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Study Design: Ambispective cohort study design. Objectives: Cervical spine metastases have distinct clinical considerations. The aim of this study was to determine the impact of surgical intervention (± radiotherapy) or radiotherapy alone on health-related quality of life (HRQOL) outcomes in patients treated for cervical metastatic spine tumours. Methods: Patients treated with surgery and/or radiotherapy for cervical spine metastases were identified from the Epidemiology, Process, and Outcomes of Spine Oncology (EPOSO) international multicentre prospective observational study. Demographic, diagnostic, treatment, and HRQOL (numerical rating scale [NRS] pain, EQ-5D (3L), SF-36v2, and SOSGOQ) measures were prospectively collected at baseline, 6 weeks, 3 months, and 6 months postintervention. Results: Fifty-five patients treated for cervical metastases were identified: 38 underwent surgery ± radiation and 17 received radiation alone. Surgically treated patients had higher mean spinal instability neoplastic scores compared with the radiation-alone group (13.0 vs 8.0, P < .001) and higher NRS pain scores and lower HRQOL scores compared to the radiation alone group ( P < .05). From baseline to 6 months posttreatment, surgically treated patients demonstrated statistically significant improvements in NRS pain, EQ-5D (5L), and SOSGOQ2.0 scores compared with nonsignificant improvements in the radiotherapy alone group. Conclusions: Surgically treated cervical metastases patients presented with higher levels of instability, worse baseline pain and HRQOL scores compared with patients who underwent radiotherapy alone. Significant improvements in pain and HRQOL were noted for those patients who received surgical intervention. Limited or no improvements were found in those treated with radiotherapy alone.

ZusammenfassungAufgrund der zunehmenden Spezialisierung in den verschiedenen Bereichen der Kardiologie und den immer anspruchsvolleren administrativen Strukturvorgaben und Mindestanforderungen an die ärztliche Qualifikation und Präsenz entwickelt sich ein Spannungsfeld zwischen verschiedenen eigenständigen Kliniken bzw. Departments innerhalb der Kardiologie in großen kardiologischen Kliniken und einer „allgemeinen Kardiologie“, die alle Schwerpunkte ohne Abteilungen oder Departmentstrukturen in sich vereint. Ganz prinzipiell ist eine Unterteilung in Departments bzw. verschiedene Abteilungen nur dann sinnvoll, wenn die Klinik eine entsprechende Größe und Struktur hat. Auf der anderen Seite muss aber auch bedacht werden, dass die Schnittstellen zwischen den verschiedenen Bereichen/Abteilungen/Departments so geregelt sind, dass die genannten Strukturvorgaben vollumfänglich realisiert werden können, um nachhaltig Qualitätsvorgaben und die inzwischen mannigfaltigen Erlösvoraussetzungen zu erfüllen. Das setzt auch interne Regelungen wirtschaftlicher Interessen im Vorfeld voraus wie z. B. ein einheitliches Budget mit jedoch differenzierter Darlegung der Leistungsdaten in den verschiedenen Bereichen inklusive Deckungsbeiträgen. Das kardiologische Behandlungsspektrum ist in weiten Teilen bestimmt durch Notfälle. Deshalb muss die Behandlung dieser Patienten in der Notaufnahme (Chest Pain Unit) und auf der Intensivstation in der Hand der Kardiologen bleiben, um eine optimale Versorgung zu sichern. Eine Unterteilung in eigenständige kardiologische Kliniken widerspricht zum Teil dem politischen Wunsch und den derzeitigen positiven Erfahrungen von Zentrumsbildungen. Wenn eine Einrichtung die entsprechende Größe hat, kann es sinnvoll sein, sogenannte Herzzentren mit Integration der Herzchirurgie zu bilden. Die wirtschaftliche Struktur dieser Herzzentren muss sehr differenziert etabliert werden, um Fehlentwicklungen und einen ungesunden internen Wettbewerb zu verhindern. Die robuste Erfüllung von Strukturvorgaben bestimmt inzwischen die Planung fast mehr als die Erfüllung medizinisch-fachlich gebotener Voraussetzungen, um einen nachhaltigen Bestand der gewählten Organisationsform der kardiologischen Klinik zu sichern. Sektorenübergreifende Versorgungsformen müssen in Zukunft mehr zur Anwendung kommen.

Background Bisphosphonates (BPs) including zoledronate (zol) have become standard care for bone metastases as they effectively inhibit tumor-induced osteolysis and associated pain. Several studies have also suggested that zol has direct anti-tumor activity. Systemic administration at high doses is the current approach to deliver zol, yet it has been associated with debilitating side effects. Local therapeutic delivery offers the ability to administer much lower total dosage, while at the same time maintaining sustained high-local drug concentration directly at the target treatment site. Here, we aimed to assess effects of lower doses of zol on bone metastases over a longer time. Methods Prostate cancer cell line LAPC4 and prostate-induced bone metastasis cells were treated with zol at 1, 3 and 10 µM for 7 days. Following treatment, cell proliferation was assessed using Almarblue®, Vybrant MTT®, and Live/Dead® viability/cytotoxicity assays. Additionally, cell migration and invasion were carried out using Falcon™ cell culture inserts and Cultrex® 3D spheroid cell invasion assays respectively. Results We show that treatment with 3–10 µM zol over 7-days significantly decreased cell proliferation in both the prostate cancer cell line LAPC4 and cells from spine metastases secondary to prostate cancer. Using the same low-dose and longer time course for treatment, we demonstrate that 10 µM zol also significantly inhibits tumor cell migration and 3D-cell growth/invasion. Conclusions This project harnesses the potential of using zol at low doses for longer treatment periods, which may be a viable treatment modality when coupled with biomaterials or biodevices for local delivery. Electronic supplementary material The online version of this article (10.1186/s12935-019-0745-x) contains supplementary material, which is available to authorized users.

