Author Correction: Mkk4 and Mkk7 are important for retinal development and axonal injury-induced retinal ganglion cell death.

There was an error introduced into Figures 4, 5, and 7 during the proofing stage which has since been corrected.

Mkk4 and Mkk7 are important for retinal development and axonal injury-induced retinal ganglion cell death.

The mitogen-activated protein kinase (MAPK) pathway has been shown to be involved in both neurodevelopment and neurodegeneration. c-Jun N-terminal kinase (JNK), a MAPK important in retinal development and after optic nerve crush injury, is regulated by two upstream kinases: MKK4 and MKK7. The specific requirements of MKK4 and MKK7 in retinal development and retinal ganglion cell (RGC) death after axonal injury, however, are currently undefined. Optic nerve injury is an important insult in many neurologic conditions including traumatic, ischemic, inflammatory, and glaucomatous optic neuropathies. Mice deficient in Mkk4, Mkk7, and both Mkk4 and Mkk7 were generated. Immunohistochemistry was used to study the distribution and structure of retinal cell types and to assess RGC survival after optic nerve injury (mechanical controlled optic nerve crush (CONC)). Adult Mkk4- and Mkk7-deficient retinas had all retinal cell types, and with the exception of small areas of disrupted photoreceptor lamination in Mkk4-deficient mice, the retinas of both mutants were grossly normal. Deficiency of Mkk4 or Mkk7 reduced JNK signaling in RGCs after axonal injury and resulted in a significantly greater percentage of surviving RGCs 35 days after CONC as compared to wild-type controls (Mkk4: 51.5%, Mkk7: 29.1%, WT: 15.2%; p < 0.001). Combined deficiency of Mkk4 and Mkk7 caused failure of optic nerve formation, irregular retinal axonal trajectories, disruption of retinal lamination, clumping of RGC bodies, and dendritic fasciculation of dopaminergic amacrine cells. These results suggest that MKK4 and MKK7 may serve redundant and unique roles in molecular signaling important for retinal development and injury response following axonal insult.

Jnk2 deficiency increases the rate of glaucomatous neurodegeneration in ocular hypertensive DBA/2J mice.

The cJun N-terminal kinases (JNKs; JNK1, JNK2, and JNK3) promote degenerative processes after neuronal injury and in disease. JNK2 and JNK3 have been shown to promote retinal ganglion cell (RGC) death after optic nerve injury. In their absence, long-term survival of RGC somas is significantly increased after mechanical optic nerve injury. In glaucoma, because optic nerve damage is thought to be a major cause of RGC death, JNKs are an important potential target for therapeutic intervention. To assess the role of JNK2 and JNK3 in an ocular hypertensive model of glaucoma, null alleles of Jnk2 and Jnk3 were backcrossed into the DBA/2J (D2) mouse. JNK activation occurred in RGCs following increased intraocular pressure in D2 mice. However, deficiency of both Jnk2 and Jnk3 together did not lessen optic nerve damage or RGC death. These results differentiate the molecular pathways controlling cell death in ocular hypertensive glaucoma compared with mechanical optic nerve injury. It is further shown that JUN, a pro-death component of the JNK pathway in RGCs, can be activated in glaucoma in the absence of JNK2 and JNK3. This implicates JNK1 in glaucomatous RGC death. Unexpectedly, at younger ages, Jnk2-deficient mice were more likely to develop features of glaucomatous neurodegeneration than D2 mice expressing Jnk2. This appears to be due to a neuroprotective effect of JNK2 and not due to a change in intraocular pressure. The Jnk2-deficient context also unmasked a lesser role for Jnk3 in glaucoma. Jnk2 and Jnk3 double knockout mice had a modestly increased risk of neurodegeneration compared with mice only deficient in Jnk2. Overall, these findings are consistent with pleiotropic effects of JNK isoforms in glaucoma and suggest caution is warranted when using JNK inhibitors to treat chronic neurodegenerative conditions.

Role of SARM1 and DR6 in retinal ganglion cell axonal and somal degeneration following axonal injury.

