Spin-ice physics in cadmium cyanide.

Spin-ices are frustrated magnets that support a particularly rich variety of emergent physics. Typically, it is the interplay of magnetic dipole interactions, spin anisotropy, and geometric frustration on the pyrochlore lattice that drives spin-ice formation. The relevant physics occurs at temperatures commensurate with the magnetic interaction strength, which for most systems is 1-5 K. Here, we show that non-magnetic cadmium cyanide, Cd(CN)2, exhibits analogous behaviour to magnetic spin-ices, but does so on a temperature scale that is nearly two orders of magnitude greater. The electric dipole moments of cyanide ions in Cd(CN)2 assume the role of magnetic pseudospins, with the difference in energy scale reflecting the increased strength of electric vs magnetic dipolar interactions. As a result, spin-ice physics influences the structural behaviour of Cd(CN)2 even at room temperature.

The Neuroanatomic Studies of Albert L. Rhoton Jr. in Historical Context: An Analysis of Origin, Evolution, and Application.

The incorporation of perspective into art and science revolutionized the study of the brain. Beginning in about 1504, Leonardo da Vinci began to model the ventricles of the brain in three dimensions. A few years later, Andreus Vesalius illustrated radically novel brain dissections. Thomas Willis' work, Cerebri Anatome (1664), illustrated by Christopher Wren, remarkably showed the brain undersurface. Later, in the early 1800s, Charles Bell's accurate images of neural structures changed surgery. In the 1960s, Albert L. Rhoton Jr. (1932-2016) began to earn his place among the preeminent neuroanatomists by focusing his lens on microanatomy to harness a knowledge of microneurosurgery, master microneurologic anatomy, and use it to improve the care of his patients. Although his biography and works are well known, no analysis has been conducted to identify the progression, impact, and trends in the totality of his publications, and no study has assessed his work in a historical context compared with the contributions of other celebrated anatomists. We analyzed 414 of 508 works authored by Rhoton; these studies were analyzed according to subjects discussed, including anatomic region, surgical approaches, subjects covered, anatomic methods used, forms of multimedia, and subspecialty. Rhoton taught detailed neuroanatomy from a surgical perspective using meticulous techniques that evolved as the technical demands of neurosurgery advanced, inspiring students and contemporaries. His work aligns him with renowned figures in neuroanatomy, arguably establishing him historically as the most influential anatomist of the neurosurgical era.

Stabilization and Transdermal Delivery of an Investigational Peptide Using MicroCor® Solid-State Dissolving Microstructure Arrays.

The formulation of biotherapeutics presents unique challenges especially with regard to physical and chemical stability and often requires refrigerated storage conditions of final drug products. Peptide A is an example of a developmental compound which showed significant stability challenges when prepared as a liquid formulation for a subcutaneous injection. The aim of the present study was to evaluate whether Peptide A can be successfully formulated in MicroCor® microstructure arrays (MSAs) as an alternative delivery option. MSAs contain a high density of dissolving microstructures allowing for transdermal delivery. In the present work, a 5600-needle MSA (~200 µm long microstructures, 2 cm2 array) was prepared with a therapeutically-relevant dose of Peptide A. The array was shown to be stable under room-temperature storage conditions for 3 months. On in vivo application to Yucatan minipigs, Peptide-A-loaded MSAs demonstrated only mild and transient skin irritation and a very high efficiency of peptide transfer from dissolving microstructures into the skin resulting in absolute bioavailability of 74%. This transdermal bioavailability was very similar to the 73% bioavailability obtained from a subcutaneous injection. This technical feasibility study demonstrated that MicroCor® technology represents a viable option for delivery of Peptide A with significant improvements in peptide stability.

Masculinity and Military Culture in VA Hospice and Palliative Care: A Narrative Review With Clinical Recommendations.