Fish mercury concentrations have received considerable attention due to human health implications. Fish mercury concentrations are variable within and among systems due to a suite of biotic and abiotic influences that vary among regions and are difficult to predict. Understanding factors associated with variability in fish mercury concentrations would help guide consumption advisories. Mercury concentrations in channel catfish (Ictalurus punctatus, n = 205), flathead catfish (Pylodictis olivaris, n = 123), northern pike (Esox lucius, n = 60), smallmouth bass (Micropterus dolomieu, n = 176), and walleye (Sander vitreus, n = 176) were assessed in ten Iowa rivers and relationships with land use, water chemistry, and fish characteristics were explored. Mercury concentrations were generally low (mean among all species = 0.17 mg/kg, n = 740) but higher in flathead catfish, northern pike, smallmouth bass, and walleye than channel catfish and were positively related to fish length, age, trophic position, and δ13C signatures. Phosphorus, sulfate, and percent open water and grassland were negatively related to fish mercury concentrations, whereas water hardness, nitrogen-ammonia, Human Threat Index, and percent wetland and forest were positively related to fish mercury concentrations. Fish collected from the Paleozoic Plateau ecoregion in northeast Iowa had higher mercury concentrations than other ecoregions in Iowa. Combined, these factors explained 70% of the variation in fish mercury concentrations. This study provides a comprehensive analysis of abiotic and biotic factors influencing fish mercury concentrations in lotic ecosystems at the individual and system scale that will help guide fish consumption advisories.

AIMS The randomized sham-controlled SPYRAL HTN-OFF MED trial demonstrated that renal denervation (RDN) using a multi-electrode catheter lowers ambulatory blood pressure (BP) in non-medicated hypertensive patients. The current report describes the effects of RDN on heart rate (HR) in this population. METHODS AND RESULTS Patients were enrolled with an office systolic BP (SBP) of ≥150 mmHg and

Retrospective review of results from a prospectively collected Canadian cohort in comparison to published literature.(1) To investigate whether patients in a universal health care system have different outcomes than those in a multitier health care system in surgical management of degenerative spondylolisthesis (DS). (2) To identify independent factors predictive of outcome in surgical DS patients.Canada has a national health insurance program with unique properties. It is a single-payer system, coverage is universal, and access to specialist care requires referral by the primary care physician. The United States on the other hand is a multitier public/private payer system with more rapid access for insured patients to specialist care.Surgical DS patients treated between 2013 and 2016 in Canada were identified through the Canadian Spine Outcome Research Network (CSORN) database, a national registry that prospectively enrolls consecutive patients with spinal pathology from 16 tertiary care academic hospitals. This population was compared with the surgical DS arm of patients treated in the Spine Patients Outcome Research Trial (SPORT) study. We compared baseline demographics, spine-related, and health-related quality of life (HRQOL) outcomes at 3 months and 1 year. Multivariate analysis was used to identify factors predictive of outcome in surgical DS patients.The CSORN cohort of 213 patients was compared with the SPORT cohort of 248 patients. Patients in the CSORN cohort were younger (mean age 60.1 vs. 65.2; p.001), comprised fewer females (60.1% vs. 67.7%; p=.09), and had a higher proportion of smokers (23.3% vs. 8.9%; p.001). The SPORT cohort had more patients receiving compensation (14.6% vs. 7.7%; p.001). The CSORN cohort consisted of patients with slightly greater baseline disability (Oswestry disability index scores: 47.7 vs. 44.0; p=.008) and had more patients with symptom duration of greater than 6 months (93.7% vs. 62.1%; p.001). The CSORN cohort showed greater satisfaction with surgical results at 3 months (91.1% vs. 66.1% somewhat or very satisfied; p.01) and 1 year (88.2% vs. 71.0%, p.01). Improvements in back and leg pain were similar comparing the two cohorts. On multivariate analysis, duration of symptoms, treatment group (CSORN vs. SPORT) or insurance type (public/Medicare/Medicaid vs. Private/Employer) predicted higher level of postoperative satisfaction. Baseline depression was also associated with worse Oswestry disability index at 1-year postoperative follow-up in both cohorts.Surgical DS patients treated in Canada (CSORN cohort) reported higher levels of satisfaction than those treated in the United States (SPORT cohort) despite similar to slightly worse baseline HRQOL measures. Symptom duration and insurance type appeared to impact satisfaction levels. Improvements in other patient-reported health-related quality of life measures were similar between the cohorts.

Background: The multicenter, international, randomized, blinded, sham-controlled RADIANCE-HTN SOLO trial (A Study of the ReCor Medical Paradise System in Clinical Hypertension) demonstrated a 6.3 mm Hg greater reduction in daytime ambulatory systolic blood pressure (BP) at 2 months by endovascular ultrasound renal denervation (RDN) compared with a sham procedure among patients not treated with antihypertensive medications. We report 6-month results after the addition of a recommended standardized stepped-care antihypertensive treatment to the randomized endovascular procedure under continued blinding to initial treatment. Methods: Patients with a daytime ambulatory BP ≥135/85 mm Hg and Results: A total of 69/74 RDN patients and 71/72 sham patients completed the 6-month ambulatory BP measurement. At 6 months, 65.2% of patients in the RDN group were treated with the standardized stepped-care antihypertensive treatment versus 84.5% in the sham group ( P =0.008), and the average number of antihypertensive medications and defined daily dose were less in the RDN group than in the sham group (0.9±0.9 versus 1.3±0.9, P =0.010 and 1.4±1.5 versus 2.0±1.8, P =0.018; respectively). Despite less intensive standardized stepped-care antihypertensive treatment, RDN reduced daytime ambulatory systolic BP to a greater extent than sham (−18.1±12.2 versus −15.6±13.2 mm Hg, respectively; difference adjusted for baseline BP and number of medications: −4.3 mm Hg, 95% confidence interval, −7.9 to −0.6, P =0.024). There were no major adverse events in either group through 6 months. Conclusions: The BP-lowering effect of endovascular ultrasound RDN was maintained at 6 months with less prescribed antihypertensive medications compared with a sham control. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02649426.

Background Traumatic atlanto-axial rotatory subluxation (AARS) in an adult is a rare condition, which if left untreated can be fatal. In addition to this, many symptoms experienced such as neck pain and stiffness are non-specific which often leads to misdiagnosis, thus delaying definitive treatment. AARS can be divided into traumatic and non-traumatic causes with the latter generally encompassing congenital cervical spine abnormalities. Case presentation We present a case of a 66-year-old female with traumatic rotatory AARS, which was initially misdiagnosed in the emergency department. This patient was subsequently recalled to the hospital when the misdiagnosis was spotted the following day from imaging results. The patient was initially managed conservatively as an inpatient using head halter cervical traction which proved to give good clinical reduction allowing discharge with Miami J upon ambulation. Upon follow up the patient was experiencing continuous pain but remained neurovascularly intact. She thus opted for definitive management with C1-C2 stabilization with an open reduction and internal fixation. Conclusion This case demonstrates the importance of having a high index of suspicion to diagnose AARS in cervical spine trauma presenting to the emergency department, until exclusion can be made using imaging and clinical examination.