Optic neuropathies such as glaucoma are characterized by the degeneration of retinal ganglion cells (RGCs) and the irreversible loss of vision. In these diseases, focal axon injury triggers a propagating axon degeneration and, eventually, cell death. Previous work by us and others identified dual leucine zipper kinase (DLK) and JUN N-terminal kinase (JNK) as key mediators of somal cell death signaling in RGCs following axonal injury. Moreover, others have shown that activation of the DLK/JNK pathway contributes to distal axonal degeneration in some neuronal subtypes and that this activation is dependent on the adaptor protein, sterile alpha and TIR motif containing 1 (SARM1). Given that SARM1 acts upstream of DLK/JNK signaling in axon degeneration, we tested whether SARM1 plays a similar role in RGC somal apoptosis in response to optic nerve injury. Using the mouse optic nerve crush (ONC) model, our results show that SARM1 is critical for RGC axonal degeneration and that axons rescued by SARM1 deficiency are electrophysiologically active. Genetic deletion of SARM1 did not, however, prevent DLK/JNK pathway activation in RGC somas nor did it prevent or delay RGC cell death. These results highlight the importance of SARM1 in RGC axon degeneration and suggest that somal activation of the DLK/JNK pathway is activated by an as-yet-unidentified SARM1-independent signal.

Assessment of intrinsic and extrinsic signaling pathway in excitotoxic retinal ganglion cell death.

Excitotoxicity leads to the activation of a cytotoxic cascade that causes neuronal death. In the retina, retinal ganglion cells (RGCs) die after an excitotoxic insult. Multiple pathways have been proposed to contribute to RGC death after an excitotoxic insult, including TNF signaling, JNK activation, and ER stress. To test the importance of these pathways in RGC death after excitotoxic injury, the excitotoxin N-methyl-D-aspartate (NMDA) was intravitreally injected into mice deficient in components of these pathways. Absence of Tnf or its canonical downstream mediator, Bid, did not confer short- or long-term protection to RGCs. Despite known activation in RGCs and a prominent role in mediating RGC death after other insults, attenuating JNK signaling did not prevent RGC death after excitotoxic insult. Additionally, deficiency of the ER stress protein DDIT3 (CHOP), which has been shown to be involved in RGC death, did not lessen NMDA induced RGC death. Furthermore, absence of both Jun (JNK's canonical target) and Ddit3, which together provide robust, long-term protection to RGC somas after axonal insult, did not lessen RGC death. Collectively, these results indicate that the drivers of excitotoxic injury remain to be identified and/or multiple cell death pathways are activated in response to injury.

Together JUN and DDIT3 (CHOP) control retinal ganglion cell death after axonal injury.

BACKGROUND: Optic nerve injury is an important pathological component in neurodegenerative diseases such as traumatic optic neuropathies and glaucoma. The molecular signaling pathway(s) critical for retinal ganglion cell (RGC) death after axonal insult, however, is/are not fully defined. RGC death after axonal injury is known to occur by BAX-dependent apoptosis. Two transcription factors JUN (the canonical target of JNK) and DDIT3 (CHOP; a key mediator of the endoplasmic reticulum stress response) are known to be important apoptotic signaling molecules after axonal injury, including in RGCs. However, neither Jun nor Ddit3 deficiency provide complete protection to RGCs after injury. Since Jun and Ddit3 are important apoptotic signaling molecules, we sought to determine if their combined deficiency might provide additive protection to RGCs after axonal injury. METHODS: To determine if DDIT3 regulated the expression of JUN after an axonal insult, mice deficient for Ddit3 were examined after optic nerve crush (ONC). In order to critically test the importance of these genes in RGC death after axonal injury, RGC survival was assessed at multiple time-points after ONC (14, 35, 60, and 120 days after injury) in Jun, Ddit3, and combined Jun/Ddit3 deficient mice. Finally, to directly assess the role of JUN and DDIT3 in axonal degeneration, compound actions potentials were recorded from Jun, Ddit3, and Jun/Ddit3 deficient mice after ONC. RESULTS: Single and combined deficiency of Jun and Ddit3 did not appear to alter gross retinal morphology. Ddit3 deficiency did not alter expression of JUN after axonal injury. Deletion of both Jun and Ddit3 provided significantly greater long-term protection to RGCs as compared to Jun or Ddit3 deficiency alone. Finally, despite the profound protection to RGC somas provided by the deficiency of Jun plus Ddit3, their combined loss did not lessen axonal degeneration. CONCLUSIONS: These results suggest JUN and DDIT3 are independently regulated pro-death signaling molecules in RGCs and together account for the vast majority of apoptotic signaling in RGCs after axonal injury. Thus, JUN and DDIT3 may represent key molecular hubs that integrate upstream signaling events triggered by axonal injury with downstream transcriptional events that ultimately culminate in RGC apoptosis.

