported working overtime, more embryologists in the UK reported being adequately compensated. Increasing levels of anxiety-related to cryostorage showed a dose-dependent increased risk of burnout on at least two MBI-GS dimensions only in the UK group, and, a dose-dependent likelihood of higher PSS and PHQ-15 scores in both groups. LIMITATIONS, REASONS FOR CAUTION: Since the two groups were surveyed 9 months apart and were self-reporting, the study is limited by the differences in responsibilities, scheduling, and workload specific to the time of year. WIDER IMPLICATIONS OF THE FINDINGS: Work-related health issues and occupational challenges shared by UK and US embryologists could be addressed by organizational enhancements and technology. Lower levels of stress and burnout among UK embryologists might be due to the HFEA-provided structure/certainty. STUDY FUNDING/COMPETING INTEREST(S): This study was supported without any external funding by TMRW Life Sciences Inc., which is developing and commercializing an automated platform for embryology. M.G.C. and M.S.L. are full-time employees and stockholders/shareholders with TMRW Life Sciences, and A.M. of Novavax, Inc. was an employee of TMRW Life Sciences. G.P. is a consultant for TMRW Life Sciences. The remaining authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: NCT05326802; NCT05708963.

Acid-degradable lipid nanoparticles enhance the delivery of mRNA.

Lipid nanoparticle (LNP)-mRNA complexes are transforming medicine. However, the medical applications of LNPs are limited by their low endosomal disruption rates, high toxicity and long tissue persistence times. LNPs that rapidly hydrolyse in endosomes (RD-LNPs) could solve the problems limiting LNP-based therapeutics and dramatically expand their applications but have been challenging to synthesize. Here we present an acid-degradable linker termed 'azido-acetal' that hydrolyses in endosomes within minutes and enables the production of RD-LNPs. Acid-degradable lipids composed of polyethylene glycol lipids, anionic lipids and cationic lipids were synthesized with the azido-acetal linker and used to generate RD-LNPs, which significantly improved the performance of LNP-mRNA complexes in vitro and in vivo. Collectively, RD-LNPs delivered mRNA more efficiently to the liver, lung, spleen and brains of mice and to haematopoietic stem and progenitor cells in vitro than conventional LNPs. These experiments demonstrate that engineering LNP hydrolysis rates in vivo has great potential for expanding the medical applications of LNPs.

Divergent synthesis of δ-valerolactones and furanones via palladium or copper-catalyzed α-hydroxycyclopropanol ring opening cyclizations.

Cyclopropanols are versatile starting materials which can undergo various ring opening reactions due to their intrisic ring strain. Herein, we report two transition metal-catalyzed α-hydroxycyclopropanol ring opening cyclizations to divergently transform the same α-hydroxycyclopropanol substrate into two different products of enhanced value. One is a palladium-catalyzed α-hydroxycyclopropanol ring opening carbonylative lactonization to synthesize δ-valerolactones. The other one is a copper-catalyzed α-hydroxycyclopropanol ring opening cyclization to access furanones.

Off-Label Use of Peripheral Paclitaxel Drug-Coated Balloons in Management of Recurrent Coronary In-Stent Restenosis.

Background: While not available for clinical use in the United States, dedicated drug-coated balloons (DCB) are currently under investigation for the management of coronary in-stent restenosis (ISR). Peripheral drug-coated balloons (P-DCB) have been used off-label for coronary ISR. Further data regarding this practice are needed. We aimed to describe outcomes in patients who underwent off-label P-DCB angioplasty for coronary ISR. Methods: We analyzed data on P-DCB angioplasty for coronary ISR at a single high-volume center between April 1, 2015, and December 30, 2017. Demographic and procedural details were collected, with systematic follow-up as clinically indicated. Results: Data from 31 patients treated with P-DCB angioplasty (mean age 68.0 ± 10.7 years) with coronary ISR (17 recurrent and 14 first time) were analyzed. Most patients presented with high-grade angina (81%) or myocardial infarction (13%). Treated ISR lesions were in native coronary arteries (68%), saphenous vein grafts (SVG, 23%), and the left internal mammary artery (10%). Diffuse intrastent ISR was common (69%) with a mean lesion length of 21.7 ± 12.4 mm. No postprocedural myocardial infarction occurred and 1 nonprocedural mortality occurred during index admission. At follow-up (median: 283, interquartile range [IQR]: 354 days), repeat angiography was performed in 19 patients (median: 212, IQR: 188 days), and 11 patients had target lesion recurrent ISR (Kaplan-Meier event-free survival estimate: 44.7%, 95% CI, 26.1%-76.5%). Conclusions: In the absence of availability of dedicated coronary DCB, treatment of coronary ISR using P-DCB angioplasty was feasible, although follow-up demonstrated continued risk for recurrent ISR in this high-risk population.