Clinical studies indicate that psychosocial stress contributes to adverse chronic pain outcomes in patients, but it is unclear how this is initiated or amplified by stress. Repeated social defeat (RSD) is a mouse model of psychosocial stress that activates microglia, increases neuroinflammatory signaling, and augments pain and anxiety-like behaviors. We hypothesized that activated microglia within the spinal cord facilitate increased pain sensitivity following RSD. Here we show that mechanical allodynia in male mice was increased with exposure to RSD. This stress-induced behavior corresponded with increased mRNA expression of several inflammatory genes, including IL-1β, TNF-α, CCL2, and TLR4 in the lumbar spinal cord. While there were several adhesion and chemokine-related genes increased in the lumbar spinal cord after RSD, there was no accumulation of monocytes or neutrophils. Notably, there was evidence of microglial activation selectively within the nociceptive neurocircuitry of the dorsal horn of the lumbar cord. Elimination of microglia using the colony stimulating factor 1 receptor antagonist PLX5622 from the brain and spinal cord prevented the development of mechanical allodynia in RSD-exposed mice. Microglial elimination also attenuated RSD-induced IL-1β, CCR2, and TLR4 mRNA expression in the lumbar spinal cord. Together, RSD-induced allodynia was associated with microglia-mediated inflammation within the dorsal horn of the lumbar spinal cord.SIGNIFICANCE STATEMENTMounting evidence indicates that psychological stress contributes to the onset and progression of adverse nociceptive conditions. We show here that repeated social defeat stress causes increased pain sensitivity due to inflammatory signaling within the nociceptive circuits of the spinal cord. Studies here mechanistically tested the role of microglia in the development of pain by stress. Pharmacological ablation of microglia prevented stress-induced pain sensitivity. These findings demonstrate that microglia are critical mediators in the induction of pain conditions by stress. Moreover, these studies provide a proof of principle that microglia can be targeted as a therapeutic strategy to mitigate adverse pain conditions.

Monitoring ichthyoplankton is useful for identifying reproductive fronts and spawning locations of bigheaded carps (Hypophthalmichthys spp.). Unfortunately, sorting and identifying ichthyoplankton to monitor for bigheaded carp reproduction is time consuming and expensive. Traditional methods require frequent egg-larvae sampling, sorting of all samples to obtain presumptively identified bigheaded carp, and genetic validation of presumptively identified eggs. Quantitative PCR (qPCR) has the potential to streamline this process by identifying samples that likely do or do not contain a target species. Our objective was to develop a genetic screening tool using qPCR with the duplex assays SCTM4/5 and BHTM1/2 to prioritize samples that have a higher likelihood of containing bigheaded carp eggs or larvae. We used tandem ichthyoplankton samples collected for monitoring bigheaded carps in the Upper Mississippi, Illinois, and St. Croix rivers to evaluate the effectiveness of qPCR as a screening tool. Samples with > 10,000 copies of DNA had 100% occurrence of bigheaded carp eggs or larvae in the traditionally sorted samples, whereas samples with

International Ocean Discovery Program (IODP) Expedition 382, Iceberg Alley and Subantarctic Ice and Ocean Dynamics, investigated the long-term climate history of Antarctica, seeking to understand how polar ice sheets responded to changes in insolation and atmospheric CO2 in the past and how ice sheet evolution influenced global sea level and vice versa. Five sites (U1534–U1538) were drilled east of the Drake Passage: two sites at 53.2°S at the northern edge of the Scotia Sea and three sites at 57.4°–59.4°S in the southern Scotia Sea. We recovered continuously deposited late Neogene sediments to reconstruct the past history and variability in Antarctic Ice Sheet (AIS) mass loss and associated changes in oceanic and atmospheric circulation. The sites from the southern Scotia Sea (Sites U1536–U1538) will be used to study the Neogene flux of icebergs through “Iceberg Alley,” the main pathway along which icebergs calved from the margin of the AIS travel as they move equatorward into the warmer waters of the Antarctic Circumpolar Current (ACC). In particular, sediments from this area will allow us to assess the magnitude of iceberg flux during key times of AIS evolution, including the middle Miocene glacial intensification of the East Antarctic Ice Sheet, the mid-Pliocene warm period, the late Pliocene glacial expansion of the West Antarctic Ice Sheet, the mid-Pleistocene transition (MPT), and the “warm interglacials” and glacial terminations of the last 800 ky. We will use the geochemical provenance of iceberg-rafted detritus and other glacially eroded material to determine regional sources of AIS mass loss. We will also address interhemispheric phasing of ice sheet growth and decay, study the distribution and history of land-based versus marine-based ice sheets around the continent over time, and explore the links between AIS variability and global sea level. By comparing north–south variations across the Scotia Sea between the Pirie Basin (Site U1538) and the Dove Basin (Sites U1536 and U1537), Expedition 382 will also deliver critical information on how climate changes in the Southern Ocean affect ocean circulation through the Drake Passage, meridional overturning in the region, water mass production, ocean–atmosphere CO2 transfer by wind-induced upwelling, sea ice variability, bottom water outflow from the Weddell Sea, Antarctic weathering inputs, and changes in oceanic and atmospheric fronts in the vicinity of the ACC. Comparing changes in dust proxy records between the Scotia Sea and Antarctic ice cores will also provide a detailed reconstruction of changes in the Southern Hemisphere westerlies on millennial and orbital timescales for the last 800 ky. Extending the ocean dust record beyond the last 800 ky will help to evaluate dust-climate couplings since the Pliocene, the potential role of dust in iron fertilization and atmospheric CO2 drawdown during glacials, and whether dust input to Antarctica played a role in the MPT. The principal scientific objective of Subantarctic Front Sites U1534 and U1535 at the northern limit of the Scotia Sea is to reconstruct and understand how intermediate water formation in the southwest Atlantic responds to changes in connectivity between the Atlantic and Pacific basins, the “cold water route.” The Subantarctic Front contourite drift, deposited between 400 and 2000 m water depth on the northern flank of an east–west trending trough off the Chilean continental shelf, is ideally situated to monitor millennial- to orbital-scale variability in the export of Antarctic Intermediate Water beneath the Subantarctic Front. During Expedition 382, we recovered continuously deposited sediments from this drift spanning the late Pleistocene (from ~0.78 Ma to recent) and from the late Pliocene (~3.1–2.6 Ma). These sites are expected to yield a wide array of paleoceanographic records that can be used to interpret past changes in the density structure of the Atlantic sector of the Southern Ocean, track migrations of the Subantarctic Front, and give insights into the role and evolution of the cold water route over significant climate episodes, including the most recent warm interglacials of the late Pleistocene and the intensification of Northern Hemisphere glaciation.

