Seasonal timing on a cyclical Earth: Towards a theoretical framework for the evolution of phenology.

Phenology refers to the seasonal timing patterns commonly exhibited by life on Earth, from blooming flowers to breeding birds to human agriculture. Climate change is altering abiotic seasonality (e.g., longer summers) and in turn, phenological patterns contained within. However, how phenology should evolve is still an unsolved problem. This problem lies at the crux of predicting future phenological changes that will likely have substantial ecosystem consequences, and more fundamentally, of understanding an undeniably global phenomenon. Most studies have associated proximate environmental variables with phenological responses in case-specific ways, making it difficult to contextualize observations within a general evolutionary framework. We outline the complex but universal ways in which seasonal timing maps onto evolutionary fitness. We borrow lessons from life history theory and evolutionary demography that have benefited from a first principles-based theoretical scaffold. Lastly, we identify key questions for theorists and empiricists to help advance our general understanding of phenology.

Acute orbital inflammation with loss of vision: a paradoxical adverse event associated with infliximab therapy for Crohn's disease.

Anti-TNF-α agents (e.g. infliximab, adalimumab, etanercept) are effective management options in various inflammatory and autoimmune diseases (e.g. inflammatory bowel disease). The occurrence during anti-TNF-α agent therapy of a new onset or exacerbation of an inflammatory condition that usually responds to this class of drug has been termed a paradoxical adverse event (PAE). A wide range of ophthalmic PAEs have been reported including uveitis, optic neuritis/neuropathy, scleritis, orbital myositis, retinal vasculitis, and others. The patient reported herein developed a dramatic orbital inflammatory PAE during his infliximab infusions, which manifested as an acute orbital apex syndrome with vision loss. Physicians using this medication should be aware of this serious vision-threatening PAE, and urgent therapy with high dose intravenous corticosteroids may be required.

INVERTED INTERNAL LIMITING MEMBRANE FLAP TECHNIQUE WITHOUT POSTOPERATIVE FACE-DOWN POSITIONING FOR MACULAR HOLE REPAIR.

PURPOSE: To describe the outcomes of the inverted internal limiting membrane flap technique without postoperative face-down positioning for macular hole (MH) closure. METHODS: This retrospective longitudinal study identified patients who had undergone surgical repair for large (>400 µm), idiopathic MHs and did not maintain face-down positioning postoperatively. Outcome measures included anatomical success, defined as confirmation of hole closure by the optical coherence tomography scan and functional success and defined as improved best-corrected visual acuity from baseline at the last follow-up. RESULTS: Of the 63 eyes enrolled in the study, 94% patients (59 of 63) achieved anatomical success and 91% patients (57 of 63) achieved functional success. Fifteen (15) of these patients presented with a MH >600 µm. This subgroup achieved an anatomical success rate of 93% and a functional success rate of 87%. Statistically significant improvement in best-corrected visual acuity was demonstrated for all subgroups of MH size (P < 0.001). CONCLUSION: We report a high success rate of large, idiopathic MH closure with the inverted internal limiting membrane flap technique without postoperative face-down positioning. The results described in this study are favorable. However, larger studies with prospective design are warranted to explore this further.

Slower environmental cycles maintain greater life-history variation within populations.

Populations in nature are comprised of individual life histories, whose variation underpins ecological and evolutionary processes. Yet the forces of environmental selection that shape intrapopulation life-history variation are still not well-understood, and efforts have largely focused on random (stochastic) fluctuations of the environment. However, a ubiquitous mode of environmental fluctuation in nature is cyclical, whose periodicities can change independently of stochasticity. Here, we test theoretically based hypotheses for whether shortened ('Fast') or lengthened ('Slow') environmental cycles should generate higher intrapopulation variation of life history phenotypes. We show, through a combination of agent-based modelling and a multi-generational laboratory selection experiment using the tidepool copepod Tigriopus californicus, that slower environmental cycles maintain higher levels of intrapopulation variation. Surprisingly, the effect of environmental periodicity on variation was much stronger than that of stochasticity. Thus, our results show that periodicity is an important facet of fluctuating environments for life-history variation.

Idiopathic Intracranial Hypertension in Pregnancy.

Idiopathic intracranial hypertension (IIH) is a syndrome characterized by elevated intracranial pressure without an identifiable underlying cause. Pregnancy has unique and important diagnostic and therapeutic implications for patients with IIH. Despite these implications, there are no guidelines to assist clinicians in managing IIH during pregnancy. Our review aims to summarize the key considerations related to the diagnosis and management of IIH during pregnancy, to optimize the care of these patients and mitigate the risk of disease-related complications. The optimal management of IIH in pregnancy should include a multidisciplinary team, including an obstetrician (or maternal-fetal medicine specialist), a neurologist, and an ophthalmologist (or neuro-ophthalmologist).