Effort in manual operation of reproductive health cryostorage facilities.

RESEARCH QUESTION: What areas of manual IVF cryostorage operations are common to the safe operation of IVF cryostorage facilities and require effort from embryologists? DESIGN: Observational time and motion data were collected by two observers equipped with the digital cameras over 2 weeks at four well-characterized US IVF centres (sites α, ß, γ and δ) from 12 participants performing cryostorage tasks. To understand the work processes of the different sites and assist in the data analysis, informal interviews were conducted with the study participants and laboratory directors. Data were analysed to identify work processes that might be eliminated or diminished by automation and software improvements. RESULTS: On average, it took 3.4 data record queries per retrieval from cryostorage to identify a cane, while the canister was lifted an average of 1.5 times per retrieval, with a mean 11.8 ± 9.2 s per lift. Of the total time spent working with cryostorage equipment, 47.25% was of a fatiguing nature. Sites α, ß and γ utilized one person to fill the liquid nitrogen storage Dewars, while site δ had two technicians working in tandem to move and fill the Dewars, with different frequencies and determination factors for refills and efficiencies. CONCLUSIONS: This time and motion study demonstrated significant time investment, task redundancy and fatiguing working conditions among embryologists using manual cryostorage processes. There was a disparity of processes and space capacity across different laboratories. Some of these issues may be addressed by the integration of automation and technology solutions.

Esophageal Bronchus-the Hidden Link. A Case Report.

An esophageal bronchus is a subtype of congenital bronchopulmonary foregut malformations in which a lobar bronchus arises directly from the esophagus, creating a communication between the esophagus and lung tissue. Early diagnosis is crucial to prevent worsening pulmonary sequelae but is challenging due to the rarity of the anomaly and nonspecific respiratory symptoms. We present a child whose esophageal bronchus was identified incidentally during preanesthetic assessment for craniosynostosis repair and discuss the role an anesthesiologist can play in identifying and managing this diagnosis.

Heat hardening improves thermal tolerance in abalone, without the trade-offs associated with chronic heat exposure.

Marine animals are challenged by chronically raised temperatures alongside an increased frequency of discrete, severe warming events. Exposure to repeated heat shocks could result in heat hardening, where sub-lethal exposure to thermal stress temporarily enhances thermotolerance, and may be an important mechanism by which marine species will cope with future thermal challenges. However, we have relatively little understanding of the effects of heat hardening in comparison to chronic exposure to elevated temperatures. Therefore, we compared the effects of heat hardening from repeated exposure to acute heat shocks and chronic exposure to elevated temperatures on thermal tolerance in the European abalone, Haliotis tuberculata. Adult abalones were exposed to either control temperature (15 °C), chronic warming (20 °C) or a regime of two events of repeated acute heat shock cycles (23-25 °C) during six months, and their thermal tolerance and performance, based upon cardiac activity, compared using a dynamic ramping assay. The cost associated with each treatment was also estimated via measurements of condition index (CI). Abalone exposed to both temperature treatments had higher upper thermal limits than the control, but heat-hardened individuals had significantly higher CI values, indicating an enhancement in condition status. Differences in the shape of the thermal performance curve suggest different mechanisms may be at play under different temperature exposure treatments. We conclude that heat hardening can boost thermal tolerance in this species, without performance trade-offs associated with chronic warming.

The effect of lens and fitting characteristics upon scleral lens centration.

PURPOSE: To quantify the impact of varying central fluid reservoir depth, lens thickness/mass and the addition of a peripheral fenestration upon scleral lens centration. METHODS: Ten young, healthy adults participated in a series of repeated-measures experiments involving short-term (90 min) open eye scleral lens wear. Scleral lens parameters (material, back optic zone radius, diameter, back vertex power and landing zone) were controlled across all experiments, and the central fluid reservoir depth (ranging from 144 to 726 µm), lens thickness (ranging from 150 to 1200 µm), lens mass (101-241 mg) and lens design (with or without a single 0.3 mm peripheral fenestration) were altered systematically. Scleral lens decentration was quantified using over-topography maps. RESULTS: On average, scleral lens centration varied by <0.10 mm over 90 min of wear. Medium and high initial fluid reservoir conditions resulted in 0.17 mm more temporal and 0.55 mm more inferior lens decentration, compared to the low fluid reservoir depth (p < 0.001). Changes in lens thickness or the addition of a peripheral fenestration did not cause clinically significant changes in centration (<0.10 mm on average) when controlling for fluid reservoir depth. Central fluid reservoir depth was the best predictor of horizontal and vertical lens decentration, explaining 62-73% of the observed variation, compared to 40-44% for lens thickness and mass. CONCLUSION: Scleral lens decentration remained relatively stable over 90 min of lens wear. A greater initial central fluid reservoir depth resulted in significantly more lens decentration, particularly inferiorly. Large variations in lens thickness, mass or the addition of a single peripheral fenestration did not substantially affect lens centration.

