A diverse portfolio of marine protected areas can better advance global conservation and equity.

Marine protected areas (MPAs) are widely used for ocean conservation, yet the relative impacts of various types of MPAs are poorly understood. We estimated impacts on fish biomass from no-take and multiple-use (fished) MPAs, employing a rigorous matched counterfactual design with a global dataset of >14,000 surveys in and around 216 MPAs. Both no-take and multiple-use MPAs generated positive conservation outcomes relative to no protection (58.2% and 12.6% fish biomass increases, respectively), with smaller estimated differences between the two MPA types when controlling for additional confounding factors (8.3% increase). Relative performance depended on context and management: no-take MPAs performed better in areas of high human pressure but similar to multiple-use in remote locations. Multiple-use MPA performance was low in high-pressure areas but improved significantly with better management, producing similar outcomes to no-take MPAs when adequately staffed and appropriate use regulations were applied. For priority conservation areas where no-take restrictions are not possible or ethical, our findings show that a portfolio of well-designed and well-managed multiple-use MPAs represents a viable and potentially equitable pathway to advance local and global conservation.

Introducing Elinor for monitoring the governance and management of area-based conservation.

Monitoring the governance and management effectiveness of area-based conservation has long been recognized as an important foundation for achieving national and global biodiversity goals and enabling adaptive management. However, there are still many barriers that prevent conservation actors, including those affected by governance and management systems from implementing conservation activities and programs and from gathering and using data on governance and management to inform decision-making across spatial scales and through time. We explored current and past efforts to assess governance and management effectiveness and barriers actors face in using the resulting data and insights to inform conservation decision-making. To help overcome these barriers, we developed Elinor, a free and open-source monitoring tool that builds on the work of Nobel Prize winner Elinor Ostrom to facilitate the gathering, storing, sharing, analyzing, and use of data on environmental governance and management across spatial scales and for areas under different governance and management types. We consider the process of codesigning and piloting Elinor with conservation scientists and practitioners and the main components of the assessment and online data system. We also consider how Elinor complements existing approaches by addressing governance and management in a single assessment at a high level for different types of area-based conservation, providing flexible options for data collection, and integrating a data system with an assessment that can support data use and sharing across different spatial scales, including global monitoring of the Global Biodiversity Framework. Although challenges will continue, the process of developing Elinor and the tool itself offer tangible solutions to barriers that prevent the systematic collection and use of governance and management data. With broader uptake, Elinor can play a valuable role in enabling more effective, inclusive, and durable area-based conservation.

Introducción de Elinor para el monitoreo de la gobernanza y la gestión de la conservación con base en zonas geográficas Resumen El monitoreo de la efectividad de la gobernanza y de la gestión de la conservación basada en zonas geográficas ha sido reconocido durante mucho tiempo como una base importante para alcanzar las metas nacionales y mundiales de la biodiversidad y permitir un manejo adaptativo. Sin embargo, todavía existen barreras que evitan que los actores de la conservación, incluidos aquellos afectados por los sistemas de gobernanza y gestión, implementen actividades y programas de conservación y recopilen y usen datos de la gobernanza y la gestión para informar las decisiones a lo largo de las escalas espaciales y a través del tiempo. Exploramos los esfuerzos hechos en la actualidad y en el pasado para evaluar la efectividad de la gobernanza y la gestión así como las barreras que los actores enfrentan al usar los datos y el conocimiento resultantes para informar la toma de decisiones de conservación. Para ayudar a derribar estas barreras desarrollamos Elinor, una herramienta de monitoreo gratuita y de software libre que parte del trabajo de la ganadora del Premio Nobel Elinor Ostrom, para facilitar la recopilación, almacenamiento, divulgación, análisis y uso de los datos sobre la gobernanza y la gestión ambiental en las escalas espaciales y para las zonas con diferentes tipos de gobernanza y gestión. Planteamos co­diseñar y pilotear Elinor con los científicos y practicantes de la conservación y usando los componentes principales del sistema de evaluación y de datos en línea. También planteamos cómo Elinor complementa las estrategias existentes al abordar la gobernanza y la gestión en una sola evaluación a un nivel elevado para diferentes tipos de conservación basada en zonas geográficas, lo que proporciona opciones flexibles para la colecta de datos, e integramos un sistema de datos con una evaluación que soporta el uso y divulgación de datos en diferentes escalas espaciales, incluido el Marco Mundial para la Biodiversidad. Aunque los retos seguirán existiendo, el proceso de desarrollo de Elinor y la propia herramienta ofrecen soluciones tangibles a las barreras que previenen la colecta sistemática y el uso de datos de la gobernanza y la gestión. Con una mayor aceptación, Elinor puede tener un papel importante en el momento de hacer posible una conservación basada en zonas geográficas más eficaz, integradora y duradera.