Elevated nutrient inputs challenge the health and functioning of aquatic ecosystems. To improve riverine water quality management, it is necessary to understand the underlying biogeochemical and physical processes, anthropogenic drivers and their interactions at catchment scale. We hypothesize that the spatial heterogeneity of nutrient sources dominantly controls the variability of in‐stream concentration dynamics among catchments. We investigated controls of mean nitrate (NO3−), phosphate (PO43−), and total organic carbon (TOC) concentrations and concentration‐discharge (C‐Q) relationships in 787 German catchments of a newly assembled data base, covering a wide range of physiographic and anthropogenic settings. We linked water quality metrics to catchment characteristics using partial least squares regressions and random forests. We found archetypal C‐Q patterns with enrichment dominating NO3− and TOC, and dilution dominating PO43− export. Both the mean NO3− concentrations and their variance among sites increased with agricultural land use. We argue that subsurface denitrification can buffer high nitrogen inputs and cause a decline in concentration with depth, resulting in chemodynamic, strongly positive C‐Q patterns. Mean PO43− concentrations were related to point sources, though the low predictive power suggests effects of unaccounted in‐stream processes. In contrast, high diffuse agricultural inputs explained observed positive PO43− C‐Q patterns. TOC levels were positively linked to the abundance of riparian wetlands, while hydrological descriptors were important for explaining TOC dynamics. Our study shows a strong modulation of anthropogenic inputs by natural controls for NO3− and PO43− concentrations and dynamics, while for TOC only natural controls dominate observed patterns across Germany., Plain Language Summary: Phosphorus, nitrogen, and organic carbon are key elements of plants and all living organisms. Humans are altering the nutrient cycles especially, to improve agricultural productivity and through domestic and industrial wastewater. Excess nutrients in surface waters have harmed many aquatic ecosystems by causing toxic algal blooms and a loss of biodiversity. Low nutrient concentrations and habitat variability are similarly important to those ecosystems, but human interference with natural drivers is not yet fully understood. To better understand and disentangle natural or human controls, we investigated nutrient concentrations and their variability across German catchments with varying landscapes and anthropogenic conditions. The human impact is clearly visible for mean nitrate concentrations, while the (natural) subsurface properties mainly controlled the variability of riverine nitrate. In the past, phosphate inputs were usually linked to wastewater, yet we found the control of agricultural activities on concentration dynamics to be unexpectedly high. Organic carbon was mainly associated with natural sources related to riparian wetlands where interactions with other nutrients are possible. This understanding of dominant controls is important in order to adapt management strategies to ensure healthy aquatic ecosystems., Key Points: Riverine NO3− dynamics are controlled by vertical concentration heterogeneity, which can result from subsurface denitrification Diffuse P sources exert a strong control on the spatial variability of PO43− export patterns in contrast to point sources Share of riparian wetlands controls the mean TOC concentrations in German catchments, Deutsche Forschungsgemeinschaft (DFG) http://dx.doi.org/10.13039/501100001659, Umweltbundesamt (UBA) http://dx.doi.org/10.13039/501100010809, Bundesministerium für Bildung und Forschung (BMBF) http://dx.doi.org/10.13039/501100002347

SUMMARYAlthough oncogenic NRAS activates MAPK signaling, inhibition of the MAPK pathway is not therapeutically efficacious in NRAS-mutant tumors. Here we report that silencing the ribosomal protein S6 kinase 2 (S6K2), while preserving the activity of S6K1, perturbs lipid metabolism, enhances fatty acid unsaturation, triggers lipid peroxidation and induces cell death selectively in NRAS-mutant melanoma cells that are resistant to MAPK inhibition. S6K2 depletion stimulates SREBP1 activity in an S6K1-dependent manner and relieves suppression of PPARα, triggering apoptosis and ferroptosis. Combining PPARα agonists and polyunsaturated fatty acids phenocopies the effects of S6K2 abrogation, blocking tumor growth. Collectively, our study establishes S6K2 and its effector subnetwork as promising targets for NRAS-mutant melanoma that are resistant to global MAPK pathway inhibitors.

Background There is an increased level of senescent cells and toll-like teceptor-1, -2, -4, and -6 (TLR) expression in degenerating intervertebral discs (IVDs) from back pain patients. However, it is currently not known if the increase in expression of TLRs is related to the senescent cells or if it is a more general increase on all cells. It is also not known if TLR activation in IVD cells will induce cell senescence. Methods Cells from non-degenerate human IVD were obtained from spine donors and cells from degenerate IVDs came from patients undergoing surgery for low back pain. Gene expression of TLR-1,2,4,6, senescence and senescence-associated secretory phenotype (SASP) markers was evaluated by RT-qPCR in isolated cells. Matrix synthesis was verified with safranin-O staining and Dimethyl-Methylene Blue Assay (DMMB) confirmed proteoglycan content. Protein expression of p16INK4a, SASP factors, and TLR-2 was evaluated by immunocytochemistry (ICC) and/or by enzyme-linked immunosorbent assay (ELISA). Results An increase in senescent cells was found following 48-h induction with a TLR-2/6 agonist in cells from both non-degenerate and degenerating human IVDs. Higher levels of SASP factors, TLR-2 gene expression, and protein expression were found following 48-h induction with TLR-2/6 agonist. Treatment with o-vanillin reduced the number of senescent cells, and increased matrix synthesis in IVD cells from back pain patients. Treatment with o-vanillin after induction with TLR-2/6 agonist reduced gene and protein expression of SASP factors and TLR-2. Co-localized staining of p16INK4a and TLR-2 demonstrated that senescent cells have a high TLR-2 expression. Conclusions Taken together our data demonstrate that activation of TLR-2/6 induce senescence and increase TLR-2 and SASP expression in cells from non-degenerate IVDs of organ donors without degeneration and back pain and in cells from degenerating human IVD of patients with disc degeneration and back pain. The senescent cells showed high TLR-2 expression suggesting a link between TLR activation and cell senescence in human IVD cells. The reduction in senescence, SASP, and TLR-2 expression suggest o-vanillin as a potential disease-modifying drug for patients with disc degeneration and back pain.