KLF9 and JNK3 Interact to Suppress Axon Regeneration in the Adult CNS.

Neurons in the adult mammalian CNS decrease in intrinsic axon growth capacity during development in concert with changes in Krüppel-like transcription factors (KLFs). KLFs regulate axon growth in CNS neurons including retinal ganglion cells (RGCs). Here, we found that knock-down of KLF9, an axon growth suppressor that is normally upregulated 250-fold in RGC development, promotes long-distance optic nerve regeneration in adult rats of both sexes. We identified a novel binding partner, MAPK10/JNK3 kinase, and found that JNK3 (c-Jun N-terminal kinase 3) is critical for KLF9's axon-growth-suppressive activity. Interfering with a JNK3-binding domain or mutating two newly discovered serine phosphorylation acceptor sites, Ser106 and Ser110, effectively abolished KLF9's neurite growth suppression in vitro and promoted axon regeneration in vivo These findings demonstrate a novel, physiologic role for the interaction of KLF9 and JNK3 in regenerative failure in the optic nerve and suggest new therapeutic strategies to promote axon regeneration in the adult CNS.SIGNIFICANCE STATEMENT Injured CNS nerves fail to regenerate spontaneously. Promoting intrinsic axon growth capacity has been a major challenge in the field. Here, we demonstrate that knocking down Krüppel-like transcription factor 9 (KLF9) via shRNA promotes long-distance axon regeneration after optic nerve injury and uncover a novel and important KLF9-JNK3 interaction that contributes to axon growth suppression in vitro and regenerative failure in vivo These studies suggest potential therapeutic approaches to promote axon regeneration in injury and other degenerative diseases in the adult CNS.

JUN is important for ocular hypertension-induced retinal ganglion cell degeneration.

Ocular hypertension, a major risk factor for glaucoma, is thought to trigger glaucomatous neurodegeneration through injury to retinal ganglion cell (RGC) axons. The molecular signaling pathway leading from ocular hypertension to RGC degeneration, however, is not well defined. JNK signaling, a component of the mitogen-activated protein kinase (MAPK) family, and its canonical target, the transcription factor JUN, have been shown to regulate neurodegeneration in many different systems. JUN is expressed after glaucoma-relevant injuries and Jun deficiency protects RGCs after mechanical injury to the optic nerve. Here, we tested the importance of JNK-JUN signaling for RGC death after ocular hypertensive axonal injury in an age-related, mouse model of ocular hypertension. Immunohistochemistry was performed to evaluate JUN expression in ocular hypertensive DBA/2J mice. JUN was expressed in a temporal and spatial pattern consistent with a role in glaucomatous injury. To determine the importance of JUN in ocular hypertension-induced RGC death, a floxed allele of Jun and a retinal expressed cre recombinase (Six3-cre) were backcrossed onto the DBA/2J background. Intraocular pressure (IOP) and gross morphology of the retina and optic nerve head were assessed to determine whether removing Jun from the developing retina altered IOP elevation or retinal development. Jun deficiency in the retina did not alter DBA/2J IOP elevation or retinal development. Optic nerves and retinas were assessed at ages known to have glaucomatous damage in DBA/2J mice. Jun deficiency protected RGC somas from ocular hypertensive injury, but did not protect RGC axons from glaucomatous neurodegeneration. Jun is a major regulator of RGC somal degeneration after glaucomatous ocular hypertensive injury. These results suggest in glaucomatous neurodegeneration, JNK-JUN signaling has a major role as a pro-death signaling pathway between axonal injury and somal degeneration.