A comparison of revision rates for stemmed and stemless primary anatomic shoulder arthroplasty with all-polyethylene glenoid components: analysis from the Australian Orthopaedic Association National Joint Replacement Registry.

BACKGROUND: We compared the rate of all-cause revision of 2 classes of primary anatomic shoulder arthroplasty, stemmed (stTSA) and stemless (slTSA), undertaken with cemented all-polyethylene glenoid components. METHODS: A large national arthroplasty registry identified 2 cohort groups for comparison, stTSA and l undertaken for all diagnoses between January 1, 2011, and December 31, 2021. A subanalysis from January 1, 2017, allowed capturing of additional patient demographics including American Society of Anesthesiologists score, body mass index, and glenoid morphology. The cumulative percent revision (CPR) was determined using Kaplan-Meier estimates of survivorship and hazard ratios (HR) from Cox proportional hazard models adjusted for age and gender. RESULTS: Of the 7995 stTSA procedures, the CPR at 9 years was 5.6% (95% confidence interval [CI]: 5.0, 6.4), and for 3156 slTSA procedures, the CPR was 4.4% (95% CI: 3.6, 5.5). There was no significant difference in the rate of revision between the study groups (HR = 0.76 [95% CI: 0.51, 1.14], P = .189, adjusted for age, gender, humeral head size, humeral fixation, bearing surface, glenoid design, and mean surgeon volume [MSV]). There was an increased rate of revision for stTSA and slTSA undertaken with humeral head sizes <44 mm (stTSA <44 mm vs. 44-50 mm, HR = 1.56 [CI: 1.18, 2.08], P = .001; slTSA <44 mm vs. 44-50 mm, HR = 2.08 [CI: 1.32, 3.33], P = .001). MSV as a continuous predictor was not a revision risk to stTSA vs. slTSA, but categorically, a low MSV (<10 stTSA + slTSA cases per annum) was associated with a higher revision rate for stTSA (10-20 cases/yr vs. <10 cases/yr, HR = 0.72 [CI: 0.55, 0.95], P = .019) but was not in slTSA. Revision rates were increased for stTSA with non-crosslinked polyethylene (XLPE) glenoids vs. XPLE after 2 years (HR = 2.20 [CI: 1.57, 3.08], P < .001) but did not significantly differ for slTSA. Metal/XPLE (humeral/glenoid) bearing surface of stTSA rate of revision was not different from each combination of slTSA bearing surface. Instability/dislocation was a revision risk for slTSA vs. stTSA (HR = 1.93 [CI: 1.28, 2.91], P = .001), but from 2017, neither of American Society of Anesthesiologists score, body mass index, and glenoid morphology changed the rate of revision. CONCLUSIONS: Revision rates of stTSA and slTSA did not significantly differ and were associated with humeral head size but not patient characteristics. Surgeon inexperience of anatomic shoulder arthroplasty and non-XLPE glenoids were risk factors for stTSA revision but not slTSA. The metal/XLPE stTSA rate of revision was not found to differ significantly from slTSA regardless of polyethylene or humeral head bearing type. Revision for instability/dislocation was more common for slTSA.

Comparable low revision rates of stemmed and stemless total anatomic shoulder arthroplasties after exclusion of metal backed glenoid components: a collaboration between the Australian and Danish national shoulder arthroplasty registries.