Emerging ice-sheet modeling suggests once initiated, retreat of the Antarctic Ice Sheet (AIS) can continue for centuries. Unfortunately, the short observational record cannot resolve the tipping points, rate of change, and timescale of responses. Iceberg-rafted debris data from Iceberg Alley identify eight retreat phases after the Last Glacial Maximum that each destabilized the AIS within a decade, contributing to global sea-level rise for centuries to a millennium, which subsequently re-stabilized equally rapidly. This dynamic response of the AIS is supported by (i) a West Antarctic blue ice record of ice-elevation drawdown >600 m during three such retreat events related to globally recognized deglacial meltwater pulses, (ii) step-wise retreat up to 400 km across the Ross Sea shelf, (iii) independent ice sheet modeling, and (iv) tipping point analysis. Our findings are consistent with a growing body of evidence suggesting the recent acceleration of AIS mass loss may mark the beginning of a prolonged period of ice sheet retreat and substantial global sea level rise.

Background The SPYRAL HTN-OFF MED Pivotal trial demonstrated that RDN was efficacious compared to a sham control. The underlying model was an extension of the analysis of covariance (ANCOVA) model, adjusted for baseline blood pressure (BP), and allowed borrowing of information from the previously reported feasibility study using a novel Bayesian method. Fundamental to the estimation of a treatment effect for efficacy are a multitude of statistical modelling assumptions, including the role of outliers, linearity of the association between baseline BP and outcome, and parallelism of the treatment effect difference over the baseline BP range. In this report, we examine the validity of these assumptions to verify the robustness of the treatment effect measured. Methods We examined the requisite modelling assumptions of the ANCOVA model fitted to the SPYRAL HTN-OFF MED Pivotal trial using Bayesian methods. To address outliers, we fit a robust regression model (with heavy tailed errors) to the data with diffuse weakly informative prior distributions on the parameters. To address linearity, we replaced the linear baseline term by a natural spline term with 4 degrees of freedom. To address parallelism, we refit the ANCOVA model with an interaction term for treatment arm and baseline BP. Results ANCOVA models were fitted to the trial data (pooled across the feasibility and pivotal cohorts) using Bayesian methodology with diffuse (non-informative) prior distributions. The modelling assumptions inherent to the ANCOVA models were shown to be broadly satisfied. A robust ANCOVA model yielded a posterior treatment effect of -4.1 mmHg (95% credible interval: -6.3 to -1.9) indicating the influence of outlier values was small. There was moderate evidence of an interaction term effect between baseline BP and treatment, but no evidence of gross violation of linearity in baseline BP. Conclusion The posterior treatment effect estimate is shown to be robust to underlying model assumptions, thus further supporting the evidence of RDN to be an efficacious treatment for resistant hypertension.

International Ocean Discovery Program (IODP) Expedition 382 in the Scotia Sea’s Iceberg Alley recovered among the most continuous and highest resolution stratigraphic records in the Southern Ocean near Antarctica spanning the last 3.3 Myr. Sites drilled in Dove Basin (U1536/U1537) have well-resolved magnetostratigraphy and a strong imprint of orbital forcing in their lithostratigraphy. All magnetic reversals of the last 3.3 Myr are identified, providing a robust age model independent of orbital tuning. During the Pleistocene, alternation of terrigenous versus diatomaceous facies shows power in the eccentricity and obliquity frequencies comparable to the amplitude modulation of benthic δ18O records. This suggests that variations in Dove Basin lithostratigraphy during the Pleistocene reflect a similar history as globally integrated ice volume at these frequencies. However, power in the precession frequencies over the entire ∼3.3 Myr record does not match the amplitude modulation of benthic δ18O records, suggesting Dove Basin contains a unique record at these frequencies. Comparing the position of magnetic reversals relative to local facies changes in Dove Basin and the same magnetic reversals relative to benthic δ18O at North Atlantic IODP Site U1308, we demonstrate Dove Basin facies change at different times than benthic δ18O during intervals between ∼3 and 1 Ma. These differences are consistent with precession phase shifts and suggest climate signals with a Southern Hemisphere summer insolation phase were recorded around Antarctica. If Dove Basin lithology reflects local Antarctic ice volume changes, these signals could represent ice sheet precession-paced variations not captured in benthic δ18O during the 41-kyr world.

The renin-angiotensin-aldosterone system plays a key role in blood pressure (BP) regulation and is the target of several antihypertensive medications. Renal denervation (RDN) is thought to interrupt the sympathetic-mediated neurohormonal pathway as part of its mechanism of action to reduce BP.\ud Objectives\ud The purpose of this study was to evaluate plasma renin activity (PRA) and aldosterone before and after RDN and to assess whether these baseline neuroendocrine markers predict response to RDN.\ud Methods\ud Analyses were conducted in patients with confirmed absence of antihypertensive medication. Aldosterone and PRA levels were compared at baseline and 3 months post-procedure for RDN and sham control groups. Patients in the SPYRAL HTN-OFF MED Pivotal trial were separated into 2 groups, those with baseline PRA ≥0.65 ng/ml/h (n = 110) versus

Orthopedic tumor resection, trauma, or degenerative disease surgeries can result in large bone defects and often require bone grafting. However, standard autologous bone grafting has been associated with donor site morbidity and/or limited quantity. As an alternate, allografts with or without metallic or polyether-etherketone have been used as grafting substitutes. However, these may have drawbacks as well, including stress shielding, pseudarthrosis, disease-transmission, and infection. There is therefore a need for alternative bone substitutes, such as the use of mechanically compliant three-dimensional (3D)-printed scaffolds. Several off-the-shelf materials are available for low-cost fused deposition 3D printing such as polylactic acid (PLA) and polycaprolactone (PCL). We have previously described the feasibility of 3D-printed PLA scaffolds to support cell activity and extracellular matrix deposition. In this study, we investigate two medical-grade filaments consistent with specifications found in American Society for Testing and Materials (ASTM) standard for semi-crystalline polylactide polymers for surgical implants, a pure polymer (100M) and a copolymeric material (7415) for their cytocompatibility and suitability in bone tissue engineering. Moreover, we assessed the impact on osteo-inductive properties with the addition of beta-tricalcium phosphate (β-TCP) minerals and assessed their mechanical properties. 100M and 7415 scaffolds with the additive β-TCP demonstrated superior mesenchymal stem cells (MSCs) differentiation detectedviaincreased alkaline phosphatase activity (6-fold and 1.5-fold, respectively) and mineralized matrix deposition (14-fold and 5-fold, respectively)in vitro. Furthermore, we evaluatedin vivocompatibility, biosafety and bone repair potential in a rat femur window defect model. 100M+β-TCPimplants displayed a positive biosafety profile and showed significantly enhanced new bone formation compared to 100M implants evidenced by μCT (39 versus 25% bone volume/tissue volume ratio) and histological analysis 6 weeks post-implantation. These scaffolds are encouraging composite biomaterials for repairing bone applications with a great potential for clinical translation. Further analyses are required with appropriate evaluation in a larger critical-sized defect animal model with long-term follow-up.