Retrospective Single Nucleotide Polymorphism Analysis of Host Resistance and Susceptibility to Ovine Johne's Disease Using Restored FFPE DNA.

Johne's disease (JD), also known as paratuberculosis, is a chronic, untreatable gastroenteritis of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP) infection. Evidence for host genetic resistance to disease progression exists, although it is limited due to the extended incubation period (years) and diagnostic challenges. To overcome this, previously restored formalin-fixed paraffin embedded tissue (FFPE) DNA from archived FFPE tissue cassettes was utilized for a novel retrospective case-control genome-wide association study (GWAS) on ovine JD. Samples from known MAP-infected flocks with ante- and postmortem diagnostic data were used. Cases (N = 9) had evidence of tissue infection, compared to controls (N = 25) without evidence of tissue infection despite positive antemortem diagnostics. A genome-wide efficient mixed model analysis (GEMMA) to conduct a GWAS using restored FFPE DNA SNP results from the Illumina Ovine SNP50 Bead Chip, identified 10 SNPs reaching genome-wide significance of p < 1 × 10-6 on chromosomes 1, 3, 4, 24, and 26. Pathway analysis using PANTHER and the Kyoto Encyclopedia of Genes and Genomes (KEGG) was completed on 45 genes found within 1 Mb of significant SNPs. Our work provides a framework for the novel use of archived FFPE tissues for animal genetic studies in complex diseases and further evidence for a genetic association in JD.

The carbon footprint of the perioperative transurethral resection of bladder tumour pathway.

OBJECTIVES: To evaluate the carbon footprint of the perioperative transurethral resection of bladder tumour (TURBT) pathway from decision to treat to postoperative discharge, and model potential greenhouse gas (GHG) emissions reduction strategies. MATERIALS AND METHODS: This process-based attributional cradle-to-grave life-cycle assessment (LCA) of GHG emissions modelled the perioperative TURBT pathway at a hospital in Southwest England. We included travel, energy and water use, all reusable and consumable items, and laundry and equipment sterilisation. Resource use for 30 patients undergoing surgery was recorded to understand average GHG emissions and the inter-case variability. Sensitivity analysis was performed for manufacturing location, pharmaceutical manufacturing carbon-intensity, and theatre list utilisation. RESULTS: The median (interquartile range) perioperative TURBT carbon footprint was 131.8 (119.8-153.6) kg of carbon dioxide equivalent. Major pathway categories contributing to GHG emissions were surgical equipment (22.2%), travel (18.6%), gas and electricity (13.3%), and anaesthesia/drugs and associated adjuncts (27.0%), primarily due to consumable items and processes. Readily modifiable GHG emissions hotspots included patient travel for preoperative assessment, glove use, catheter use, irrigation delivery and extraction, and mitomycin C disposal. GHG emissions were higher for those admitted as inpatients after surgery. CONCLUSIONS: This cradle-to-grave LCA found multiple modifiable GHG emissions hotspots. Key mitigation themes include minimising avoidable patient travel, rationalising equipment use, optimally filling operating theatre lists, and safely avoiding postoperative catheterisation and hospital admission where possible. A crucial next step is to design and deliver an implementation strategy for the environmentally sustainable changes demonstrated herein.

The Uniform Determination of Death Act is Not Changing. Will Physicians Continue to Misdiagnose Brain Death?

Efforts to revise the Uniform Determination of Death Act in order to align law with medical practice have failed. Medical practice must now align with the law. People who are not dead under the law that defines death should not be declared dead. There is no compelling reason to continue the practice of declaring legally living persons to be dead.