BACKGROUND: The stemmed anatomical total shoulder arthroplasty is the gold standard in the treatment of glenohumeral osteoarthritis. However, the use of stemless total shoulder arthroplasties has increased in recent years. The number of revision procedures are relatively low and therefore it has been recommended that national joint replacement registries should collaborate when comparing revision rates. Therefore, we aimed to compare the revision rates of stemmed and stemless TSA used for the diagnosis of glenohumeral osteoarthritis using data from both the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) and the Danish Shoulder Arthroplasty Registry (DSR). METHODS: We included all patients who were registered in the AOANJRR and the DSR from January 1 2012 to December 2021 with an anatomical total shoulder arthroplasty used for osteoarthritis. Revision for any reason was used as the primary outcome. We used the Kaplan-Meier method to illustrate the cumulative revision rates and a multivariate cox regression model to calculate the hazard ratios. All analyses were performed separately for data from AOANJRR and DSR, and the results were then reported using a qualitative approach. RESULTS: 13066 arthroplasties from AOANJRR and 2882 arthroplasties from DSR were included. The hazard ratio for revision of stemmed TSA with stemless TSA as reference, adjusted for age and gender, was 1.67 (95% CI 1.34-2.09, p<0.001) in AOANJRR and 0.57 (95% CI 0.36-0.89, p=0.014) in DSR. When including glenoid type and fixation, surface bearing (only in AOANJRR) and hospital volume in the cox regression model the hazard ratio for revision of stemmed TSA compared to stemless TSA was 1.22 (95% CI 0.85-1.75, p=0.286) in AOANJRR and 1.50 (95% CI 0.91-2.45, p=0.109) in DSR. The adjusted hazard ratio for revision of total shoulder arthroplasties with metal backed glenoid components compared to all-polyethylene glenoid components was 2.54 (95% CI 1.70-3.79, p < 0.001) in AOANJRR and 4.1 (95% CI 1.92-8.58, p<0.001) in DSR. CONCLUSION: Based on data from two national shoulder arthroplasty registries, we found no significant difference in risk of revision between stemmed and stemless total shoulder arthroplasties after adjusting for the type of glenoid component. We advocate that metal-backed glenoid components should be used with caution and not on a routine basis.

Predictors of Cognitive Change in Parkinson Disease: A 2-year Follow-up Study.

BACKGROUND: Mild cognitive impairment is common in Parkinson disease (PD-MCI). However, instability in this clinical diagnosis and variability in rates of progression to dementia raises questions regarding its utility for longitudinal tracking and prediction of cognitive change in PD. We examined baseline neuropsychological test and cognitive diagnosis predictors of cognitive change in PD. METHODS: Persons with PD, without dementia PD (N=138) underwent comprehensive neuropsychological assessment at baseline and were followed up to 2 years. Level II Movement Disorder Society criteria for PD-MCI and PD dementia (PDD) were applied annually. Composite global and domain cognitive z -scores were calculated based on a 10-test neuropsychological battery. RESULTS: Baseline diagnosis of PD-MCI was not associated with a change in global cognitive z -scores. Lower baseline attention and higher executive domain z -scores were associated with greater global cognitive z -score worsening regardless of cognitive diagnosis. Worse baseline domain z -scores in the attention and language domains were associated with progression to MCI or PDD, whereas higher baseline scores in all cognitive domains except executive function were associated with clinical and psychometric reversion to "normal" cognition. CONCLUSIONS: Lower scores on cognitive tests of attention were predictive of worse global cognition over 2 years of follow-up in PD, and lower baseline attention and language scores were associated with progression to MCI or PDD. However, PD-MCI diagnosis per se was not predictive of cognitive decline over 2 years. The association between higher executive domain z -scores and greater global cognitive worsening is probably a spurious result.

Effects of management objectives and rules on marine conservation outcomes.

Understanding the relative effectiveness and enabling conditions of different area-based management tools is essential for supporting efforts that achieve positive biodiversity outcomes as area-based conservation coverage increases to meet newly set international targets. We used data from a coastal social-ecological monitoring program in 6 Indo-Pacific countries to analyze whether social, ecological, and economic objectives and specific management rules (temporal closures, fishing gear-specific, species-specific restrictions) were associated with coral reef fish biomass above sustainable yield levels across different types of area-based management tools (i.e., comparing those designated as marine protected areas [MPAs] with other types of area-based management). All categories of objectives, multiple combinations of rules, and all types of area-based management had some sites that were able to sustain high levels of reef fish biomass-a key measure for coral reef functioning-compared with reference sites with no area-based management. Yet, the same management types also had sites with low biomass. As governments advance their commitments to the Kunming-Montreal Global Biodiversity Framework and the target to conserve 30% of the planet's land and oceans by 2030, we found that although different types of management can be effective, most of the managed areas in our study regions did not meet criteria for effectiveness. These findings underscore the importance of strong management and governance of managed areas and the need to measure the ecological impact of area-based management rather than counting areas because of their designation.