The economic crisis caused by the COVID-19 pandemic has sharply reduced mobility and economic activity, disrupting the lives of people around the globe. This paper presents estimates on the early impact of the crisis on labor markets in 39 countries based on high-frequency phone survey data collected between April and July 2020. Workers in these countries experienced severe labor market disruptions following the COVID-19 outbreak. Based on simple averages across countries, 34 percent of the respondents reported stopping work, 20 percent of wage workers reported lack of payment for work performed, 9 percent reported job changes due to the pandemic, and 62 percent reported income loss in their household. Stopping work was more prevalent in the industrial and service sectors than in agriculture. Measures of work stoppage and income loss in the high-frequency phone survey are generally consistent with gross domestic product growth projections in Latin America and the Caribbean but not in Sub-Saharan Africa. This suggests that the survey data contribute new and important information on economic impacts in low-income countries.

Highlights • Core-log-seismic correlation allows to assign ages to the Scotia Sea seismic record. • Major implications are derived on the relation between regional and global events. • The main stratigraphic events are much younger than previously proposed. • Three major phases for the regional oceanography are observed from late Miocene. • These phases appear to be closely linked to the Antarctic Ice Sheet dynamics. Scotia Sea and the Drake Passage is key towards understanding the development of modern oceanic circulation patterns and their implications for ice sheet growth and decay. The sedimentary record of the southern Scotia Sea basins documents the regional tectonic, oceanographic and climatic evolution since the Eocene. However, a lack of accurate age estimations has prevented the calibration of the reconstructed history. The upper sedimentary record of the Scotia Sea was scientifically drilled for the first time in 2019 during International Ocean Discovery Program (IODP) Expedition 382, recovering sediments down to ∼643 and 676 m below sea floor in the Dove and Pirie basins respectively. Here, we report newly acquired high resolution physical properties data and the first accurate age constraints for the seismic sequences of the upper sedimentary record of the Scotia Sea to the late Miocene. The drilled record contains four basin-wide reflectors – Reflector-c, -b, -a and -a' previously estimated to be ∼12.6 Ma, ∼6.4 Ma, ∼3.8 Ma and ∼2.6 Ma, respectively. By extrapolating our new Scotia Sea age model to previous morpho-structural and seismic-stratigraphic analyses of the wider region we found, however, that the four discontinuities drilled are much younger than previously thought. Reflector-c actually formed before 8.4 Ma, Reflector-b at ∼4.5/3.7 Ma, Reflector-a at ∼1.7 Ma, and Reflector-a' at ∼0.4 Ma. Our updated age model of these discontinuities has major implications for their correlation with regional tectonic, oceanographic and cryospheric events. According to our results, the outflow of Antarctic Bottom Water to northern latitudes controlled the Antarctic Circumpolar Current flow from late Miocene. Subsequent variability of the Antarctic ice sheets has influenced the oceanic circulation pattern linked to major global climatic changes during early Pliocene, Mid-Pleistocene and the Marine Isotope Stage 11.

Purpose Available data of event-based clinical outcomes trials show that little evidence supports the guidelines recommendations to lower blood pressure (BP) to

Defining effective measures to reduce nitrate pollution in heterogeneous mesoscale catchments remains challenging when based on concentration measurements at the outlet only. One reason for this is our limited understanding of the subcatchment contributions to nitrate export and their importance at different time scales. While upstream subcatchments often disproportionally contribute to runoff generation and in turn to nutrient export, agricultural areas (which are typically found in downstream lowlands) are known to be a major source of nitrate pollution. To examine the interplay of different subcatchments, we analyzed seasonal long‐term trends and event dynamics of nitrate concentrations, loads, and the concentration–discharge relationship in three nested catchments within the Selke catchment (456 km2), Germany. The upstream subcatchments (40.4% of total catchment area, 34.5% of N input) had short transit times and dynamic concentration–discharge relationships with elevated nitrate concentrations during wet seasons and events. Consequently, the upstream subcatchments dominated nitrate export during high flow and disproportionally contributed to overall annual nitrate loads at the outlet (64.2%). The downstream subcatchment was characterized by higher N input, longer transit times, and relatively constant nitrate concentrations between seasons, dominating nitrate export during low‐flow periods. Neglecting the disproportional role of upstream subcatchments for temporally elevated nitrate concentrations and net annual loads can lead to an overestimation of the role of agricultural lowlands. Nonetheless, constantly high concentrations from nitrate legacies pose a long‐term threat to water quality in agricultural lowlands. This knowledge is crucial for an effective and site‐specific water quality management., Plain Language Summary: To efficiently remove nitrate pollution, we need to understand how it is transported, mobilized, and stored within large and heterogeneous catchments. Previous studies have shown that upstream catchments often have a disproportional impact on nutrient export, while agriculture (a major nitrate source) is often located in downstream lowlands. To understand which parts of a catchment contribute most to nitrate export and when, we analyzed long‐term (1983–2016) and high‐frequency (2010–2016) data in the Selke catchment (Germany) at three locations. The mountainous upstream part dominated nitrate transport during winter, spring, and rain events. It had a surprisingly high contribution to annual nitrate loads. The agricultural downstream part of the catchment dominated nitrate export during summer and autumn, with relatively constant concentrations between seasons. Here, nitrogen inputs needed more than a decade to travel through the subsurface of the catchment, which causes a time lag between measures to reduce nitrate pollution and their measurable effect. The resulting storage of nitrate in the groundwater threatens drinking water quality for decades to come. While the role of agricultural lowlands for nitrate export can be overestimated if neglecting the disproportional role of upstream subcatchments, their impact poses a long‐term threat to water quality., Key Points: Analyzing the CQ relationship across time scales allows the disentanglement of the impact of catchment heterogeneity on nitrate export. Mountainous upstream subcatchments can dominate nitrate export during high flows and disproportionally contribute to nitrate loads. Agricultural downstream subcatchments can dominate nitrate export during low flow and pose a long‐term threat to water quality., DFG collaborative research center (SFB) 1253 “CAMPOS”, Helmholtz Research Program, Integrated Project “Water and Matter Flux Dynamics in Catchments”, Initiative and Networking Fund of the Helmholtz Association through the project Advanced Earth System Modelling Capacity (ESM)