Ophthalmic adverse effects of lithium.

Lithium is the current mainstay treatment for both acute and maintenance management of bipolar disorders. However, its narrow therapeutic index and array of side effects, although well-documented, can be challenging to manage. Comparatively, the side effects of lithium that involve the ophthalmic structures are not as well established in the literature and only partially appreciated, which can potentially lead to noncompliance. In this article, an extensive literature review of lithium and its ophthalmic adverse effects were performed and comprehensively summarized. Based on the search, documented ophthalmic adverse effects of lithium include: exophthalmos; abnormal eye movements; ocular myasthenia gravis; papilledema; photophobia; and abnormal tear film, contributing to dry eye disease. Additional studies are anticipated to be helpful in expanding the current understanding of lithium and its adverse ophthalmic side effects and certainly warranted to fill the knowledge gap. Close interprofessional management between psychiatrists and ophthalmologists is expected to be beneficial in patient care.

Cyclical environments drive variation in life-history strategies: a general theory of cyclical phenology.

Cycles, such as seasons or tides, characterize many systems in nature. Overwhelming evidence shows that climate change-driven alterations to environmental cycles-such as longer seasons-are associated with phenological shifts around the world, suggesting a deep link between environmental cycles and life cycles. However, general mechanisms of life-history evolution in cyclical environments are still not well understood. Here, I build a demographic framework and ask how life-history strategies optimize fitness when the environment perturbs a structured population cyclically and how strategies should change as cyclicality changes. I show that cycle periodicity alters optimality predictions of classic life-history theory because repeated cycles have rippling selective consequences over time and generations. Notably, fitness landscapes that relate environmental cyclicality and life-history optimality vary dramatically depending on which trade-offs govern a given species. The model tuned with known life-history trade-offs in a marine intertidal copepod Tigriopus californicus successfully predicted the shape of life-history variation across natural populations spanning a gradient of tidal periodicities. This framework shows how environmental cycles can drive life-history variation-without complex assumptions of individual responses to cues such as temperature-thus expanding the range of life-history diversity explained by theory and providing a basis for adaptive phenology.

Association between positive corneal rim cultures and microbiology screening protocols in Ontario.

OBJECTIVE: (i) To assess the rate of positive microbiological cultures of corneas prepared by the Eye Bank of Canada (Ontario Division) between January 1, 2012, and December 31, 2013; (ii) to review the microbiology protocols at the 5 major transplant centres in Ontario; and (iii) to assess the incidence of endophthalmitis during the study period. DESIGN: Retrospective chart review. PARTICIPANTS: A total of 4186 consecutive cultured corneal tissues prepared by the Eye Bank from January 1, 2012, to December 31, 2013. METHODS: Rates of culture-positive cornea rims and incidence of postkeratoplasty endophthalmitis at 5 surgical centres in Ontario were determined, and the protocols used to culture rims at each site were concurrently reviewed. Culture results were analyzed via logistic regression for positive cultures. RESULTS: The rate of positive cultures at each sites were as follows: centre A, 3.74%; centre B, 3.26%; centre C, 0.51%; centre D, 0.48%; and centre E, 0.04%. Centres A, B, and D were noted to have significantly higher positive rates than centre E. In comparing microbiology protocols, longer incubation period (11 days) was 12 times more likely to be associated with higher positive culture rates than shorter period (4-5 days). Six-month follow-up of all keratoplasties revealed zero reported cases of endophthalmitis. CONCLUSIONS: A literature review regarding the predictive value of routine culturing reveals conflicting data. Our findings suggest that differences in the microbiology protocols directly influence the rates of positive rim cultures. Without a standardized protocol, it is not possible to evaluate the predictive value of routine corneal rim culturing in predicting postkeratoplasty endophthalmitis.

Evolutionary history of Daphnia drives divergence in grazing selectivity and alters temporal community dynamics of producers.

Consumers with different seasonal life histories encounter different communities of producers during specific seasonal phases. If consumers evolve to prefer the producers that they encounter, then consumers may reciprocally influence the temporal composition of producer communities. Here, we study the keystone consumer Daphnia ambigua, whose seasonal life history has diverged due to intraspecific predator divergence across lakes of New England. We ask whether grazing preferences of Daphnia have diverged also and test whether any grazing differences influence temporal composition patterns of producers. We reared clonal populations of Daphnia from natural populations representing the two diverged life history types for multiple generations. We conducted short-term (24 hr) and long-term (27 days) grazing experiments in equal polycultures consisting of three diatom and two green algae species, treated with no consumer, Daphnia from lakes with anadromous alewife, or from lakes with landlocked alewife. After 24 hr, life history and grazing preference divergence in Daphnia ambigua drove significant differences in producer composition. However, those differences disappeared at the end of the 27-day experiment. Our results illustrate that, despite potentially more complex long-term dynamics, a multitrophic cascade of evolutionary divergence from a predator can influence temporal community dynamics at the producer level.