Efectos de las reglas y objetivos de manejo sobre los resultados de conservación marina Resumen Es esencial entender la efectividad relativa y las condiciones habilitantes de las diferentes herramientas de manejo basadas en el área para respaldar los esfuerzos que brindan resultados positivos para la biodiversidad conforme aumenta la cobertura de la conservación basada en el área para alcanzar los objetivos internacionales recién establecidos. Usamos los datos de un programa de monitoreo socioeconómico costero en seis países del Indo-Pacífico para analizar si los objetivos sociales, ecológicos y económicos y las reglas específicas de manejo (cierres temporales, restricciones de equipo de pesca, vedas de especies) se asociaban con la biomasa de los peces de arrecife de coral por encima de los niveles de producción sustentable en diferentes tipos de herramientas de manejo basadas en el área (es decir, comparar aquellas designadas como áreas marinas protegidas[AMP] con otros tipos de manejo basado en el área). Todas las categorías de objetivos, las múltiples combinaciones de reglas y todos los tipos de manejo basado en el área tuvieron algunos sitios capaces de mantener los niveles altos de biomasa de peces de arrecife-una medida importante para el funcionamiento de los arrecifes-en comparación con los sitios de referencia sin manejo basado en el área. Sin embargo, los mismos tipos de manejo también tuvieron sitios con baja biomasa. Conforme los gobiernos avanzan en sus compromisos con el Marco Global de Biodiversidad de Kunming-Montreal y hacia el objetivo de conservar el 30% del suelo y los océanos del planeta para el 2030, descubrimos que, aunque diferentes tipos de manejo pueden ser efectivos, la mayoría de las áreas manejadas en nuestras regiones de estudio no cumplieron con los criterios de efectividad. Este descubrimiento enfatiza la importancia de una gestión y un gobierno sólidos de las áreas manejadas y la necesidad de medir el impacto ecológico del manejo basado en el área en lugar de contar las áreas por su designación.

Capacity shortfalls hinder the performance of marine protected areas globally.

Marine protected areas (MPAs) are increasingly being used globally to conserve marine resources. However, whether many MPAs are being effectively and equitably managed, and how MPA management influences substantive outcomes remain unknown. We developed a global database of management and fish population data (433 and 218 MPAs, respectively) to assess: MPA management processes; the effects of MPAs on fish populations; and relationships between management processes and ecological effects. Here we report that many MPAs failed to meet thresholds for effective and equitable management processes, with widespread shortfalls in staff and financial resources. Although 71% of MPAs positively influenced fish populations, these conservation impacts were highly variable. Staff and budget capacity were the strongest predictors of conservation impact: MPAs with adequate staff capacity had ecological effects 2.9 times greater than MPAs with inadequate capacity. Thus, continued global expansion of MPAs without adequate investment in human and financial capacity is likely to lead to sub-optimal conservation outcomes.

Lessons learned through crisis: the effect of Covid-19 on pre-service Technology Education teacher development.

The Covid-19 pandemic forced post-secondary institutions to shift their technical offerings to blended and/or remote delivery. The Pandemic was a catalyst for pre-service Technology Education programs, traditionally designed for face-to-face learning, to explore innovative pedagogical arrangements. The purpose of this study was to understand the experiences and perceptions of pre-service teachers as they navigated their way through their Pandemic-impacted Technology Education Diploma program. In particular, pre-service teachers were asked about the challenges, benefits, and lessons learned through their lived experiences dealing with the re-organization for remote and blended learning in response to the various waves of the Covid-19 Pandemic. An exploration of the learner experience within pre-service Technology Education programs contributes to a growing body of literature that continues to offer meaningful insight on the institutional arrangements to cope with the limitations brought on by the Pandemic. Interviews from a purposeful sample of nine (N = 9) pre-service teachers was the primary data source within this qualitative study that sought to understand the following research question: How have institutional responses to Covid-19 impacted the experiences and perceptions of pre-service teachers enrolled in a re-organized Technology Education Diploma program? Thematic analysis was used to identify and explore recurring nodes within the data. The findings of this study suggest that the shift in instructional modality had significant impacts on how pre-service teachers experienced their Technology Education program. The reorganization delayed the development of peer relationships within the program cohorts and disrupted lines of communication.

Evidence of an additional centre of apple domestication in Iran, with contributions from the Caucasian crab apple Malus orientalis Uglitzk. to the cultivated apple gene pool.

Divergence processes in crop-wild fruit tree complexes in pivotal regions for plant domestication such as the Caucasus and Iran remain little studied. We investigated anthropogenic and natural divergence processes in apples in these regions using 26 microsatellite markers amplified in 550 wild and cultivated samples. We found two genetically distinct cultivated populations in Iran that are differentiated from Malus domestica, the standard cultivated apple worldwide. Coalescent-based inferences showed that these two cultivated populations originated from specific domestication events of Malus orientalis in Iran. We found evidence of substantial wild-crop and crop-crop gene flow in the Caucasus and Iran, as has been described in apple in Europe. In addition, we identified seven genetically differentiated populations of wild apple (M. orientalis), not introgressed by the cultivated apple. Niche modelling combined with genetic diversity estimates indicated that these wild populations likely resulted from range changes during past glaciations. This study identifies Iran as a key region in the domestication of apple and M. orientalis as an additional contributor to the cultivated apple gene pool. Domestication of the apple tree therefore involved multiple origins of domestication in different geographic locations and substantial crop-wild hybridization, as found in other fruit trees. This study also highlights the impact of climate change on the natural divergence of a wild fruit tree and provides a starting point for apple conservation and breeding programmes in the Caucasus and Iran.

