Characteristics of Ocular Inflammatory Side Effects Associated with Immune Checkpoint Inhibitors in a Northern California Population.

PURPOSE: To characterize the ocular inflammatory side effects associated with immune checkpoint inhibitor (CPI) treatment in a Northern California population. DESIGN: Retrospective case series. PARTICIPANTS: Patients receiving CPI within an integrated healthcare delivery system. METHODS: All patients within Kaiser Permanente Northern California receiving CPI between January 1, 2012 and November 1, 2018 were identified. Medical records of those seen in the ophthalmology clinic at least once were retrospectively reviewed. MAIN OUTCOME MEASURES: Type and duration of ocular inflammation, indication for and exposure to CPI, time from exposure to diagnosis of ocular inflammation. RESULTS: 31 cases of ocular inflammation were identified in 5061 patients (0.61%) receiving CPI. Mean ± SD age was 67 ± 11.9 (range 38-89). Mean time from exposure to diagnosis was 6.8 ± 5.5 months (range 0.5-17). 87% of cases were bilateral, and 43% of cases were chronic. Average ophthalmology follow-up was 16 ± 18 months (range 0-71). 16/31 (52%) had anterior uveitis, 7/31 (23%) had serous retinal detachment or panuveitis resembling Vogt-Koyanagi-Harada syndrome, 4/31 (13%) had papillitis, and 6/31 (19%) had diplopia or ocular motility defect. There was one case each (3.2%) of melanoma associated retinopathy, corneal edema, granulomatous lacrimal gland enlargement, and choroidal neovascularization. CONCLUSIONS: Ocular inflammation is a rare immune associated side effect of CPI treatment, the most common manifestation of which is anterior uveitis.

Iris Heterochromia in Acquired Horner Syndrome Following Surgical Excision of Parapharyngeal Neuroblastoma.

This report describes an infant who developed iris heterochromia 2 years after presenting at age 2 months with acquired Horner syndrome following excision of a parapharyngeal neuroblastoma. Iris heterochromia is classically associated with congenital, not acquired, Horner syndrome due to a disruption of the oculosympathetic pathway early in life that alters iris melanocyte migration, leading to an ipsilateral lighter colored iris compared to the fellow iris. In the case reported here, the disruption to the oculosympathetic pathway occurred so early in life that normal iris melanocyte migration was impacted on the affected side, leading to eventual iris heterochromia that was noted almost 2 years later.

Bilateral primary orbital xanthogranulomas: A case report and comparison of xanthomatous conditions.

This report describes an unusual and diagnostically challenging case of subcutaneous soft tissue xanthogranulomas of bilateral orbits of a 58-year-old female patient seen in a private oculoplastics practice. Accurate and timely diagnosis is crucial in xanthogranulomatous diseases so that any systemic manifestations can be identified and addressed in a multidisciplinary fashion. Periorbital xanthogranuloma is a frequent early manifestation of adult xanthogranulomatous disease, and its association with life-threatening systemic disease requires accurate diagnosis and prompt work-up. This case describes an otherwise asymptomatic patient who presented with bilateral orbital masses causing visually significant ptosis, initially diagnosed as soft tissue xanthomas, and later identified as xanthogranulomas. It is important for physicians of all fields, from primary care to surgical subspecialty, to be aware that xanthogranulomatous disease may first present as periorbital lesions and/or orbital masses, and that further work-up for vision and life-threatening systemic disease is warranted.

Measuring volatile emissions from moss gametophytes: A review of methodologies and new applications.

Mosses inhabit nearly all terrestrial ecosystems and engage in important interactions with nitrogen-fixing microbes, sperm-dispersing arthropods, and other plants. It is hypothesized that these interactions could be mediated by biogenic volatile organic compounds (BVOCs). Moss BVOCs may play fundamental roles in influencing local ecologies, such as biosphere-atmosphere-hydrosphere communications, physiological and evolutionary dynamics, plant-microbe interactions, and gametophyte stress physiology. Further progress in quantifying the composition, magnitude, and variability of moss BVOC emissions, and their response to environmental drivers and metabolic requirements, is limited by methodological and analytical challenges. We review several sampling techniques with various analytical approaches and describe best practices in generating moss gametophyte BVOC measures. We emphasize the importance of characterizing the composition and magnitude of moss BVOC emissions across a variety of species to better inform and stimulate important cross-disciplinary studies. We conclude by highlighting how current methods could be employed, as well as best practices for choosing methodologies.