Background Arterial hypertension is a common and life-threatening condition and poses a large global health burden. Device-based treatments have been developed as adjunctive or alternative therapy, to be used with or without antihypertensive medication for treating uncontrolled hypertension. The safety and feasibility of chemical renal denervation (RDN) using the Peregrine Catheter and alcohol were demonstrated in a first-in-man and open-label clinical trials, prompting the initiation of the ongoing TARGET BP OFF-MED and TARGET BP I trials. Design The TARGET BP trials are randomized, blinded, sham-controlled trials designed to assess the safety and efficacy of alcohol-mediated RDN for the treatment of uncontrolled hypertension in the absence of antihypertensive medications (TARGET BP OFF-MED) or in addition to prescribed antihypertensive medications (TARGET BP I). Subjects with confirmed uncontrolled hypertension and suitable renal artery anatomy are randomized (1:1) to receive either RDN using the Peregrine Kit with alcohol (0.6 mL per renal artery) infused through the Peregrine Catheter or diagnostic renal angiography only (sham procedure). TARGET BP OFF-MED completed enrollment and randomized 96 subjects. TARGET BP I will randomize approximately 300 subjects and will transition to an open-label safety cohort of approximately 300 subjects receiving RDN once the primary efficacy endpoint of the Randomized Controlled Trial (RCT) cohort has been met. Primary endpoints are change in mean 24-hour ambulatory systolic blood pressure from baseline to 8 weeks (TARGET BP OFF-MED) and 3 months (TARGET BP I) post-procedure. Conclusion The TARGET BP trials are the first large-scale, international, randomized trials aimed to investigate the safety and BP lowering efficacy of a novel RDN method, with perivascular alcohol delivery using the Peregrine Kit.

Summary The Cretaceous reservoir of the KMZ field consists of brecciated, carbonate rocks characterized by the presence of a complex system of natural fractures and solution vugs. As this high-permeability system plays a major role on the fluid circulation in the field, it is crucial to build-up a 3D model in order to quantify its dynamic impact. To do this, we applied the methodology for the analysis of fractured reservoir FracaFlowTM developed by the IFPEN/Beicip-Franlab group, integrating BHI data, structural information (3D seismic) and dynamic data. Both diffuse and fault-related fractures were recognized in the field, whereas vugs largely affect mainly the brecciated layers of the reservoir. The innovation of the present study is the modeling of the vugs, with the software FracaFlowTM, as independent objects overprinting the matrix properties and distributed independently from fractures. This allows to take into account and calibrate separately the permeability of the vugs and fractures.

The SWATH-D experiment involved the deployment of a dense temporary broadband seismic network in the Eastern Alps. Its primary purpose was enhanced seismic imaging of the crust and crust–mantle transition, as well as improved constraints on local event locations and focal mechanisms in a complex part of the Alpine orogen. The study region is a key area of the Alps, where European crust in the north is juxtaposed and partially interwoven with Adriatic crust in the south, and a significant jump in the Moho depth was observed by the 2002 TRANSALP north–south profile. Here, a flip in subduction polarity has been suggested to occur. This dense network encompasses 163 stations and complements the larger-scale sparser AlpArray seismic network. The nominal station spacing in SWATH-D is 15 km in a high alpine, yet densely populated and industrialized region. We present here the challenges resulting from operating a large broadband network under these conditions and summarize how we addressed them, including the way we planned, deployed, maintained, and operated the stations in the field. Finally, we present some recommendations based on our experiences.

Renal denervation (RDN) is effective in lowering blood pressure (BP) in patients with hypertension. The issue remains how to best identify potential responders. Ambulatory BP monitoring may be useful. Baseline nighttime systolic BP (SBP) ≥136 mm Hg and its variability (SD) ≥12 mm Hg in DENER-HTN trial or 24-hour heart rate ≥73.5 bpm in SPYRAL HTN-OFF MED Trial were shown to predict the BP response to RDN. We applied these criteria to the patients with hypertension in the sham-controlled RADIANCE-HTN SOLO trial to predict the BP response to ultrasound RDN at 2 months while patients were maintained off medications. BP responders were defined as: clinical with 24-hour SBP 90% irrespective of definition) but low sensitivity (from 9.1% to 30% depending on the definition) to predict responders; the heart rate criterion had insufficient predictive value. This analysis suggests the potential role of nighttime SBP and its variability to predict BP response to RDN in patients with hypertension. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02649426.

Objectives This study reports the 12-month results of the RADIANCE-HTN (A Study of the ReCor Medical Paradise System in Clinical Hypertension) SOLO trial following unblinding of patients at 6 months. Background The blood pressure (BP)–lowering efficacy and safety of endovascular ultrasound renal denervation (RDN) in the absence (2 months) and presence (6 months) of antihypertensive medications were previously reported. Methods Patients with daytime ambulatory BP ≥135/85 mm Hg after 4 weeks off medication were randomized to RDN (n = 74) or sham (n = 72) and maintained off medication for 2 months. A standardized medication escalation protocol was instituted between 2 and 5 months (blinded phase). Between 6 and 12 months (unblinded phase), patients received antihypertensive medications at physicians’ discretion. Outcomes at 12 months included medication burden, change in daytime ambulatory systolic BP (dASBP) and office or home systolic BP (SBP), visit-to-visit variability in SBP, and safety. Results Sixty-five of 74 RDN patients and 67 of 72 sham patients had 12-month dASBP measurements. The proportion of patients on ≥2 medications (27.7% vs. 44.8%; p = 0.041), the number of medications (1.0 vs. 1.4; p = 0.015), and defined daily dose (1.4 vs. 2.2; p = 0.007) were less with RDN versus sham. The decrease in dASBP from baseline in the RDN group (−16.5 ± 12.9 mm Hg) remained stable at 12 months. The RDN versus sham adjusted difference at 12 months was −2.3 mm Hg (95% confidence interval [CI]: −5.9 to 1.3 mm Hg; p = 0.201) for dASBP, −6.3 mm Hg (95% CI: −11.1 to −1.5 mm Hg; p = 0.010) for office SBP, and −3.4 mm Hg (95% CI: −6.9 to 0.1 mm Hg; p = 0.062) for home SBP. Visit-to-visit variability in SBP was smaller in the RDN group. No renal artery injury was detected on computed tomographic or magnetic resonance angiography. Conclusions Despite unblinding, the BP-lowering effect of RDN was maintained at 12 months with fewer prescribed medications compared with sham.