The effect of surgery type on survival and recurrence in very young women with breast cancer.

BACKGROUND: The impact of surgical treatment on outcomes in breast cacner in very young women remains unclear. We sought to determine the effect of surgery type on risk of recurrence and survival in a population-based cohort. METHODS: All women diagnosed with breast cancer aged ≤35 (1994-2003) were identified from the Ontario Cancer Registry. Patient, tumor, and treatment variables, including primary surgery, recurrences, and death were abstracted from chart review. Cox regression models were fit to determine the effect of surgery type on recurrence and overall survival. RESULTS: We identified 1,381 patients with 11-year median follow-up of which 793 (57%) had BCS. Of the remaining mastectomy patients, 52% had postmastectomy radiation. Overall, 41% of patients sustained a recurrence of any type and 31% died. Controlling for known confounders, there was no association between type of surgery and death from any cause (HR = 0.98, 95% CI = 0.78, 1.25) or first recurrence (HR = 0.93, 95% CI = 0.75, 1.14). Distant recurrence was most common (13% in BCS; 25.3% in mastectomy) with local recurrence 12.4% after BCS and 7.5% after mastectomy. CONCLUSIONS: In this cohort of very young women who were selected for treatment with BCS and mastectomy, we found similar oncologic outcomes. J. Surg. Oncol. 2017;115:122-130. © 2017 Wiley Periodicals, Inc.

Cancer Mortality Among Recipients of Solid-Organ Transplantation in Ontario, Canada.

IMPORTANCE: Solid-organ transplant recipients (SOTRs) are at greater risk of developing some cancers than the general population; however, because they are also at increased risk of mortality from noncancer causes, the effect of transplantation on cancer mortality is unclear. OBJECTIVE: To describe cancer mortality in SOTRs and to assess whether SOTRs are at increased risk of cancer mortality compared with the general population. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study of patients who underwent solid-organ transplantation in Ontario, Canada, between 1991 and 2010 with 85 557 person-years of follow-up through December 31, 2011. Solid-organ transplantation was identified using the national transplant register and linked to the provincial cancer registry and administrative databases. The analysis was conducted between November 2013 and February 2015. EXPOSURE: Solid-organ transplantation. MAIN OUTCOMES AND MEASURES: Cancer mortality for SOTRs was compared with that of the general population using standardized mortality ratios (SMRs). Mortality and cause of death were ascertained by record linkage between the Canadian Organ Replacement Register, the Ontario Cancer Registry, and the Office of the Registrar General of Ontario death database. RESULTS: A total of 11 061 SOTRs were identified, including 6516 kidney, 2606 liver, 929 heart, and 705 lung transplantations. Recipients had a median (interquartile range) age of 49 (37-58) years, and 4004 (36.2%) were women. Of 3068 deaths, 603 (20%) were cancer related. Cancer mortality in SOTRs was significantly elevated compared with the Ontario population (SMR, 2.84 [95% CI, 2.61-3.07]). The risk remained elevated when patients with pretransplant malignant neoplasms (n = 1124) were excluded (SMR, 1.93 [95% CI, 1.75-2.13]). The increased risk was observed irrespective of transplanted organ. The SMR for cancer death after solid-organ transplantation was higher in children (SMR, 84.61 [95% CI, 52.00-128.40]) and lower in patients older than 60 years (SMR, 1.88 [95% CI, 1.62-2.18]) but remained elevated compared with the general population at all ages. CONCLUSIONS AND RELEVANCE: Cancer death rate in SOTRs was increased compared with that expected in the general population; cancer was the second leading cause of death in these patients. Advances in prevention, clinical surveillance, and cancer treatment modalities for SOTRs are needed to reduce the burden of cancer mortality in this population.

Sensitivity and specificity of administrative mortality data for identifying prescription opioid-related deaths.