Species-specific interactions in avian-bryophyte dispersal networks.

Studies from seed plants have shown that animal dispersal fundamentally alters the success of plant dispersal, shaping community composition through time. Our understanding of this phenomenon in spore plants is comparatively limited. Though little is known about species-specific dispersal relationships between passerine birds and bryophytes, birds are particularly attractive as a potential bryophyte dispersal vector given their highly vagile nature as well as their association with bryophytes when foraging and building nests. We captured birds in Gifford Pinchot National Forest to sample their legs and tails for bryophyte propagules. We found 24 bryophyte species across 34 bird species. We examined the level of interaction specificity: (i) within the overall network to assess community level patterns; and (ii) at the plant species level to determine the effect of bird behaviour on network structure. We found that avian-bryophyte associations are constrained within the network, with species-specific and foraging guild effects on the variety of bryophytes found on bird species. Our findings suggest that diffuse bird-bryophyte dispersal networks are likely to be common in habitats where birds readily encounter bryophytes and that further work aimed at understanding individual bird-bryophyte species relationships may prove valuable in determining nuance within this newly described dispersal mechanism.

Microarthropod contributions to fitness variation in the common moss Ceratodon purpureus.

The evolution of sustained plant-animal interactions depends critically upon genetic variation in the fitness benefits from the interaction. Genetic analyses of such interactions are limited to a few model systems, in part because genetic variation may be absent or the interacting species may be experimentally intractable. Here, we examine the role of sperm-dispersing microarthropods in shaping reproduction and genetic variation in mosses. We established experimental mesocosms with known moss genotypes and inferred the parents of progeny from mesocosms with and without microarthropods, using a pooled sequencing approach. Moss reproductive rates increased fivefold in the presence of microarthropods, relative to control mesocosms. Furthermore, the presence of microarthropods increased the total number of reproducing moss genotypes, and changed the rank-order of fitness of male and female moss genotypes. Interestingly, the genotypes that reproduced most frequently did not produce sporophytes with the most spores, highlighting the challenge of defining fitness in mosses. These results demonstrate that microarthropods provide a fitness benefit for mosses, and highlight the potential for biotic dispersal agents to alter fitness among moss genotypes.

Accuracy of a universal theoretical formula for power calculation in pediatric intraocular lens implantation.

PURPOSE: To compare the accuracy of Barrett Universal II formula with other formulas (Holladay 2, Hoffer Q, and SRK/T formulas) in the prediction of postoperative refraction for pediatric intraocular lens implantation. SETTING: Academic medical center/children's hospital, San Francisco, California. DESIGN: Retrospective case series. METHODS: Children aged 16 years or younger who underwent cataract extraction and IOL implantation (2012 to 2019) and had refraction assessed at 3 to 16 weeks postoperatively were included. Prediction error (PE) was calculated as postoperative mean spherical equivalent minus the target refraction. Mean, median, and standard deviation was calculated for PE and absolute PE. Performance across covariables (axial length, age, biometry type, keratometry, etc.) was studied, and a multivariate regression analysis was performed using a single prediction model for each formula. RESULTS: Sixty-four eyes of 64 patients, aged 1.5 to 15.5 years, were included. Barrett Universal II formula had the lowest mean PE (-0.22 diopters [D]), SD (1.18 D), median PE (-0.26 D), and median absolute PE (0.71) compared with those of the other formulas. Holladay 2 formula performed similarly to Barrett Universal II formula, and SRK/T formula had the greatest mean PE (-0.50 D) and SD (1.22 D). Barrett Universal II formula predictions were stable across all variables. CONCLUSIONS: Barrett Universal II formula demonstrated similar or superior performance when compared with other formulas in this pediatric study. Holladay 2 formula performed similarly to Barrett Universal II formula, and SRK/T formula had the least reliable performance, across several key biometric characteristics. Although PEs can be highly variable in pediatric populations, this study supports Barrett Universal II formula as a reasonable and reliable option for lens power calculation in children, including those with extreme biometric measurements.

