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Objective: The win ratio is a statistical methodology to evaluate clinical trial outcomes using multiple hierarchical endpoints. We applied the win ratio to patients in SPYRAL HTN-ON MED pilot study to quantify potential differences in renal denervation (RDN) efficacy utilizing different blood pressure (BP) reduction thresholds. Methods: In the SPYRAL HTN-ON MED pilot study, patients were enrolled with office systolic BP (OSBP) ≥150 mmHg and Results: The calculated win ratio favored RDN: 2.78 (95% CI: 1.58, 5.48, p Conclusions: Win ratio methodology applied to the SPYRAL HTN-ON MED pilot study demonstrated that RDN was associated with a 2.6-2.8 times greater likelihood of BP or drug reduction compared with sham patients when evaluated across different BP reduction thresholds at 6 months.

Study Design: International multicenter prospective observational cohort study on patients undergoing radiation +/− surgical intervention for the treatment of symptomatic spinal metastases. Objectives: To investigate the association between the total Spinal Instability Neoplastic Score (SINS), individual SINS components and PROs. Methods: Data regarding patient demographics, diagnostics, treatment, and PROs (SF-36, SOSGOQ, EQ-5D) was collected at baseline, 6 weeks, and 12 weeks post-treatment. The SINS was assessed using routine diagnostic imaging. The association between SINS, PRO at baseline and change in PROs was examined with the Spearmans rank test. Results: A total of 307 patients, including 174 patients who underwent surgery+/− radiotherapy and 133 patients who underwent radiotherapy were eligible for analyses. In the surgery+/− radiotherapy group, 18 (10.3%) patients with SINS score between 0-6, 118 (67.8%) with a SINS between 7-12 and 38 (21.8%) with a SINS between 13-18, as compared to 55 (41.4%) SINS 0-6, 71(53.4%) SINS 7-12 and 7 (5.2%) SINS 13-18 in the radiotherapy alone group. At baseline, the total SINS and the presence of mechanical pain was significantly associated with the SOSGOQ pain domain (r = −0.519, P < 0.001) and the NRS pain score (r = 0.445, P < 0.001) for all patients. The presence of mechanical pain demonstrated to be moderately associated with a positive change in PROs at 12 weeks post-treatment. Conclusion: Spinal instability, as defined by the SINS, was significantly correlated with PROs at baseline and change in PROs post-treatment. Mechanical pain, as a single SINS component, showed the highest correlations with PROs.

Objective: Patients presenting with neurological deficit secondary to metastatic epidural spinal cord compression (MESCC) are often treated with surgery in combination with high-dose corticosteroids. Despite steroids being commonly used, the evidence regarding the effect of corticosteroids on patient outcomes is limited. The objective of this study was to describe the effect of corticosteroid use on preoperative neurological function in patients with MESCC.Methods: Patients who underwent surgery between August 2013 and February 2017 for the treatment of spinal metastases and received steroids to prevent neurologic deficits were included. Data regarding demographics, diagnosis, treatment, neurological function, adverse events, health-related quality of life, and survival were extracted from an international multicenter prospective cohort.Results: A total of 30 patients treated surgically and receiving steroids at baseline were identified. Patients had a mean age of 58.2 years (standard deviation, 11.2 years) at time of surgery. Preoperatively, 50% of the patients experienced deterioration of neurological function, while in 30% neurological function was stable and 20% improved in neurological function. Lengthier steroid use did not correlate with improved or stabilized neurological function. Postoperative adverse events were observed in 18 patients (60%). Patients that stabilized or improved neurologically after steroid use showed a trend towards improved survival at 3- and 24-month postsurgery.Conclusion: This study described the effect of steroids on preoperative neurological function in patients with MESCC. Stabilization or improvement of preoperative neurological function occurred in 50% of the patients.