This article examines the intersection between masculinity, military culture, and hospice and palliative care (HPC). The authors conducted a narrative literature review, supplemented with clinical annotations, to identify the impact of masculinity and military culture on the following topics salient to end-of-life care with older male veterans: pain management, mental health, coping, communication, autonomy and respect, and family roles. Findings suggest that traits associated with masculinity and military culture have an influence on the end-of-life process and HPC for older male veterans. Specifically, results suggest that older male veterans may deny or minimize physical pain, decline mental health treatment, utilize maladaptive coping strategies, avoid emotional conversations, struggle to manage perceived shifts in autonomy, and experience challenges negotiating changing family roles. The authors provide clinical recommendations for providers across various disciplines to address the aforementioned concerns with older male veterans in HPC. Overall, information presented in this article may be an important contribution to the literature for building cultural competencies with older male veterans and has the potential to improve the delivery of HPC for veterans and their families.

Coated microneedles for transdermal delivery of a potent pharmaceutical peptide.

Minimally invasive delivery of peptide and protein molecules represents a significant opportunity for product differentiation and value creation versus standard injectable routes of administration. One such technology utilizes microneedle (MN) patches and it has made considerable clinical advances in systemic delivery of potent macromolecules and vaccines. A sub-class of this technology has focused on preparation of solid dense MN arrays followed by precision formulation coating on the tips of the MN. The objective of this study was to develop a drug product using the MN technology that has similar bioperformance when compared to subcutaneous route of delivery and can provide improved stability under storage. Therapeutic peptide (Peptide A, Merck & Co., Inc., Kenilworth, NJ, USA) is being developed as a subcutaneous injection for chronic dosing with a submilligram estimated therapeutic dose. Peptide A has chemical and physical stability challenges in solution and this led to exploration of a viable drug product which could provide therapeutic dosages while overcoming the stability issues seen with the compound. This work focused on developing a coated solid microstructure transdermal system (sMTS) for Peptide A followed by detailed in vitro and preclinical evaluation for two different coating formulations. Based on initial assessment, ~250 µg of Peptide A could be coated with precision on a 1.27cm2 patch which contained 316 MN's. The delivery from these systems was achieved with absolute bioavailability being similar to the subcutaneous delivery (88% and 74% for coated sMTS 1 & 2 and 75% for subcutaneous delivery). Stability of Peptide A was also found to be significantly improved when coated on the sMTS system with minimal degradation recorded at room temperature storage as compared to the subcutaneous liquid formulation. Additionally, skin irritation (on pig skin) was also measured in this study and it was found to be minimal and self-resolving. This evaluation provided a viable option for developing a drug product with improved stability and successful delivery of the investigated molecule. Graphical abstractSchematic showing uncoated sMTS, resulting product with coated peptide, successful skin penetration with high delivery efficiency and bioavailability.

A likelihood ratio test for changes in homeolog expression bias.

BACKGROUND: Gene duplications are a major source of raw material for evolution and a likely contributor to the diversity of life on earth. Duplicate genes (i.e., homeologs, in the case of a whole genome duplication) may retain their ancestral function, sub- or neofunctionalize, or be lost entirely. A primary way that duplicate genes evolve new functions is by altering their expression patterns. Comparing the expression patterns of duplicate genes gives clues as to whether any of these evolutionary processes have occurred. RESULTS: We develop a likelihood ratio test for the analysis of the expression ratios of duplicate genes across two conditions (e.g., tissues). We demonstrate an application of this test by comparing homeolog expression patterns of 1448 homeologous gene pairs using RNA-seq data generated from leaves and petals of an allotetraploid monkeyflower (Mimulus luteus). We assess the sensitivity of this test to different levels of homeolog expression bias and compare the method to several alternatives. CONCLUSIONS: The likelihood ratio test derived here is a direct, transparent, and easily implemented method for detecting changes in homeolog expression bias that outperforms alternative approaches. While our method was derived with homeolog analysis in mind, this method can be used to analyze changes in the ratio of expression levels between any two genes in any two conditions.

Origin and evolution of the octoploid strawberry genome.