BACKGROUND: Comprehensive systems for surveilling prescription opioid-related harms provide clear evidence that deaths from prescription opioids have increased dramatically in the United States. However, these harms are not systematically monitored in Canada. In light of a growing public health crisis, accessible, nationwide data sources to examine prescription opioid-related harms in Canada are needed. We sought to examine the performance of 5 algorithms to identify prescription opioid-related deaths from vital statistics data against data abstracted from the Office of the Chief Coroner of Ontario as a gold standard. METHODS: We identified all prescription opioid-related deaths from Ontario coroners' data that occurred between Jan. 31, 2003, and Dec. 31, 2010. We then used 5 different algorithms to identify prescription opioid-related deaths from vital statistics death data in 2010. We selected the algorithm with the highest sensitivity and a positive predictive value of more than 80% as the optimal algorithm for identifying prescription opioid-related deaths. RESULTS: Four of the 5 algorithms had positive predictive values of more than 80%. The algorithm with the highest sensitivity (75%) in 2010 improved slightly in its predictive performance from 2003 to 2010. INTERPRETATION: In the absence of specific systems for monitoring prescription opioid-related deaths in Canada, readily available national vital statistics data can be used to study prescription opioid-related mortality with considerable accuracy. Despite some limitations, these data may facilitate the implementation of national surveillance and monitoring strategies.

Quantitative measurement of retinal ganglion cell populations via histology-based random forest classification.

The inner surface of the retina contains a complex mixture of neurons, glia, and vasculature, including retinal ganglion cells (RGCs), the final output neurons of the retina and primary neurons that are damaged in several blinding diseases. The goal of the current work was two-fold: to assess the feasibility of using computer-assisted detection of nuclei and random forest classification to automate the quantification of RGCs in hematoxylin/eosin (H&E)-stained retinal whole-mounts; and if possible, to use the approach to examine how nuclear size influences disease susceptibility among RGC populations. To achieve this, data from RetFM-J, a semi-automated ImageJ-based module that detects, counts, and collects quantitative data on nuclei of H&E-stained whole-mounted retinas, were used in conjunction with a manually curated set of images to train a random forest classifier. To test performance, computer-derived outputs were compared to previously published features of several well-characterized mouse models of ophthalmic disease and their controls: normal C57BL/6J mice; Jun-sufficient and Jun-deficient mice subjected to controlled optic nerve crush (CONC); and DBA/2J mice with naturally occurring glaucoma. The result of these efforts was development of RetFM-Class, a command-line-based tool that uses data output from RetFM-J to perform random forest classification of cell type. Comparative testing revealed that manual and automated classifications by RetFM-Class correlated well, with 83.2% classification accuracy for RGCs. Automated characterization of C57BL/6J retinas predicted 54,642 RGCs per normal retina, and identified a 48.3% Jun-dependent loss of cells at 35 days post CONC and a 71.2% loss of RGCs among 16-month-old DBA/2J mice with glaucoma. Output from automated analyses was used to compare nuclear area among large numbers of RGCs from DBA/2J mice (n = 127,361). In aged DBA/2J mice with glaucoma, RetFM-Class detected a decrease in median and mean nucleus size of cells classified into the RGC category, as did an independent confirmation study using manual measurements of nuclear area demarcated by BRN3A-immunoreactivity. In conclusion, we have demonstrated that histology-based random forest classification is feasible and can be utilized to study RGCs in a high-throughput fashion. Despite having some limitations, this approach demonstrated a significant association between the size of the RGC nucleus and the DBA/2J form of glaucoma.

Ticagrelor and bradycardia: a nested case-control study.

PURPOSE: Ticagrelor increases serum adenosine concentrations, slowing conduction and possibly leading to bradycardia. Clinical trial data have shown numerically, though not statistically significantly, higher rates of bradyarrhythmias with ticagrelor versus clopidogrel. Additionally, recent case reports have further raised concerns for this adverse effect. We explored the association between ticagrelor and hospitalization for bradycardia in a real-world setting. METHODS: We conducted a population-based, nested case-control study of Ontario residents, 66 years of age or older, discharged after a first acute coronary syndrome by linking multiple healthcare databases. Cases included patients hospitalized for bradycardia within 1 year of starting a P2Y12 inhibitor. For each case, we identified 4 controls matched on age, sex, index date, and current use of a P2Y12 inhibitor. The exposure of interest was a prescription for ticagrelor within 90 days, with clopidogrel use as the reference group. RESULTS: From April 2012 to March 2014, we identified 140 cases and 560 controls who met the study criteria. We found no significant association between bradycardia and exposure to ticagrelor relative to clopidogrel in the previous 90 days prior to the index date (adjusted odds ratio 1.06, 95% confidence interval 0.65-2.21). Further adjustment for potential confounders also did not identify a significant association. CONCLUSIONS: Among older patients with a first acute coronary syndrome, use of ticagrelor was not associated with a greater risk of admission for bradycardia relative to clopidogrel.