The advent of molecularly targeted therapies has revolutionized the treatment of Non-Hodgkin's Lymphoma (NHL), including Chronic Lymphocytic Leukemia (CLL). Venetoclax (VEN, an inhibitor of Bcl-2) and ibrutinib (IBR, an inhibitor of BTK) generated excellent clinical responses in CLL patients singly and even more effectively in combination (Portell et al. Blood, 2019; Tam et al.NEJM, 2018). Despite its efficacy, the majority of VEN or VEN+IBR responses are partial and resistance usually develops. We previously reported that treatment with microenvironmental agonists ex vivo can generate anti-apoptotic resistance to the VEN+IBR combination in CLL cells via NF-kB-dependent upregulation of multiple anti-apoptotic proteins (Mcl-1 and Bcl-xL) (Jayappa et al. Blood Adv, 2017). Here, we report that circulating CLL cells of lymph node origin (CD69positive) exhibit resistance to several BH-domain antagonists (inhibitors of Bcl-2, Mcl-1, and Bcl-xL) when used as single agents. Apoptosis resistance was shown to occur at a pre-mitochondrial level by insufficient activation of Bax/Bak proteins (Fig. 1A-B). Supportive of these findings, ex vivo treatment of primary CLL cells with agonists (sCD40L, TLR9 agonist CpG-ODN, and IL10) known to be expressed in the cancer microenvironment in vivoalso resulted in apoptosis restriction due to defective Bax/Bak activation. Our molecular studies suggest that this resistance is driven by the upregulation of anti-apoptotic proteins, which generates an intracellular environment in which single-drug treatments allow pro-apoptotic proteins (e.g. Bim) to swap between upregulated anti-apoptotic proteins (Mcl-1/Bcl-xL/Bcl-2), leading to defective Bax/Bak activation. Hence, therapies aimed at depleting this reservoir must block multiple anti-apoptotic proteins simultaneously or bypass Bax/Bak-dependent apoptosis. Several cancers, including NHL, have evolved mechanisms to suppress the activity of Protein Phosphatase 2A (PP2A), a serine/threonine phosphatase known to regulate cell survival/proliferation. In our current study involving various cancer cell lines (~250), a small molecule agonist of PP2A (SMAP, TRC-382) showed broad activity across blood cancer cell lines. A further pharmacologically optimized SMAP compound (DT061), also known to be safe in animal models (Tohmé et al. JCI Insight, 2019), was effective even in blood cancer cell lines and agonist treated CLL samples resistant to several BH-domain antagonists (inhibitors on Mcl-1, Bcl-xL, and Bcl-2), suggesting that PP2A activation could overcome pre-mitochondrial apoptosis restriction. DT061 was able to overcome drug resistance in patient-derived CD69positive CLL cells through the induction of Bax/Bak-independent apoptosis (Fig. 1C). Supportive of this finding, DT061 was also able to induce apoptosis in Bax/Bak double knockout CLL cell line (MEC1) (Fig. 1D). To determine the mechanisms underlying SMAP-induced apoptosis, we examined additional pathways capable of triggering apoptosis such as mitochondrial permeability transition pore (MPTP), calcium channels, and VDAC1 using selected small molecule inhibitors. Only inhibitors blocking MPTP (NIM811 or cyclopsorin-A/CspA) significantly impaired the DT061- but not VEN-induced apoptosis in primary CLL cells (Fig. 2A-B). Additionally, our analysis using the CalceinAM/CoCl2 method revealed that DT061 was able to induce MPTP opening in primary CLL cells, which was inhibited in the presence of NIM811 or CspA, suggesting that DT061 induces apoptosis through MPTP activation (Fig. 2C). In summary, we identify, in the circulation of treatment-naïve and treated CLL patients, microenvironmentally-activated leukemic B cells that exhibit apoptosis resistance at the level of Bax/Bak activation. Therapies aimed at depleting this reservoir of drug-resistant leukemic B cells must trigger a process of Bax/Bak independent apoptosis. We demonstrate that PP2A activation using the SMAP (DT061) induces apoptosis in drug resistant CLL cells bypassing the Bax/Bak pathway. The apoptosis induction was dependent on MPTP activation. Collectively, this work highlights the existence of an anti-apoptotic multi-drug resistant pool of CLL cells in patients, and validates a novel pharmaceutically tractable pathway to deplete this reservoir. Disclosures Williams: Janssen: Research Funding; Pharmacyclics: Research Funding; TG Therapuetics: Research Funding; Celgene: Honoraria; Gilead: Honoraria; TG Therapeutics: Honoraria; Abbvie: Honoraria; Kite: Honoraria; Xian Janssen: Honoraria. Portell:Xencor: Research Funding; Roche/Genentech: Consultancy, Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding. Narla:The Icahn School of Medicine at Mount Sinai: Patents & Royalties: nternational Application Numbers: PCT/US15/19770, PCT/US15/19764; and US Patent: US 9,540,358 B2; Mount Sinai: Other: Mount Sinai is actively seeking commercial partners for the further development of the technology. G.N. has a financial interest in the commercialization of the technology.; RAPPTA Therapeutics: Consultancy, Current equity holder in private company.

Key Messages About 1/4th of adults have high blood pressure which is the single most important risk for death (including heart disease and stroke). There are effective policies that could facilitate people making healthy choices to prevent raised blood pressure, and if fully implemented, could largely prevent hypertension from occurring. Hypertension is easy to screen and treat for BUT only about 50% of adults with hypertension are aware of their condition and only about 1 in 7 is adequately treated. Preventing and controlling high blood pressure is the major mechanism for NCD prevention and control and a model for other NCD risks. Effective lifestyle and drug treatments could prevent and control hypertension in most individuals if systematically applied to the population, simple interventions are feasible in all settings, and can be used to enhance primary care. Urgent sustained action is needed is needed for effective public polcies and health system changes to prevent and control hypertension