Species-specific effects of passive warming in an Antarctic moss system.

Polar systems are experiencing rapid climate change and the high sensitivity of these Arctic and Antarctic ecosystems make them especially vulnerable to accelerated ecological transformation. In Antarctica, warming results in a mosaic of ice-free terrestrial habitats dominated by a diverse assemblage of cryptogamic plants (i.e. mosses and lichens). Although these plants provide key habitat for a wide array of microorganisms and invertebrates, we have little understanding of the interaction between trophic levels in this terrestrial ecosystem and whether there are functional effects of plant species on higher trophic levels that may alter with warming. Here, we used open top chambers on Fildes Peninsula, King George Island, Antarctica, to examine the effects of passive warming and moss species on the abiotic environment and ultimately on higher trophic levels. For the dominant mosses, Polytrichastrum alpinum and Sanionia georgicouncinata, we found species-specific effects on the abiotic environment, including moss canopy temperature and soil moisture. In addition, we found distinct shifts in sexual expression in P. alpinum plants under warming compared to mosses without warming, and invertebrate communities in this moss species were strongly correlated with plant reproduction. Mosses under warming had substantially larger total invertebrate communities, and some invertebrate taxa were influenced differentially by moss species. However, warmed moss plants showed lower fungal biomass than control moss plants, and fungal biomass differed between moss species. Our results indicate that continued warming may impact the reproductive output of Antarctic moss species, potentially altering terrestrial ecosystems dynamics from the bottom up. Understanding these effects requires clarifying the foundational, mechanistic role that individual plant species play in mediating complex interactions in Antarctica's terrestrial food webs.

Characteristics Associated with Adherence to Annual Dilated Eye Examinations among US Patients with Diagnosed Diabetes.

PURPOSE: To identify the characteristics that are associated with adherence to annual diabetic eye exams and patient awareness of retinopathy using a nationally representative sample from the United States. DESIGN: Cross-sectional, secondary analysis. PARTICIPANTS: National Health and Nutrition Examination Survey (NHANES) participants from 2005 to 2016 aged 20 years and older with diabetes mellitus. METHODS: The NHANES collected surveys every 2 years from 2005 to 2016, which contained demographic information, clinical information, and time to last dilated eye exam. From 2005 to 2008, retinal photographs were taken of all participants older than 40 years of age. We used univariate and multivariable logistic regression to determine the demographic and clinical factors associated with adherence to annual diabetic eye examinations and those associated with correctly reporting their retinopathy status. MAIN OUTCOME MEASURE: Factors associated with adherence defined as having an eye exam within the preceding 12 or 24 months. RESULTS: From 2005 to 2016, NHANES surveyed 4072 individuals who represent 20 million Americans aged 20 years and older with self-report of diabetes. By using the adherence definitions of 12 and 24 months, 63.4% and 78.7%, respectively, were adherent to diabetic eye examinations. The nonadherence rates of 36.6% and 21.3% for this national estimate did not change from 2005 to 2016 (P = 0.7, logistic regression). Insurance status, age, education, income, cholesterol levels, duration of diabetes, and self-reported retinopathy were all significantly associated with adherence with both definitions (all P < 0.05, logistic regression). Insurance status had the highest predictive value, with 76% of Americans on combination private-public insurance adherent compared with 36% of uninsured. Most Americans with retinopathy incorrectly denied having the diagnosis (2 727 144/3 896 093 or 70%). CONCLUSIONS: Multiple variables were associated with nonadherence to eye exams, with insurance status having the strongest association. Adherence with annual eye exams has not improved over the past decade. The majority of patients with retinopathy are unaware of this diagnosis, including the majority of those with a dilated funduscopic examination in the past year. Further improvements in education and adherence may reduce the visual morbidity caused by diabetes.