Structural basis of G-quadruplex DNA recognition by the yeast telomeric protein Rap1.

G-quadruplexes are four-stranded nucleic acid structures involved in multiple cellular pathways including DNA replication and telomere maintenance. Such structures are formed by G-rich DNA sequences typified by telomeric DNA repeats. Whilst there is evidence for proteins that bind and regulate G-quadruplex formation, the molecular basis for this remains poorly understood. The budding yeast telomeric protein Rap1, originally identified as a transcriptional regulator functioning by recognizing double-stranded DNA binding sites, was one of the first proteins to be discovered to also bind and promote G-quadruplex formation in vitro. Here, we present the 2.4 Å resolution crystal structure of the Rap1 DNA-binding domain in complex with a G-quadruplex. Our structure not only provides a detailed insight into the structural basis for G-quadruplex recognition by a protein, but also gives a mechanistic understanding of how the same DNA-binding domain adapts to specifically recognize different DNA structures. The key observation is the DNA-recognition helix functions in a bimodal manner: In double-stranded DNA recognition one helix face makes electrostatic interactions with the major groove of DNA, whereas in G-quadruplex recognition a different helix face is used to make primarily hydrophobic interactions with the planar face of a G-tetrad.

A Comparison of Revision Rates for Osteoarthritis of Primary Reverse Total Shoulder Arthroplasty to Primary Anatomic Shoulder Arthroplasty with a Cemented All-polyethylene Glenoid: Analysis from the Australian Orthopaedic Association National Joint Replacement Registry.

BACKGROUND: There has been decreased use of anatomic total shoulder arthroplasty (aTSA) because reverse TSA (rTSA) is increasingly being used for the same indications. Although short-term studies generally have not found survivorship differences between these implant designs, these studies are often small and their follow-up is limited to the short term. Likewise, the degree to which patient characteristics (such as gender, age, and American Society of Anesthesiologists [ASA] score) may or may not be associated with survivorship differences calls for larger and longer-term studies than is often possible in single-center designs. Large national registry studies may be able to help answer these questions. QUESTIONS/PURPOSES: By analyzing a large Australian registry series of primary aTSAs with cemented all-polyethylene glenoids and rTSA for osteoarthritis (OA), we asked: (1) Is the revision risk for OA higher for aTSA with all-polyethylene glenoids or for rTSA, adjusting for patient characteristics such as age, gender, ASA score, and BMI? (2) Is the patient's gender associated with differences in the revision risk after controlling for the potentially confounding factors of age, ASA score, and BMI? METHODS: In this comparative, observational registry study performed between January 1, 2015, and December 31, 2019, all primary aTSAs with all-polyethylene glenoids and rTSA for OA as determined by the treating surgeon and reported to our national registry formed two groups for analysis. The study period was set to time-match for the collection of ASA score and BMI in 2012 and 2015, respectively. Our registry enrolls more than 97% of all shoulder arthroplasties undertaken in Australia. There were 29,294 primary shoulder arthroplasties; 1592 hemiarthroplasties, 1876 resurfacing and stemless shoulders, 269 stemmed, and 11,674 reverse shoulder arthroplasties were excluded for other diagnoses. A total of 1210 metal-backed glenoids in stemmed aTSA for OA were excluded. A total of 3795 primary aTSAs with all-polyethylene glenoids and 8878 primary rTSAs for OA were compared. An aTSA with an all-polyethylene glenoid and rTSA were more likely to be performed in women (56% and 61% of patients, respectively). The mean age was 69 ± 8 years for aTSA with all-polyethylene glenoids and 74 ± 8 years for rTSA. One aTSA for OA was performed in a patient with an unknown glenoid type. The ASA score (n = 12,438) and BMI (n = 11,233) were also recorded. The maximum follow-up was 5 years for both groups, and the mean follow-up was 2.6 ± 1.4 years for aTSA with all-polyethylene glenoids and 2.1 ± 1.4 years for rTSA. The endpoint was time to revision (all causes), and the cumulative percent revision was determined using Kaplan-Meier estimates of survivorship (time to revision) and HRs from Cox proportional hazard models that were adjusted for age, gender, ASA score, and BMI category. RESULTS: Overall, there were no differences in the 4-year cumulative percent revision between the groups; the 4-year cumulative percent revision was 3.5% for aTSA with all-polyethylene glenoids (95% CI 2.9%-4.2%) and 3.0% for rTSA (95% CI 2.6%-3.5%). There was an increased risk of revision of rTSA compared with aTSA using all-polyethylene glenoids in the first 3 months (HR 2.17 [95% CI 1.25-3.70]; p = 0.006, adjusted for age, gender, ASA score, and BMI). After that time, there was no difference in the rate of revision, with the same adjustments. In the first 3 months, men undergoing rTSA had a higher rate of revision than men with aTSA using all-polyethylene glenoids (HR 4.0 [95% CI 1.72-9.09]; p = 0.001, adjusted for age, BMI, and ASA). There was no difference between men in the two groups after that time. Women with aTSA using all-polyethylene glenoids were at a greater risk of revision than women with rTSA from 3 months onward (HR 2.77 [95% CI 1.55-4.92]; p < 0.001, adjusted for age, BMI, and ASA), with no difference before that time. CONCLUSION: Given the absence of survivorship differences at 4 years between rTSA and aTSA, but in light of the differences in the revision risk between men and women, surgeons might select an aTSA with an all-polyethylene glenoid to treat OA, despite the current popularity of rTSA. However, there are survivorship differences between genders. Future studies should evaluate whether our comparative findings are replicated in men and women undergoing aTSA with all-polyethylene glenoids and rTSA for primary diagnoses such as rheumatoid arthritis or post-traumatic arthritis, and whether there are functional differences between the two implant designs when used for OA. LEVEL OF EVIDENCE: Level III, therapeutic study.