Cultivated strawberry emerged from the hybridization of two wild octoploid species, both descendants from the merger of four diploid progenitor species into a single nucleus more than 1 million years ago. Here we report a near-complete chromosome-scale assembly for cultivated octoploid strawberry (Fragaria × ananassa) and uncovered the origin and evolutionary processes that shaped this complex allopolyploid. We identified the extant relatives of each diploid progenitor species and provide support for the North American origin of octoploid strawberry. We examined the dynamics among the four subgenomes in octoploid strawberry and uncovered the presence of a single dominant subgenome with significantly greater gene content, gene expression abundance, and biased exchanges between homoeologous chromosomes, as compared with the other subgenomes. Pathway analysis showed that certain metabolomic and disease-resistance traits are largely controlled by the dominant subgenome. These findings and the reference genome should serve as a powerful platform for future evolutionary studies and enable molecular breeding in strawberry.

Radical Approach to Thioester-Containing Polymers.

A new approach to radical ring-opening polymerization is presented that employs a new thionolactone monomer to generate polymers with thioester-containing backbones. The use of a thiocarbonyl acceptor overcomes longstanding reactivity problems in the field to give complete ring-opening and quantitative incorporation into a variety of acrylate polymers. The resulting copolymers readily degrade under hydrolytic conditions, in addition to cysteine-mediated degradation through transthioesterification. The strategy is compatible with reversible addition-fragmentation chain transfer (RAFT) polymerization and permits the synthesis of block polymers for the preparation of well-defined macromolecular structures.

Clinical spectrum of KIAA2022 pathogenic variants in males: Case report of two boys with KIAA2022 pathogenic variants and review of the literature.

KIAA2022 is an X-linked intellectual disability (XLID) syndrome affecting males more severely than females. Few males with KIAA2022 variants and XLID have been reported. We present a clinical report of two unrelated males, with two nonsense KIAA2022 pathogenic variants, with profound intellectual disabilities, limited language development, strikingly similar autistic behavior, delay in motor milestones, and postnatal growth restriction. Patient 1, 19-years-old, has long ears, deeply set eyes with keratoconus, strabismus, a narrow forehead, anteverted nares, café-au-lait spots, macroglossia, thick vermilion of the upper and lower lips, and prognathism. He has gastroesophageal reflux, constipation with delayed rectosigmoid colonic transit time, difficulty regulating temperature, several musculoskeletal issues, and a history of one grand mal seizure. Patient 2, 10-years-old, has mild dysmorphic features, therapy resistant vomiting with diminished motility of the stomach, mild constipation, cortical visual impairment with intermittent strabismus, axial hypotonia, difficulty regulating temperature, and cutaneous mastocytosis. Genetic testing identified KIAA2022 variant c.652C > T(p.Arg218*) in Patient 1, and a novel nonsense de novo variant c.2707G > T(p.Glu903*) in Patient 2. We also summarized features of all reported males with KIAA2022 variants to date. This report not only adds knowledge of a novel pathogenic variant to the KIAA2022 variant database, but also likely extends the spectrum by describing novel dysmorphic features and medical conditions including macroglossia, café-au-lait spots, keratoconus, severe cutaneous mastocytosis, and motility problems of the GI tract, which may help physicians involved in the care of patients with this syndrome. Lastly, we describe the power of social media in bringing families with rare medical conditions together.

Transcriptome of neonatal preBötzinger complex neurones in Dbx1 reporter mice.

We sequenced the transcriptome of brainstem interneurons in the specialized respiratory rhythmogenic site dubbed preBötzinger Complex (preBötC) from newborn mice. To distinguish molecular characteristics of the core oscillator we compared preBötC neurons derived from Dbx1-expressing progenitors that are respiratory rhythmogenic to neighbouring non-Dbx1-derived neurons, which support other respiratory and non-respiratory functions. Results in three categories are particularly salient. First, Dbx1 preBötC neurons express κ-opioid receptors in addition to µ-opioid receptors that heretofore have been associated with opiate respiratory depression, which may have clinical applications. Second, Dbx1 preBötC neurons express the hypoxia-inducible transcription factor Hif1a at levels three-times higher than non-Dbx1 neurons, which links core rhythmogenic microcircuits to O2-related chemosensation for the first time. Third, we detected a suite of transcription factors including Hoxa4 whose expression pattern may define the rostral preBötC border, Pbx3 that may influence ipsilateral connectivity, and Pax8 that may pertain to a ventrally-derived subset of Dbx1 preBötC neurons. These data establish the transcriptomic signature of the core respiratory oscillator at a perinatal stage of development.