Forest passerines as a novel dispersal vector of viable bryophyte propagules.

Animal dispersal influences the community structure and diversity of a wide variety of plant taxa, yet the potential effects of animal dispersal in bryophytes (hornworts, liverworts, and mosses) is poorly understood. In many communities, birds use bryophyte-abundant niche space for foraging and gathering nest material, suggesting that birds may play a role in bryophyte dispersal. As highly motile animals with long migratory routes, birds potentially provide a means for both local and long-distance bryophyte dispersal in a manner that differs greatly from passive, aerial spore dispersal. To examine this phenomenon, we collected and germinated bryophyte propagules from the legs, feet and tails of 224 birds from 34 species within a temperate forest community. In total we found 1512 spores, and were able to germinate 242 bryophyte propagules. In addition, we provide evidence that topical (externally-carried) spore load varies by bird species and behaviour. Tail feather spore abundance is highest in bark and foliage gleaning species and is positively correlated with tarsal length. Together, these data suggest that a variety of forest birds exhibit the potential to act as dispersal vectors for bryophyte propagules, including an abundance of spores, and that understanding the effects of animal behaviour on bryophyte dispersal will be key to further understanding this interaction.

Rapid population sex-ratio changes in the moss Ceratodon purpureus.

PREMISE OF THE STUDY: Sex-ratio variation occurs widely in dioecious plants, but the mechanisms of population sex-ratio bias are poorly understood. In bryophytes, sex ratios are often female biased, and little information is available about how and when bias forms. METHODS: To test whether population sex-ratio variation can emerge during the gametophytic phase and is not purely a product of spore sex ratios, we created artificial populations of the moss Ceratodon purpureus, with male- and female-biased sex ratios, and placed half under a stress treatment. We hypothesized that male-majority populations would become female-biased and that stress would increase this transition. After 18 mo, when sporophytes were initially forming, we used sex-specific molecular markers to determine population sex ratios. KEY RESULTS: Female-majority populations did not differ significantly from their original bias, whereas male-majority populations became significantly more female biased. The plants had only just produced their first spores, so these sex-ratio changes occurred during the gametophytic generation, as a result of sex-specific growth or survival. Sporophytes occurred only in populations with female-biased final sex ratios, which suggests that females in male-majority populations may have invested energy in ramets rather than in sporophyte production. The stress treatment was mild and had no effect on sex ratio. CONCLUSIONS: Our results suggest that female bias can be generated during the gametophytic generation, before plants reach sexual maturity. These results, combined with those of previous work, suggest that both the gametophytic and the sporophytic stages drive population sex ratios in C. purpureus, thus indicating that multiple mechanisms operate to create biased population sex ratios.

Sex-specific morphological and physiological differences in the moss Ceratodon purpureus (Dicranales).

Background and Aims: Dioecy and sexual dimorphism occur in many terrestrial plant species but are especially widespread among the bryophytes. Despite the prevalence of dioecy in non-vascular plants, surprisingly little is known about how fine-scale sex-specific cell and leaf morphological traits are correlated with sex-specific physiology and population sex ratios. Such data are critical to understanding the inter-relationship between sex-specific morphological and physiological characters and how their relationship influences population structure. In this study, these data types were assessed to determine how they vary across three populations within one moss species and whether fine-scale morphological traits scale up to physiological and sex ratio characteristics. Methods: Twenty cell-, leaf- and canopy-level traits and two photochemical measurements were compared between sexes and populations of the dioecious moss Ceratodon purpureus . Field population-expressed sex ratios were obtained for the same populations. Key Results: Male and female plants differed in cell, leaf and photochemical measures. These sexual dimorphisms were female biased, with females having larger and thicker leaves and greater values for chlorophyll fluorescence-based, leaf photochemistry measurements than males. Female traits were also more variable than male traits. Interestingly, field population sex ratios were significantly male biased in two study populations and female biased in the third study population. Conclusions: The results demonstrate that the larger morphology and the greater physiological output of female C. purpureus gametophytes compared with males occurs across populations and is likely to have significant effects on resource allocation and biotic interactions. However, this high level of dimorphism does not explain population sex ratio variation in the three study populations tested. This research lays the groundwork for future studies on how differential sex-specific variation in cell and leaf traits influences bryophyte plant fitness.