A Pounding Problem: A Case of Recurrent Headache Caused by Anti-NMDA Receptor Encephalitis.

BACKGROUND: Anti-N-methyl-d-aspartate receptor (Anti-NMDAR) encephalitis is a serious autoimmune disease in which antibody production against the NMDA receptor results in profound neurotransmitter dysregulation. Patients may present with a wide variety of symptoms, including psychosis, orofacial dyskinesias, dysautonomia, hallucinations, mental status changes, seizures, and headaches. CASE REPORT: A previously healthy 25-year-old woman presented on several occasions to the Emergency Department with a severe pounding headache that initially responded well to treatment. She later developed signs consistent with meningoencephalitis along with altered mental status and neuropsychiatric changes. She was diagnosed with anti-NMDAR encephalitis after hospitalization. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Anti-NMDAR encephalitis is an under-recognized condition with diverse presentations. Recurrent headaches that improve with treatment may be an early sign of this disorder. Anti-NMDAR encephalitis should be considered in patients with recurrent undifferentiated headaches, and an appropriate work-up should be performed. Early recognition and diagnosis of this condition is critical to optimize favorable patient outcomes, as delays to diagnosis may lead to fatalities and long-term neurologic sequelae.

The rate of 2nd revision for shoulder arthroplasty as analyzed by the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR).

Background and purpose - The increase in shoulder arthroplasty may lead to a burden of revision surgery. This study compared the rate of (2nd) revision following aseptic 1st revision shoulder arthroplasty, considering the type of primary, and the class and type of the revision.Patients and methods - All aseptic 1st revisions of primary total reverse shoulder arthroplasty (rTSA group) and of primary total stemmed and stemless total shoulder arthroplasty (non-rTSA group) procedures reported to our national registry between April 2004 to December 2018 were included. The rate of 2nd revision was determined using Kaplan-Meier estimates and comparisons were made using Cox proportional hazards models.Results - There was an increased risk of 2nd revision in the 1st month only for the rTSA group (n = 700) compared with the non-rTSA group (n = 991); hazard ratio (HR) = 4.8 (95% CI 2.2-9). The cumulative percentage of 2nd revisions (CPR) was 24% in the rTSA group and 20% in the non-rTSA group at 8 years. There was an increased risk of 2nd revision for the type (cup vs. head) HR = 2.2 (CI 1.2-4.2), but not class of revision for the rTSA group. Minor (> 3 months) vs. major class revision, and humeral revision vs. all other revision types were second revision risk factors for the non-rTSA group.Interpretation - The CPR of revision shoulder arthroplasty was > 20% at 8 years and was influenced by the type of primary, the class, and the type of revision. The most common reasons for 2nd revision were instability/dislocation, loosening, and infection.