Subgenome Dominance in an Interspecific Hybrid, Synthetic Allopolyploid, and a 140-Year-Old Naturally Established Neo-Allopolyploid Monkeyflower.

Recent studies have shown that one of the parental subgenomes in ancient polyploids is generally more dominant, having retained more genes and being more highly expressed, a phenomenon termed subgenome dominance. The genomic features that determine how quickly and which subgenome dominates within a newly formed polyploid remain poorly understood. To investigate the rate of emergence of subgenome dominance, we examined gene expression, gene methylation, and transposable element (TE) methylation in a natural, <140-year-old allopolyploid (Mimulus peregrinus), a resynthesized interspecies triploid hybrid (M. robertsii), a resynthesized allopolyploid (M. peregrinus), and progenitor species (M. guttatus and M. luteus). We show that subgenome expression dominance occurs instantly following the hybridization of divergent genomes and significantly increases over generations. Additionally, CHH methylation levels are reduced in regions near genes and within TEs in the first-generation hybrid, intermediate in the resynthesized allopolyploid, and are repatterned differently between the dominant and recessive subgenomes in the natural allopolyploid. Subgenome differences in levels of TE methylation mirror the increase in expression bias observed over the generations following hybridization. These findings provide important insights into genomic and epigenomic shock that occurs following hybridization and polyploid events and may also contribute to uncovering the mechanistic basis of heterosis and subgenome dominance.

Late-onset, snowstorm-like appearance of calcium deposits coating a poly(methyl methacrylate) posterior chamber intraocular lens.

UNLABELLED: An 81-year-old man developed decreased vision associated with diffuse precipitates on his poly(methyl methacrylate) (PMMA) posterior chamber intraocular lens (IOL), on his corneal endothelium, and in his anterior chamber approximately 35 years after IOL implantation. Slitlamp evaluation showed diffuse white material on the surface of the IOL, white precipitates on the corneal endothelium, and visible debris in the anterior chamber. The patient had IOL exchange, and pathological analysis showed numerous calcium deposits within the Soemmerring ring that diffusely spread to the anterior surface of the PMMA IOL. This case of diffuse calcium precipitates on the IOL and the corneal endothelium and in the anterior chamber 35 years after implantation shows that even long after IOL implantation, lens epithelium proliferation and metabolism can result in sequestered material that can be released many years later. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned.

Evaluating teaching methods: validation of an evaluation tool for hydrodissection and phacoemulsification portions of cataract surgery.

PURPOSE: To develop and assess the validity of an evaluation tool to assess quantitatively the hydrodissection and phacoemulsification portions of cataract surgery performed by residents. DESIGN: Case series. SETTING: Jules Stein Eye Institute, Olive View-UCLA Medical Center, and Veterans Administration Medical Center, Los Angeles, California, USA. METHODS: The UCLA ophthalmology faculty members were surveyed and the literature was reviewed to develop a grading tool consisting of 15 questions to evaluate surgical technique, including questions from the Global Rating Assessment of Skills in Intraocular Surgery and from the International Council of Ophthalmology's Ophthalmology Surgical Competency Assessment Rubric. Video clips of the hydrodissection and phacoemulsification portions of cataract surgery performed by 1 postgraduate year 2 (PGY2) resident, 1 PGY3 resident, 2 PGY4 residents, and an advanced surgeon were independently graded in a masked fashion by an 8-member faculty panel. RESULTS: Eleven of the 15 questions had a significant association with surgical experience level (P<.05, analysis of variance). Interobserver variability in grading yielded intraclass correlation coefficients between 0.28 and 0.72. The questions with the lowest interobserver variability were hydrodissection questions on instrument handling, flow of operation, and nucleus rotation. Nucleus cracking also had low variability. Less directly visible tasks, especially 3-dimensional tasks, had wider interobserver variability. CONCLUSIONS: Surgical performance can be validly measured using an evaluation tool. Improved videography and studies to identify the best questions for evaluating each step of cataract surgery may help ophthalmic educators more precisely measure training outcomes for improving teaching interventions. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Evaluating teaching methods of cataract surgery: validation of an evaluation tool for assessing surgical technique of capsulorhexis.