Structural and molecular imaging-based characterization of soft tissue and vascular calcification in hyperphosphatemic familial tumoral calcinosis.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare disorder caused by deficient FGF23 signaling and resultant ectopic calcification. Here, we systematically characterized and quantified macro- and micro-calcification in a HFTC cohort using CT and 18F-sodium fluoride PET/CT (18F-NaF PET/CT). Fourier-transform infrared (FTIR) spectroscopy was performed on 4 phenotypically different calcifications from a patient with HFTC, showing the dominant component to be hydroxyapatite. Eleven patients with HFTC were studied with CT and/or 18F-NaF PET/CT. Qualitative review was done to describe the spectrum of imaging findings on both modalities. CT-based measures of volume (eg, total calcific burden and lesion volume) and density (Hounsfield units) were quantified and compared to PET-based measures of mineralization activity (eg, mean standardized uptake values-SUVs). Microcalcification scores were calculated for the vasculature of 6 patients using 18F-NaF PET/CT and visualized on a standardized vascular atlas. Ectopic calcifications were present in 82% of patients, predominantly near joints and the distal extremities. Considerable heterogeneity was observed in total calcific burden per patient (823.0 ± 670.1 cm3, n = 9) and lesion volume (282.5 ± 414.8 cm3, n = 27). The largest lesions were found at the hips and shoulders. 18F-NaF PET offered the ability to differentiate active vs quiescent calcifications. Calcifications were also noted in multiple anatomic locations, including brain parenchyma (50%). Vascular calcification was seen in the abdominal aorta, carotid, and coronaries in 50%, 73%, and 50%, respectively. 18F-NaF-avid, but CT-negative calcification was seen in a 17-year-old patient, implicating early onset vascular calcification. This first systematic assessment of calcifications in a cohort of patients with HFTC has identified the early onset, prevalence, and extent of calcification. It supports 18F-NaF PET/CT as a clinical tool for distinguishing between active and inactive calcification, informing disease progression, and quantification of ectopic and vascular disease burden.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare disorder in which patients develop sometimes large debilitating calcifications of soft tissues and blood vessels. It is caused by deficient fibroblast growth factor-23 that leads to high phosphate levels, which contributes to the calcifications. The calcifications and manifestations of this disorder have not been well characterized. We determined the mineral composition of the calcifications to be hydroxyapatite. Capitalizing on the fact fluoride can be integrated into hydroxyapatite, we used radiolabeled sodium fluoride PET/CT scans (18F-NaF PET/CT) to characterize and quantify the calcifications in 11 patients. Eighty-two percent of the patients had calcifications, with the largest located at the hips and shoulders. Micro-calcifications were found in the blood vessels of most patients, including children. The technique also enabled us to differentiate between active vs stable calcifications. This first systematic assessment of calcifications in patients with HFTC showed the utility of 18F-NaF PET/CT as a tool to identify and quantify calcifications, as well as distinguish between active and stable calcifications. This approach will inform disease progression and may prove useful for measuring response to treatment.

Working Memory Recovery in Adolescents with Concussion: Longitudinal fMRI Study.

Background: Understanding the behavioral and neural underpinnings of the post-concussion recovery of working memory function is critically important for improving clinical outcomes and adequately planning return-to-activity decisions. Previous studies provided inconsistent results due to small sample sizes and the use of a mixed population of participants who were at different post-injury time points. We aimed to examine working memory recovery during the first 6 months post-concussion in adolescents. Methods: We used functional magnetic resonance imaging (fMRI) to scan 45 concussed adolescents [CONCs] at baseline (<10 days post-concussion) and at 6 months post-concussion. Healthy control adolescents [HCs; n = 32] without a history of concussion were scanned once. During the scans, participants performed one-back and two-back working memory tasks with letters as the stimuli and angry, happy, neutral, and sad faces as distractors. Results: All affected adolescents were asymptomatic and cleared to return to activity 6 months after concussion. Working memory recovery was associated with faster and more accurate responses at 6 months vs. baseline (p-values < 0.05). It was also characterized by significant difficulty-related activation increases in the left inferior frontal gyrus (LIFG) and the left orbitofrontal cortex (LOFC) at 6 months vs. baseline. Although the activation differences between one-back and two-back were comparable between HCs and CONCs at 6 months, HCs had more pronounced activation in the LIFG than concussed adolescents. Conclusions: Post-concussion recovery is associated with significant performance improvements in speed and accuracy, as well as the normalization of brain responses in the LIFG and LOFC during the n-back task. The observed patterns of LOFC activation might reflect compensatory strategies to distribute neural processing and reduce neural fatigue post-concussion.

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.