Clinical Report: Warsaw Breakage Syndrome with small radii and fibulae.

We present two new cases of Warsaw Breakage Syndrome (WABS), an autosomal recessive cohesinopathy, in sisters aged 13 and 11 years who both had compound heterozygous mutations in DDX11. After exclusion of Fanconi anemia, Bloom syndrome and Nijmegen breakage syndrome, whole exome sequencing revealed two novel variants-c.1523T>G, predicting (p.Leu508Arg) and c.1949-1G>A (IVS19-1G>A), that were confirmed with Sanger sequencing in both affected individuals. DDX11 encodes an iron-sulfur-containing DNA helicase, and mutations in this gene have been reported in the five WABS cases previously identified to date. The sisters reported here display the distinguishing clinical features of WABS: pre- and post-natal growth restriction, microcephaly, intellectual disability, sensorineural hearing loss with cochlear abnormalities, and facial dysmorphic features. In addition, our cases had early menarche at 8 and 10 years of age, bilateral small thumbs, and the younger, more severely affected sister had small fibulae. These findings broaden the WABS phenotype and the limb malformations demonstrate further clinical overlap with Fanconi anemia and other cohesinopathies, such as Roberts Syndrome.

Passive warming reduces stress and shifts reproductive effort in the Antarctic moss, Polytrichastrum alpinum.

BACKGROUND AND AIMS: The Western Antarctic Peninsula is one of the most rapidly warming regions on Earth, and many biotic communities inhabiting this dynamic region are responding to these well-documented climatic shifts. Yet some of the most prevalent organisms of terrestrial Antarctica, the mosses, and their responses to warming have been relatively overlooked and understudied. In this research, the impacts of 6 years of passive warming were investigated using open top chambers (OTCs), on moss communities of Fildes Peninsula, King George Island, Antarctica. METHODS: The effects of experimental passive warming on the morphology, sexual reproductive effort and stress physiology of a common dioicous Antarctic moss, Polytrichastrum alpinum ,: were tested, gaining the first species-specific mechanistic insight into moss responses to warming in the Antarctic. Additionally community analyses were conducted examining the impact of warming on overall moss percentage cover and sporophyte production in intact Antarctic moss communities. KEY RESULTS: Our results show a generally greater percentage moss cover under warming conditions as well as increased gametangia production in P. alpinum Distinct morphological and physiological shifts in P. alpinum were found under passive warming compared with those without warming: warmed mosses reduced investment in cellular stress defences, but invested more towards primary productivity and gametangia development. CONCLUSIONS: Taken together, results from this study of mosses under passive warming imply that in ice-free moss-dominated regions, continued climate warming will probably have profound impacts on moss biology and colonization along the Western Antarctic Peninsula. Such findings highlight the fundamental role that mosses will play in influencing the terrestrialization of a warming Antarctica.

Life on the Edge-the Biology of Organisms Inhabiting Extreme Environments: An Introduction to the Symposium.

Life persists, even under extremely harsh conditions. While the existence of extremophiles is well known, the mechanisms by which these organisms evolve, perform basic metabolic functions, reproduce, and survive under extreme physical stress are often entirely unknown. Recent technological advances in terms of both sampling and studying extremophiles have yielded new insight into their evolution, physiology and behavior, from microbes and viruses to plants to eukaryotes. The goal of the "Life on the Edge-the Biology of Organisms Inhabiting Extreme Environments" symposium was to unite researchers from taxonomically and methodologically diverse backgrounds to highlight new advances in extremophile biology. Common themes and new insight that emerged from the symposium included the important role of symbiotic associations, the continued challenges associated with sampling and studying extremophiles and the important role these organisms play in terms of studying climate change. As we continue to explore our planet, especially in difficult to reach areas from the poles to the deep sea, we expect to continue to discover new and extreme circumstances under which life can persist.