Barriers to electronic medical record implementation: a comparison between ophthalmology and other surgical specialties in Canada.

OBJECTIVE: In the present study, the barriers limiting widespread adoption of electronic medical records (EMRs) among Canadian ophthalmologists were evaluated in comparison with physicians from other surgical specialities. The published literature regarding EMR use in ophthalmic practice was also reviewed. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: A total of 1199 Canadian surgeons participating in the 2014 National Physician Survey (NPS). METHODS: Data regarding speciality surgeons' adoption of EMR programs were extracted from the 2014 NPS, a nationwide survey of practicing physicians in Canada. The data were entered into a spreadsheet, and basic statistical analyses, including χ2 analyses, were performed to compare the responses of ophthalmologists to other surgeons. RESULTS: Compared with other surgeons, ophthalmologists surveyed were significantly more likely to identify the following barriers to EMR adoption: "no suitable product for my practice" (p = 0.01), "too costly" (p = 0.0006), "too time consuming" (p < 0.0001), and "planning to retire soon" (p = 0.001). No statistically detectable differences were found between ophthalmologists and other surgeons for the following barriers: privacy concerns, reliability concerns, and lack of training. CONCLUSIONS: The barriers that limit increased EMR adoption among Canadian ophthalmologists are different from those of other surgeons. This may be attributed to unique features of the field, including heavy reliance on hand-drawn figures in documentation, high patient volume, and the high costs associated with independent practice. Given the well-established benefits of EMR technology, consideration should be given to implementing strategies to mitigate these barriers. Additional research may help determine which specific improvements can be made to increase the use of EMR systems by ophthalmologists.

Species-Specific Expression of Full-Length and Alternatively Spliced Variant Forms of CDK5RAP2.

CDK5RAP2 is one of the primary microcephaly genes that are associated with reduced brain size and mental retardation. We have previously shown that human CDK5RAP2 exists as a full-length form (hCDK5RAP2) or an alternatively spliced variant form (hCDK5RAP2-V1) that is lacking exon 32. The equivalent of hCDK5RAP2-V1 has been reported in rat and mouse but the presence of full-length equivalent hCDK5RAP2 in rat and mouse has not been examined. Here, we demonstrate that rat expresses both a full length and an alternatively spliced variant form of CDK5RAP2 that are equivalent to our previously reported hCDK5RAP2 and hCDK5RAP2-V1, repectively. However, mouse expresses only one form of CDK5RAP2 that is equivalent to the human and rat alternatively spliced variant forms. Knowledge of this expression of different forms of CDK5RAP2 in human, rat and mouse is essential in selecting the appropriate model for studies of CDK5RAP2 and primary microcephaly but our findings further indicate the evolutionary divergence of mouse from the human and rat species.

Valid MR imaging predictors of prior knee arthroscopy.

PURPOSE: To determine whether fibrosis of the medial patellar reticulum (MPR), lateral patellar reticulum (LPR), deep medial aspect of Hoffa's fat pad (MDH), or deep lateral aspect of Hoffa's fat pad (LDH) is a valid predictor of prior knee arthroscopy. MATERIALS AND METHODS: Institutional review board approval and waiver of informed consent were obtained for this HIPPA-compliant study. Initially, fibrosis of the MPR, LPR, MDH, or LDH in MR imaging studies of 50 patients with prior knee arthroscopy and 100 patients without was recorded. Subsequently, two additional radiologists, blinded to clinical data, retrospectively and independently recorded the presence of fibrosis of the MPR in 50 patients with prior knee arthroscopy and 50 without. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for detecting the presence of fibrosis in the MPR were calculated. κ statistics were used to analyze inter-observer agreement. RESULTS: Fibrosis of each of the regions examined during the first portion of the study showed a significant association with prior knee arthroscopy (p < 0.005 for each). A patient with fibrosis of the MPR, LDH, or LPR was 45.5, 9, or 3.7 times more likely, respectively, to have had a prior knee arthroscopy. Logistic regression analysis indicated that fibrosis of the MPR supplanted the diagnostic utility of identifying fibrosis of the LPR, LDH, or MDH, or combinations of these (p ≥ 0.09 for all combinations). In the second portion of the study, fibrosis of the MPR demonstrated a mean sensitivity of 82%, specificity of 72%, PPV of 75%, NPV of 81%, and accuracy of 77% for predicting prior knee arthroscopy. CONCLUSIONS: Analysis of MR images can be used to determine if a patient has had prior knee arthroscopy by identifying fibrosis of the MPR, LPR, MDH, or LDH. Fibrosis of the MPR was the strongest predictor of prior knee arthroscopy.