OBJECTIVE Previous works investigating rates of adverse events (AEs) in spine surgery have been retrospective, with data collection from administrative databases, and often from single centers. To date, there have been no prospective reports capturing AEs in spine surgery on a national level, with comparison among centers. METHODS The Spine Adverse Events Severity system was used to define the incidence and severity of AEs after spine surgery by using data from the Canadian Spine Outcomes and Research Network (CSORN) prospective registry. Patient data were collected prospectively and during hospital admission for those undergoing elective spine surgery for degenerative conditions. The Spine Adverse Events Severity system defined minor and major AEs as grades 1–2 and 3–6, respectively. RESULTS There were 3533 patients enrolled in this cohort. There were 85 (2.4%) individual patients with at least one major AE and 680 (19.2%) individual patients with at least one minor AE. There were 25 individual patients with 28 major intraoperative AEs and 260 patients with 275 minor intraoperative AEs. Postoperatively there were 61 patients with a total of 80 major AEs. Of the 487 patients with minor AEs postoperatively there were 698 total AEs. The average enrollment was 321 patients (range 47–1237 patients) per site. The rate of major AEs was consistent among sites (mean 2.9% ± 2.4%, range 0%–9.1%). However, the rate of minor AEs varied widely among sites—from 7.9% to 42.5%, with a mean of 18.8% ± 9.7%. The rate of minor AEs varied depending on how they were reported, with surgeon reporting associated with the lowest rates (p < 0.01). CONCLUSIONS The rate of major AEs after lumbar spine surgery is consistent among different sites but the rate of minor AEs appears to vary substantially. The method by which AEs are reported impacts the rate of minor AEs. These data have implications for the detection and reporting of AEs and the design of strategies aimed at mitigating complications.

Emerging ice-sheet modeling suggests once initiated, retreat of the Antarctic Ice Sheet (AIS) can continue for centuries. Unfortunately, the short observational record cannot resolve the tipping points, rate of change, and timescale of responses. Iceberg-rafted debris data from Iceberg Alley identify eight retreat phases after the Last Glacial Maximum that each destabilized the AIS within a decade, contributing to global sea-level rise for centuries to a millennium, which subsequently re-stabilized equally rapidly. This dynamic response of the AIS is supported by (i) a West Antarctic blue ice record of ice-elevation drawdown >600 m during three such retreat events related to globally recognized deglacial meltwater pulses, (ii) step-wise retreat up to 400 km across the Ross Sea shelf, (iii) independent ice sheet modeling, and (iv) tipping point analysis. Our findings are consistent with a growing body of evidence suggesting the recent acceleration of AIS mass loss may mark the beginning of a prolonged period of ice sheet retreat and substantial global sea level rise., It may have taken only a decade to repeatedly destabilize the Antarctic Ice Sheet after the last Ice Age as shown by a new data-model study. The ice sheet lost ice for centuries each time before it abruptly re-stabilized again.

Identifying waterbodies where fish methylmercury concentrations are elevated is critical for development of consumption guidelines. However, mercury concentrations vary among waterbodies and fishes due to a suite of environmental conditions and detection of elevated mercury concentrations is imperfect, resulting in inaccurate consumption guidelines. Occupancy models may be a useful approach for addressing these issues but have not been used for these purposes. Our objectives were to use occupancy modeling to (1) estimate number of samples needed to detect mercury levels surpassing0.30 mg/kg wet weight in fish at a waterbody (2) identify individual fish-level factors associated with detection probability, and (3) identify environmental-level factors linked to elevated mercury levels in fish at a waterbody. Mercury concentrations were estimated from500 largemouth bass Micropterus salmoides and walleye Sander vitreus from 30 waterbodies throughout Iowa, USA to identify individuals with concentrationsor0.30 mg/kg. Probability of detecting mercury concentrations0.30 mg/kg varied between species and increased with fish length; consequently, more samples were needed to detect elevated mercury concentrations in small versus large fish. The probability of a waterbody having fish with elevated mercury levels increased with the percent grassland and declined with percent agriculture in the watershed, providing prioritization metrics for mercury surveillance programs. Our results demonstrate that occupancy models can be a valuable tool for mercury surveillance due to their ability to estimate necessary sample sizes and identify fish sizes and waterbodies with elevated mercury concentrations while accounting for imperfect detection probabilities.

The Antarctic Ice Sheet (AIS) is out of equilibrium with the current anthropogenic‐enhanced climate forcing. Paleoenvironmental records and ice sheet models reveal that the AIS has been tightly coupled to the climate system during the past and indicate the potential for accelerated and sustained Antarctic ice mass loss into the future. Modern observations by contrast suggest that the AIS has only just started to respond to climate change in recent decades. The maximum projected sea level contribution from Antarctica to 2100 has increased significantly since the Intergovernmental Panel on Climate Change (IPCC) 5th Assessment Report, although estimates continue to evolve with new observational and theoretical advances. This review brings together recent literature highlighting the progress made on the known processes and feedbacks that influence the stability of the AIS. Reducing the uncertainty in the magnitude and timing of the future sea level response to AIS change requires a multidisciplinary approach that integrates knowledge of the interactions between the ice sheet, solid Earth, atmosphere, and ocean systems and across time scales of days to millennia. We start by reviewing the processes affecting AIS mass change, from atmospheric and oceanic processes acting on short time scales (days to decades), through to ice processes acting on intermediate time scales (decades to centuries) and the response to solid Earth interactions over longer time scales (decades to millennia). We then review the evidence of AIS changes from the Pliocene to the present and consider the projections of global sea level rise and their consequences. We highlight priority research areas required to improve our understanding of the processes and feedbacks governing AIS change.