Using genetic mouse models to gain insight into glaucoma: Past results and future possibilities.

While all forms of glaucoma are characterized by a specific pattern of retinal ganglion cell death, they are clinically divided into several distinct subclasses, including normal tension glaucoma, primary open angle glaucoma, congenital glaucoma, and secondary glaucoma. For each type of glaucoma there are likely numerous molecular pathways that control susceptibility to the disease. Given this complexity, a single animal model will never precisely model all aspects of all the different types of human glaucoma. Therefore, multiple animal models have been utilized to study glaucoma but more are needed. Because of the powerful genetic tools available to use in the laboratory mouse, it has proven to be a highly useful mammalian system for studying the pathophysiology of human disease. The similarity between human and mouse eyes coupled with the ability to use a combination of advanced cell biological and genetic tools in mice have led to a large increase in the number of studies using mice to model specific glaucoma phenotypes. Over the last decade, numerous new mouse models and genetic tools have emerged, providing important insight into the cell biology and genetics of glaucoma. In this review, we describe available mouse genetic models that can be used to study glaucoma-relevant disease/pathobiology. Furthermore, we discuss how these models have been used to gain insights into ocular hypertension (a major risk factor for glaucoma) and glaucomatous retinal ganglion cell death. Finally, the potential for developing new mouse models and using advanced genetic tools and resources for studying glaucoma are discussed.

A population-based study of the drug interaction between clopidogrel and angiotensin converting enzyme inhibitors.

AIMS: Clopidogrel and angiotensin converting enzyme (ACE) inhibitors are commonly co-prescribed drugs. Clopidogrel inhibits carboxylesterase 1 (CES1), the enzyme responsible for converting prodrug ACE inhibitors (such as ramipril and perindopril) to their active metabolites. The clinical implications of this potential drug interaction are unknown. The clinical consequences of the potential drug interaction between clopidogrel and prodrug ACE inhibitors were examined. METHODS: We conducted a nested case-control study of Ontarians aged 66 years and older treated with clopidogrel between September 1 2003 and March 31 2013 following acute myocardial infarction. Cases were subjects who died or were hospitalized for reinfarction or heart failure in the subsequent year, and each was matched with up to four controls. The primary outcome was a composite of reinfarction, heart failure or death. The primary analysis examined whether use of the prodrug ACE inhibitors ramipril or perindopril was more common among cases than use of lisinopril, an active ACE inhibitor. RESULTS: Among 45 918 patients treated with clopidogrel following myocardial infarction, we identified 4203 cases and 14 964 controls. After adjustment, we found no association between the composite outcome and use of perindopril (adjusted odds ratio (aOR) 0.94, 95% confidence interval (CI) 0.76, 1.16) or ramipril (aOR 0.97, 95% CI 0.80, 1.18), relative to lisinopril. Secondary analyses of each element of the composite outcome yielded similar findings. CONCLUSIONS: Following myocardial infarction, use of clopidogrel with ACE inhibitors activated by CES1 is not associated with an increased risk of adverse cardiovascular outcomes relative to lisinopril. These findings suggest that the recently described drug interaction between clopidogrel and prodrug ACE inhibitors is of little clinical relevance.

Small-area variation in screening for cancer, glucose and cholesterol in Ontario: a cross-sectional study.