Moss antheridia are desiccation tolerant: Rehydration dynamics influence sperm release in Bryum argenteum.

PREMISE OF THE STUDY: Free-living sperm of mosses are known to be partially desiccation tolerant. We hypothesized that mature moss antheridia should also tolerate desiccation and that rehydration to partial turgor (prehydration) or rehydration to full turgor (rehydration) before immersion in water is required for full recovery from any damaging effects of prior desiccation. METHODS: Bryum argenteum (silvery-thread moss) was grown in continuous culture for several months, produced mature perigonia (clusters of antheridia), and these were subjected to a slow rate of drying (∼36 h from full turgor to desiccation) and equilibration with 50% relative humidity. Perigonia were prehydrated (exposed to a saturated atmosphere) or rehydrated (planted upright in saturated media) for 0, 45, 90, 135, 180, and 1440 min, then immersed in sterile water. Time to first sperm mass release, number of antheridia releasing sperm masses, and the integrity of the first sperm mass released were assessed. KEY RESULTS: Rehydration of dried antheridia for at least 3 h before immersion in water resulted in antheridia functioning similar to control undried antheridia. Compared with rehydration, prehydration was not effective in the recovery of antheridia from desiccation. CONCLUSIONS: For the first time, moss antheridia are shown to be fully desiccation tolerant at a functional level, capable of releasing fully functional sperm following a slow drying event provided the antheridia are allowed to rehydrate at least 3 h before immersion in water.

Distribution drivers and physiological responses in geothermal bryophyte communities.

PREMISE OF STUDY: Our ability to explain community structure rests on our ability to define the importance of ecological niches, including realized ecological niches, in shaping communities, but few studies of plant distributions have combined predictive models with physiological measures. METHODS: Using field surveys and statistical modeling, we predicted distribution drivers in geothermal bryophyte (moss) communities of Lassen Volcanic National Park (California, USA). In the laboratory, we used drying and rewetting experiments to test whether the strong species-specific effects of relative humidity on distributions predicted by the models were correlated with physiological characters. KEY RESULTS: We found that the three most common bryophytes in geothermal communities were significantly affected by three distinct distribution drivers: temperature, light, and relative humidity. Aulacomnium palustre, whose distribution is significantly affected by relative humidity according to our model, and which occurs in high-humidity sites, showed extreme signs of stress after drying and never recovered optimal values of PSII efficiency after rewetting. Campylopus introflexus, whose distribution is not affected by humidity according to our model, was able to maintain optimal values of PSII efficiency for 48 hr at 50% water loss and recovered optimal values of PSII efficiency after rewetting. CONCLUSIONS: Our results suggest that species-specific environmental stressors tightly constrain the ecological niches of geothermal bryophytes. Tests of tolerance to drying in two bryophyte species corresponded with model predictions of the comparative importance of relative humidity as distribution drivers for these species.

Sex-specific volatile compounds influence microarthropod-mediated fertilization of moss.

Sexual reproduction in non-vascular plants requires unicellular free-motile sperm to travel from male to female reproductive structures across the terrestrial landscape. Recent data suggest that microarthropods can disperse sperm in mosses. However, little is known about the chemical communication, if any, that is involved in this interaction or the relative importance of microarthropod dispersal compared to abiotic dispersal agents in mosses. Here we show that tissues of the cosmopolitan moss Ceratodon purpureus emit complex volatile scents, similar in chemical diversity to those described in pollination mutualisms between flowering plants and insects, that the chemical composition of C. purpureus volatiles are sex-specific, and that moss-dwelling microarthropods are differentially attracted to these sex-specific moss volatile cues. Furthermore, using experimental microcosms, we show that microarthropods significantly increase moss fertilization rates, even in the presence of water spray, highlighting the important role of microarthropod dispersal in contributing to moss mating success. Taken together, our results indicate the presence of a scent-based 'plant-pollinator-like' relationship that has evolved between two of Earth's most ancient terrestrial lineages, mosses and microarthropods.