Modulation of Premetastatic Niche by the Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor Pazopanib in Localized High-Risk Prostate Cancer Followed by Radical Prostatectomy: A Phase II Randomized Trial.

LESSONS LEARNED: Pazopanib was not effective in altering the premetastatic niche in the neoadjuvant setting.Pazopanib was safe and well tolerated without any new safety signals. BACKGROUND: Vascular endothelial growth factor receptor 1 (VEGFR1) expressing myeloid-derived suppressor cells (VEGFR1+ MDSCs) potentially foster metastases by establishing a premetastatic niche. In a preclinical study, VEGFR1+ clustering in lymph nodes (LNs) independently predicted time to biochemical recurrence (TTBR) in localized prostate cancer [1]. The hypothesis was that neoadjuvant pazopanib therapy will decrease VEGFR1+ clusters in pelvic lymph nodes and improve outcomes. METHODS: This is a phase II trial (NCT01832259) of neoadjuvant pazopanib 800 mg versus placebo daily for 4 weeks in high-risk localized prostate cancer. The primary endpoint was a decrease in VEGFR1+ MDSC clustering assessed by immunohistochemistry (IHC) analysis. Secondary endpoints were safety, feasibility, and TTBR. RESULTS: Thirty patients were randomized to pazopanib versus placebo, with 15 patients randomized to each arm. Demographic and disease characteristics were similar in both arms. There was no difference in the VEGFR1+ clustering between the treatment arms (p = .345). Neoadjuvant therapy with pazopanib was well tolerated, and surgical complications were similar in both arms. CONCLUSION: Neoadjuvant pazopanib therapy did not alter the premetastatic niche; however, treatment targeting vascular endothelial growth factor (VEGF) in the preoperative period was safe and feasible, which may open up the avenue to investigate novel combinatorial regimens, including a VEGF inhibitor in combination with immune checkpoint inhibitor in this setting.

Overview of Current and Future First-Line Systemic Therapy for Metastatic Clear Cell Renal Cell Carcinoma.

OPINION STATEMENT: Treatment of metastatic clear cell renal cancer (mccRCC) has seen substantial progress over the last 20 years, with many regulatory approvals since 2006 culminating in a substantial increase to overall survival (OS). Six therapies are currently available for first-line use, with additional treatments currently being tested in this setting, some of which are expected to be approved soon based on new data from the CABOSUN and CheckMate-214 trials. Based on the available evidence, we strongly believe that vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) therapy over mechanistic target or rapamycin (mTOR; formerly known as mammalian target of rapamycin) inhibitor therapy is the most effective first-line option regardless of risk category assignment. High-dose interleukin-2 (HDIL-2) therapy remains a reasonable treatment option in patients with Eastern Cooperative Oncology Group (ECOG) performance status 0-1 and have minimal comorbid conditions. In the near future, these agents are likely to be surpassed by cabozantinib and by combination immune checkpoint inhibitor therapy with nivolumab and ipilimumab. Independent review has recently confirmed superiority of first-line cabozantinib over sunitinib in a phase 2 trial of 157 patients with intermediate or poor risk mccRCC (progression-free survival [PFS] 8.6 vs 5.3 months, hazard ratio [HR] 0.48, p = 0.0008). In a separate study of 1096 patients treated with either upfront sunitinib or the combination of nivolumab and ipilimumab, those with intermediate and poor risk had significant improvement in both PFS (11.6 vs 8.4 months, HR 0.82, p = 0.0331) and OS (not reached vs 26 months, p < 0.0001). Responses were greater in patients with positive programmed death receptor ligand-1 (PD-L1) tumor staining, and pending regulatory approval may become standard of care in untreated patients with intermediate to poor risk disease with positive PD-L1 status. This likely represents the beginning of additional novel immunotherapy combinations for the first-line treatment of mccRCC.

Marine Socio-Environmental Covariates: queryable global layers of environmental and anthropogenic variables for marine ecosystem studies.