PURPOSE: To develop and assess the validity of an evaluation tool to quantitatively assess the capsulorhexis portion of cataract surgery performed by residents. SETTING: University of California at Los Angeles (UCLA), Department of Ophthalmology, Jules Stein Eye Institute, Los Angeles, California, USA. DESIGN: Masked prospective case series. METHODS: Ophthalmology faculty members at UCLA were surveyed and literature was reviewed to develop a grading tool comprising 12 questions to evaluate surgical technique, including 4 from the Global Rating Assessment of Skills in Intraocular Surgery and 2 from the International Council of Ophthalmology's Ophthalmology Surgical Competency Assessment Rubric. Video clips of continuous curvilinear capsulorhexis (CCC) performed by 2 postgraduate year (PGY) 3 residents, 2 PGY 4 residents, and 2 advanced surgeons were independently graded in a masked fashion by a 7-member faculty panel. RESULTS: Four questions had low interobserver variability and a significant correlation with surgical skill level (intraclass correlation coefficient >0.75; P<.05, analysis of variance; 42 observations). The 4 questions were visual Likert-scale questions grading flow of operation, set up for regrasp, commencement of flap and formation, and circular completion of the CCC. CONCLUSIONS: Surgical performance can be validly measured using an evaluation tool. However, not all evaluation questions produced reliable results. The reliability and accuracy of the measurements appear to depend on the form and content of the question. Studies to optimize assessment tools identifying the best questions for evaluating each step of cataract surgery may help ophthalmic educators more precisely measure outcomes for improving teaching interventions. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Early surgical debridement in the management of infectious scleritis after pterygium excision.

PURPOSE: The purpose of this study was to report outcomes of infectious scleritis after pterygium surgery, managed with antibiotic therapies and early scleral debridement. METHODS: Retrospective chart review of 13 consecutive cases of infectious scleritis after pterygium excision between 1999 and 2009 was conducted. Collected data included prior medical and surgical history, latency period between pterygium surgery and presentation of infectious scleritis, culture and histopathologic findings, antibiotic regimen, length of hospital stay, visual acuity before and after treatment, and complications. RESULTS: Median follow-up was at 14 months. Twelve patients underwent prompt surgical debridement after infectious scleritis diagnosis (median, 2.5 days). Debridement was delayed in one patient. Median hospital stay was 3 days. Best-corrected visual acuity improved in ten patients, remained stable in one patient, and decreased in two patients following treatment. Complications included scleral thinning requiring scleral patch graft (1/13), glaucoma (3/13), and progression to phthisis bulbi (1/13). No patients required enucleation. CONCLUSIONS: In contrast to the generally poor outcomes in the literature, early surgical debridement of pterygium-associated infectious scleritis appears to offer improved prognosis.

The intraoperative impression and postoperative outcomes of gamma-irradiated corneas in corneal and glaucoma patch surgery.

PURPOSE: To report the short-term outcome of gamma-irradiated sterile cornea in corneal and glaucoma patch graft surgeries when viable endothelium is not necessary. METHODS: Surgeons who have used the irradiated corneas were asked to rate their impression from 1 (fair) to 4 (very good). Specific intraoperative questions included availability, ease of use, clarity, thickness, tensile strength, and suturing. Postoperative outcomes included epithelialization, biological incorporation, and clarity of tissue, as well as any adverse outcomes. RESULTS: Irradiated sterile cornea has been used in more than 150 surgeries so far. The major uses for irradiated cornea were as glaucoma patch graft (65.3%), as corneal patch graft (14%), in anterior lamellar keratoplasty (10.7%), and in keratoprosthesis (10%). The mean score for packaging of tissue was 3.75 (SD, 0.45), ease of use 3.83 (SD, 0.39), clarity 3.62 (SD, 0.51), thickness 3.67 (SD, 0.49), tensile strength 3.64 (SD, 0.50), and suturing 3.62 (SD, 0.65). Postoperative outcomes were also favorable, including epithelialization (mean ± SD, 3.46 ± 0.69), biological incorporation (mean ± SD, 3.46 ± 0.69), and clarity (mean ± SD, 3.43 ± 0.85). There were 4 episodes of corneal melt (all occurred in patients with previous corneal melt). There were no reported cases of tissue rejection or infection. CONCLUSIONS: Gamma-irradiated sterile cornea is a promising new development that may help increase the supply of donor cornea tissue. It virtually eliminates the risk of infection while providing a long shelf life. It is particularly helpful in emergency situations or in remote areas. However, longer follow-up and a prospective study comparing the outcomes of the irradiated corneas with those of the optisol-stored corneas are needed.