BACKGROUND: Screening for cervical, breast and colon cancers, and elevations of cholesterol and glucose, reduces premature cause-specific mortality from these cancers and circulatory diseases. Despite primary care reforms and incentives, and promotion of cancer-screening programs among individuals, participation is suboptimal. We aimed to examine participation as of Dec. 31, 2011, by factors of deprivation, demographics and primary care at the small-area level. METHODS: From health care administrative databases, we identified people eligible for each screening test, and their participation, in each dissemination area (referred to as small areas, n = 18 950) in Ontario. We calculated rates for each test among small areas (overall and stratified by demographic, socioeconomic and primary care descriptors) and stratified by sex for all tests combined. We loaded all data into a geographic information system. Funnel plots were generated showing the percentage of eligible people who completed screening for all tests by small area, stratified by sex. Overall and stratified screening prevalence ratios were calculated among small areas. RESULTS: Among small areas, the mean and SD for participation in all tests combined was 31.6% (SD 11.0%) for women and 41.2% (SD 12.0%) for men. Screening prevalence among small areas, for each test and for all tests combined, overall and stratified by sex, declined with decreasing percentage with high school completion, decreasing socioeconomic quintile, and decreasing percentage with an identifiable primary care physician. INTERPRETATION: Our results show that the rate of participation in all eligible screening tests among small areas is much lower than the rate of participation in any one particular test. This finding has implications for the design and implementation of strategies to improve rates of screening.

The impact of the use of aspirin and other nonsteroidal anti-inflammatory drugs on the risk of prostate cancer detection on biopsy.

OBJECTIVE: To evaluate the association between nonsteroidal anti-inflammatory drug (NSAID) use and the risk of prostate cancer (PC) detection in men undergoing biopsy. METHODS: Men were identified using our academic institution's prospectively maintained prostate biopsy database. Patients were classified as aspirin (ASA) users, users of other NSAIDs, or nonusers. The primary outcome was any PC on biopsy, and the secondary outcome was clinically significant PC (CSPC; Gleason sum ≥7). Multivariate logistic regression analyses were performed to adjust for a priori defined clinical confounders. RESULTS: Of 839 patients, 408 (48.6%) were diagnosed with PC and 201 (24.0%) had CSPC. A higher proportion of ASA users (63.5%) and other NSAID users (61.2%) had PC compared with nonusers (41.9%; P <.001). CSPC was more common among ASA users (34.9%; P <.001) compared with other NSAID users (20.0%) and nonusers (20.9%). In multivariate regression analyses, ASA use (odds ratio [OR] = 2.04; 95% confidence interval [CI] = 1.32-3.13; P = .001) and other NSAID use (OR = 2.42; 95% CI = 1.36-431; P = .003) were associated with higher odds of PC detection, whereas ASA use was associated with higher odds of CSPC (OR = 1.62; 95% CI = 1.00-2.62; P = .048). CONCLUSION: In men undergoing biopsy, ASA and other NSAID use were associated with increased probability of detecting PC, whereas ASA use was associated with the risk of detecting CSPC. Although NSAID use might have a protective biological effect against PC, men who develop elevated prostate-specific antigen levels while on NSAIDs may nonetheless be less likely to have an inflammatory etiology and more likely to harbor PC. It may be warranted for clinicians to consider the influence of NSAIDs when evaluating patients being considered for biopsy.

Involvement of low- and middle-income countries in randomized controlled trial publications in oncology.

BACKGROUND: We describe trends in participation by investigators from low- and middle-income countries (LMCs) in publications describing oncology randomized control trials (RCTs) over a decade. METHODS: We used Medline to identify RCTs published in English from 1998 to 2008 evaluating treatment in lung, breast, colorectal, stomach and liver cancers. Data on author affiliations, authorship roles, trial characteristics, funding and interventions were extracted from each article. Countries were stratified as low-, middle- or high-income using World Bank data. Interventions were categorized as requiring basic, limited, enhanced or maximal resources as per the Breast Health Global Initiative classification. Logistic regression was used to identify factors associated with authorship by investigators from LMCs. RESULTS: 454 publications were identified. Proportion of articles with at least one LMC author increased over time from 20% in 1998 to 29% in 2008 (p = 0.01), but almost all LMC authors were from middle-income countries. Proportion of articles with at least one LMC author was higher among articles that explicitly reported recruitment in at least one LMC vs those that did not (76% vs 13%). Among 87 articles (19%) that involved authors from LMCs, 17% had LMC authors as first or corresponding authors, and 67% evaluated interventions requiring enhanced or maximal resources. Factors associated with LMC authorship included industry funding (OR = 3.54, p = 0.0001), placebo comparator arm (OR = 2.57, p = 0.02) and palliative intent treatment (OR = 4.00, p = 0.0003). CONCLUSION: An increasing number of publications describing oncology RCTs involve authors from LMC countries but primarily in non-leadership roles in industry-funded trials.