Biophysical conditions, including climate, environmental stress, and habitat availability, are key drivers of many ecological processes (e.g., community assembly and productivity) and associated ecosystem services (e.g., carbon sequestration and fishery production). Furthermore, anthropogenic impacts such as coastal development and fishing can have drastic effects on the structure and function of marine ecosystems. Scientists need to account for environmental variation and human impacts to accurately model, manage, and conserve marine ecosystems. Although there are many types of environmental data available from global remote sensing and open-source data products, some are inaccessible to potential end-users because they exist as global layers in high temporal and spatial resolutions which require considerable computational power to process. Additionally, coastal locations often suffer from missing data or data quality issues which limit the utility of some global marine products for coastal sites. Herein we present the Marine Socio-Environmental Covariates dataset for the global oceans, which consists of environmental and anthropogenic variables summarized in ecologically relevant ways. The dataset includes four sets of environmental variables related to biophysical conditions (net primary productivity models corrected for shallow-water reflectance, wave energy including sheltered-coastline corrections) and landscape context (coral reef and land cover within varying radii). We also present two sets of anthropogenic variables, human population density (within varying radii) and distance to large population center, which can serve as indicators of local human impacts. We have paired global, summarized layers available for download with an online data querying platform that allows users to extract data for specific point locations with finer control of summary statistics. In creating these global layers and online platform, we hope to make the data accessible to a wide array of end-users with the goal of advancing marine ecosystem studies.

Neutrophil-lymphocyte ratio as a predictive biomarker for response to high dose interleukin-2 in patients with renal cell carcinoma.

BACKGROUND: Immunotherapy with high-dose interleukin-2 (HD-IL2) results in long-term survival in some metastatic renal cell carcinoma (mRCC) patients but has significant acute toxicities. Biomarkers predicting response to therapy are needed to better select patients most likely to benefit. NLR (absolute neutrophil count (ANC)/absolute lymphocyte count (ALC)) is a prognostic and predicative biomarker in various malignancies. The goal was to determine whether NLR can predict response to HD-IL2 in this setting. METHODS: Patients with clear cell mRCC treated with HD-IL2 were identified from an institutional database from 2003-2012. Baseline variables for the assessment of IMDC risk criteria, and neutrophil and lymphocyte count, were collected. Best response criteria were based on RECIST 1.0. Wilcoxon rank-sum test was used to evaluate the association of continuous baseline variables with disease control. NLR was stratified by ≤4 or >4. Progression free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and Cox proportional hazard models assessed associations of NLR with survival. RESULTS: In 71 eligible patients, median NLR in those with an objective response (n = 14, 20%) was 2.3 vs 3.4 in those without (n = 57, 80%, p = 0.02). NLR ≤4 was associated with improved progression free and overall survival. After adjustment for IMDC risk criteria, NLR remained a significant predictor of OS (ANC/ALC ≤4 vs >4, HR 0.41, 95% CI 1.09-5.46, p = 0.03; ANC/ALC continuous variable per unit change in NLR, HR 1.08, 95% CI 1.01-1.14, p = 0.03). CONCLUSIONS: In this discovery set, NLR predicts overall survival in patients treated with HD-IL2 in mRCC, and may allow better patient selection in this setting. Data needs validation in an independent cohort.

Extension of overall survival beyond objective responses in patients with metastatic renal cell carcinoma treated with high-dose interleukin-2.

PURPOSE: In metastatic renal cell carcinoma (mRCC), survival benefit associated with objective response rates of 16-20 % with high-dose interleukin-2 (HDIL-2) is well established and discussed. Based on recently emerged data on efficacy of cancer immunotherapy, we hypothesized that the survival benefit with HDIL-2 extends beyond those achieving objective responses, i.e., to those who achieve stable disease as the best response to treatment. MATERIALS AND METHODS: All sequential treatment naïve mRCC patients treated with HDIL-2 at the University of Utah (1988-2013) and University of Michigan (1997-2013) were included. Best responses on treatment were associated with survival outcomes using log-rank and COX regression with a landmark analysis at 2 months. RESULTS: 391 patients (75 % male; median age 55 years) were included and belonged to the following prognostic risk categories: 20 % good, 64 % intermediate, and 15 % poor. Best responses on treatment were complete response (9 %), partial response (10 %), stable disease (32 %), progressive disease (42 %), and not evaluable for response (7 %). No significant differences in progression-free survival (HR 0.74, 95 % CI 0.48-1.1, p = 0.14) or overall survival (HR 0.66, 95 % CI 0.39-1.09, p = 0.11) were observed between patients achieving partial response versus stable disease. Significant differences in progression-free survival (HR 0.13, 95 % CI 0.09-0.22, p < 0.0001) and overall survival (HR 0.33, 95 % CI 0.23-0.48, p < 0.0001) were observed between patients achieving stable disease compared to those with progressive disease and who were not evaluable. CONCLUSIONS: Survival benefit with HDIL-2 is achieved in ~50 % patients and extends beyond those achieving objective responses.