Técnica de separação da membrana de Descemet para transplante de células endoteliais da córnea: estudo experimental em coelhos / Technique for separating Descemet membrane for corneal endothelial cells transplantation: experimental study in rabbits

OBJETIVO: Avaliar a porcentagem de dano endotelial induzido por uma técnica cirúrgica para a separação da membrana de Descemet contendo endotélio sadio, analisar a viabilidade e eficácia desta técnica, e avaliar a porcentagem de dano endotelial causado pela inversão da córnea em câmara anterior artificial. MÉTODOS: As córneas de três grupos de 12 coelhos da linhagem Nova Zelândia foram avaliadas. O grupo 1 foi usado como controle; portanto, as córneas foram analisadas após coletadas e trepanadas. O grupo 2 foi analisado após a inversão da córnea (endotélio para cima na posição convexa), montada em câmara anterior artificial, para o cálculo da porcentagem do dano endotelial induzido por esta inversão. O grupo 3 foi avaliado após a separação entre a membrana de Descemet e o estroma com o uso de substância viscoelástica em córneas invertidas e montadas em câmara anterior artificial. O dano endotelial foi avaliado por meio de fotografias digitais tiradas no microscópio após impregnar o endotélio com vermelho de alizarina. Amostras do grupo 3 foram processadas para avaliação histopatológica. RESULTADOS: O grupo 3 (separação viscoelástica) apresentou um índice de lesão celular endotelial de 10,06 por cento, o grupo 2 apresentou um índice de 3,58 por cento e o grupo controle um índice de 0,18 por cento de lesão celular endotelial (p<0,05). A avaliação histológica das córneas do grupo 3 revelou que aproximadamente 120 µm de espessura estromal manteve-se aderido à membrana de Descemet. CONCLUSÃO: Esta técnica deve ser melhor investigada, pois é uma alternativa viável e eficaz de separação da membrana de Descemet para transplante celular endotelial, já que o porcentual de dano celular induzido é de 10,06 por cento. A porcentagem de dano celular causado pela inversão da córnea em câmara anterior artificial foi de 3,58 por cento.

PURPOSE: To evaluate the percentage of endothelial cell damage induced during a surgical technique of Descemet's membrane separation containing healthy endothelium, analyze the viability and efficacy of this technique, and evaluate the percentage of endothelial cell damage caused by inversion of the cornea on an artificial anterior chamber. METHODS: The corneas from three groups of 12 New Zealand rabbits were evaluated. The Group one was used as the control, so the corneas were analyzed after collected and trephinated. The Group two was analyzed after inversion of the cornea (endothelial side up at a convex shape) mounted on an artificial anterior chamber to calculate the percentage of endothelial cell damage caused by this inversion. The Group three was evaluated after the separation between the Descemet's membrane and the stroma using viscoelastic substance in corneas inverted and mounted on an artificial anterior chamber. The endothelial cell damage was analyzed by digital photographs taken under a microscope after staining the endothelium with alizarin red. Group three samples were processed for histologic evaluation. RESULTS: The Group three (viscoelastic separation) showed an index of endothelial cell damage of 10.06 percent, the Group two showed an index of 3.58 percent and the control group an index of 0.18 percent of endothelial cell damage (p<0.05). Histological evaluation of the Group three corneas revealed that approximately a 120 µm thickness of stroma remained attached to the Descemet's membrane. CONCLUSION: This technique should be better investigated because it is a viable and efficient alternative of Descemet's membrane separation for endothelial cells transplantation, since the percentage of induced cell damage is 10.06 percent. The percentage of endothelial cell damage caused by inversion of the cornea on an artificial anterior chamber was 3.58 percent.