Tumor necrosis factor alpha has an early protective effect on retinal ganglion cells after optic nerve crush.

BACKGROUND: Glaucoma is an optic neuropathy that is characterized by the loss of retinal ganglion cells (RGCs) initiated by damage to axons in the optic nerve. The degeneration and death of RGCs has been thought to occur in two waves. The first is axogenic, caused by direct insult to the axon. The second is somatic, and is thought to be caused by the production of inflammatory cytokines from the activated retinal innate immune cells. One of the cytokines consistently linked to glaucoma and RGC damage has been TNFα. Despite strong evidence implicating this protein in neurodegeneration, a direct injection of TNFα does not mimic the rapid loss of RGCs observed after acute optic nerve trauma or exposure to excitotoxins. This suggests that our understanding of TNFα signaling is incomplete. METHODS: RGC death was induced by optic nerve crush in mice. The role of TNFα in this process was examined by quantitative PCR of Tnfα gene expression, and quantification of cell loss in Tnfα (-/-) mice or in wild-type animals receiving an intraocular injection of exongenous TNFα either before or after crush. Signaling pathways downstream of TNFα were examined by immunolabeling for JUN protein accumulation or activation of EGFP expression in NFκB reporter mice. RESULTS: Optic nerve crush caused a modest increase in Tnfα gene expression, with kinetics similar to the activation of both macroglia and microglia. A pre-injection of TNFα attenuated ganglion cell loss after crush, while ganglion cell loss was more severe in Tnfα (-/-) mice. Conversely, over the long term, a single exposure to TNFα induced extrinsic apoptosis in RGCs. Müller cells responded to exogenous TNFα by accumulating JUN and activating NFκB. CONCLUSION: Early after optic nerve crush, TNFα appears to have a protective role for RGCs, which may be mediated through Müller cells.

Barriers to immediate breast reconstruction in the Canadian universal health care system.

PURPOSE: To describe the population-based rates of immediate breast reconstruction (IBR) for all women undergoing mastectomy for treatment or prophylaxis of breast cancer in the past decade, and to evaluate geographic, institutional, and patient factors that influence use in the publically funded Canadian health care system. METHODS: This population-based retrospective cohort study used administrative data that included 28,176 women who underwent mastectomy (25,141 mastectomy alone and 3,035 IBR) between April 1, 2002, and March 31, 2012, in Ontario, Canada. We evaluated factors associated with IBR by using a multivariable logistic regression model with the generalized estimating equation approach. RESULTS: The population-based, age-adjusted IBR rate increased from 5.1 procedures to 8.7 in 100,000 adult women (43.7%; P < .001), and the increase was greatest for prophylactic mastectomy or therapeutic mastectomy for in situ breast cancer (78.6%; P < .001). Women who lived in neighborhoods with higher median income had significantly increased odds of IBR compared with mastectomy alone (odds ratio [OR], 1.71; 95% CI, 1.47 to 2.00), and immigrant women had significantly lower odds (OR, 0.59; 95% CI, 0.44 to 0.78). A patient had nearly twice the odds of receiving IBR when she was treated at a teaching hospital (OR, 1.84; 95% CI, 1.1 to 3.06) or at a hospital with two or more available plastic surgeons (OR, 2.01; 95% CI, 1.53 to 2.65). Patients who received IBR traveled significantly farther compared with those who received mastectomy alone (OR, 1.04; 95% CI, 1.02 to 1.05 for every 10 km increase). CONCLUSION: IBR is available to select patients with favorable clinical and demographic characteristics who travel farther to undergo surgery at teaching hospitals with two or more available plastic surgeons.