Expression of a bcr-1 isoform of RARalpha-PML does not affect the penetrance of acute promyelocytic leukemia or the acquisition of an interstitial deletion on mouse chromosome 2.

Expression of a bcr-3 isoform of retinoic acid receptor alpha-promyelocytic leukemia (RARalpha-PML) in mice expressing a bcr-1 isoform of PML-RARalpha is associated with increased penetrance of murine acute promyelocytic leukemia (APL) and the frequent acquisition of an interstitial deletion of one copy of mouse chromosome 2 (del(2)). To determine whether the isoform of RARalpha-PML is important for these effects, we created mice that expressed a bcr-1 isoform of RARalpha-PML. Coexpression with the bcr-1 isoform of PML-RARalpha did not increase the penetrance of APL (7 of 45 animals developed APL with PML-RARalpha alone vs 12 of 44 with both transgenes; P=.19). Furthermore, the frequency of del(2) in APL cells from doubly transgenic mice was not different from that of mice expressing PML-RARalpha alone (3 of 6 vs 6 of 12, respectively-P=1.38-compared with 11 of 11 for mice coexpressing PML-RARalpha and bcr-3 RARalpha-PML). The bcr-1 and bcr-3 isoforms of RARalpha-PML, therefore, have different biological activities that may be relevant for the pathogenesis of murine APL.

Reduced PU.1 expression causes myeloid progenitor expansion and increased leukemia penetrance in mice expressing PML-RARalpha.

PU.1 is a member of the ETS family of transcription factors that is known to be important for hematopoietic development. Recently, haploinsufficiency for PU.1 has been shown to cause a shift in myelomonocytic progenitor fate toward the myeloid lineage. We have previously shown that transgenic mice expressing PML-RARalpha (PR) and RARalpha-PML frequently develop acute promyelocytic leukemia (APL) in association with a large (>20 Mb) interstitial deletion of chromosome 2 that includes PU.1. To directly assess the relevance of levels of expression of PU.1 for leukemia progression, we bred hCG-PR mice with PU.1+/- mice and assessed their phenotype. Young, nonleukemic hCG-PR x PU.1+/- mice developed splenomegaly because of the abnormal expansion of myeloid cells in their spleens. hCG-PR x PU.1+/- mice developed a typical APL syndrome after a long latent period, but the penetrance of disease was 84%, compared with 7% in hCG-PR x PU.1+/+ mice (P < 0.0001). The residual PU.1 allele in hCG-PR x PU.1+/- APL cells was expressed, and complete exonic resequencing revealed no detectable mutations in nine of nine samples. However, PR expression in U937 myelomonocytic cells and primary murine myeloid bone marrow cells caused a reduction in PU.1 mRNA levels. Therefore, the loss of one copy of PU.1 through a deletional mechanism, plus down-regulation of the residual allele caused by PR expression, may synergize to expand the pool of myeloid progenitors that are susceptible to transformation, increasing the penetrance of APL.

Expression profiling of murine acute promyelocytic leukemia cells reveals multiple model-dependent progression signatures.

Leukemia results from the expansion of self-renewing hematopoietic cells that are thought to contain mutations that contribute to disease initiation and progression. Studies of the gene expression profiles of human acute myeloid leukemia samples has allowed their classification based on the presence of translocations and French-American-British subtypes, but it is not yet clear whether their molecular signatures reflect the initiating mutations or mutations acquired during progression. To begin to address this question, we examined the expression profiles of normal murine promyelocyte-enriched samples, nontransformed murine promyelocytes expressing human promyelocytic leukemia-retinoic acid receptor alpha (PML-RARalpha) fusion gene, and primary acute promyelocytic leukemia cells. The expression profile of nontransformed cells expressing PML-RARalpha was remarkably similar to that of wild-type promyelocytes. In contrast, the expression profiles of fully transformed cells from three acute promyelocytic leukemia model systems were all different, suggesting that the expression signature of acute promyelocytic leukemia cells reflects the genetic changes that contributed to progression. To further evaluate these progression events, we compared two high-penetrance acute promyelocytic leukemia models that both commonly acquire an interstitial deletion of chromosome 2 during progression. The two models exhibited distinct gene expression profiles, suggesting that the dominant molecular signatures of murine acute promyelocytic leukemia can be influenced by several independent progression events.