Publication rate can indirectly assess the quality of research presented in scientific meetings. Considering presentations at orthopedic surgery and neurosurgery meetings, 10.5-66% of abstracts are published in scientific journals. Publication rate of abstracts presented at CSS Meetings is unknown. The objective of this study was to evaluate the publication rate of abstracts presented at the Canadian Spine Society(CSS) Annual Meetings from 2005to2014.In October2018, a systematic PubMed search was performed using title and authors of all abstracts presented at CSS Meetings from 2005 to 2014. The following information was retrieved from the articles and abstracts: year, type of presentation, publication in PubMed, time from presentation to final publication, journal and its impact factor(IF).A total of 621 abstracts were presented at CSS meetings from 2005 to 2014. Publication rate in PubMed was 54.8%(N=340/621). Oral presentations were more likely to be published than poster presentations(63.8%vs44.0%; OR=1.45; CI95%=1.20-1.75; P0.0001). The mean time from presentation to publication was 1.76 years(±1.93). The 340 identified articles were published in 87 different journals. Most common journals were Spine(N=75; 22.1%), The Spine Journal(N=40;11.8%), and Journal of Neurosurgery:Spine(N=28;8.2%). IF ranged from 0.18 to 47.66(mean=3.73±4.68). IF of articles presented orally were higher than those presented as poster(P=0.038).The CSS scientific meeting maintain along the years a steady high quality research presentations as manifested by its significant publication rate(54.8%) in medical journals with mean IF of 3.73. In comparison with other spine scientific meetings, publication rates of abstracts presented at CSS meeting is amongst the highest.

Study Design: Meta-analysis of randomized controlled trials (RCTs). Objectives: The aim was to analyze the efficacy of zoledronic acid (ZA) versus denosumab in the prevention of spinal cord compression in patients with spine metastases from advanced cancers, by evaluating all available RCTs on this subject. Methods: A systematic search of electronic databases (PubMed and MEDLINE) was performed to identify all published RCTs comparing ZA with denosumab in prevention of spinal cord compressions in spine metastases. Risk of bias of the studies was assessed. The primary outcomes evaluated were spinal cord compression. Results: Three RCTs (5274 patients) were included. Denosumab was not significantly superior to ZA in reducing the likelihood of spinal cord compression, when all tumor types were combined (odds ratio [OR] 0.92, 95% confidence interval [CI; 0.66, 1.28], P = .66). Denosumab was not significantly favored over ZA in endodermal origin (breast and prostate; OR 0.72, 95% CI [0.43, 1.19], P = .20) and mesodermal origin tumors (solid tumors and multiple myeloma; OR 1.10, 95% CI [0.72, 1.69], P = .66). Conclusion: Denosumab does not significantly reduce the likelihood of spinal cord compressions in comparison to ZA in patients with spine metastases. When spinal cord compressions were grouped by tumor origin (endodermal or mesodermal), there remained no significant difference between denosumab and ZA. Further long-term studies are needed to determine the effectiveness of these treatment regimens.

Use of amlodipine for treatment of arterial hypertension and stable coronary artery disease (CAD) is sometimes limited by occurrence of peripheral edema and headache. We aimed to explore the true magnitude of this phenomenon by determining the rate and placebo-adjusted rate of these side effects.We performed a meta-analysis by including all randomized, placebo-controlled trials reporting edema and headache with amlodipine in patients with arterial hypertension and CAD. Placebo-adjusted rate (%) was determined as follows: (SE amlodipine % - SE placebo %)/SE amlodipine %.Data from 7226 patients of 22 trials were analyzed. Rate of edema was higher on amlodipine vs. placebo (16.6 vs. 6.2%, risk ratio: 2.9, 95% CI: 2.50-3.36, P 0.0001). The placebo-adjusted rate was 63%, indicating that 37% of edema cases were unrelated to amlodipine. Treatment with low/medium doses (2.5-5 mg) resulted in lower rates of edema (risk ratio: 2.01, 95% CI: 1.41-2.88, P = 0.0001) vs. high dose (10 mg) (risk ratio: 3.08, 95% CI 2.62-3.60, P 0.0001, Pforinteraction = 0.03). Incidence of headache was reduced using amlodipine vs. placebo (7.9 vs. 10.9%, risk ratio: 0.77, 95% CI: 0.65-0.90, P = 0.002) and was driven by use of low/medium doses (risk ratio: 0.52, 95% CI: 0.40-0.69, P 0.00001 vs. risk ratio: 0.92, 95%-CI: 0.74-1.15, P = 0.45, for high doses, Pforinteraction = 0.002).Although risks of peripheral edema are three-fold higher on amlodipine, up to one-third of edema cases on amlodipine might not be induced by amlodipine. Headache is reduced on amlodipine treatment, mainly driven by use of this drug at low/medium doses.

Background Patient satisfaction is infrequently investigated despite its importance in assessing efficacy and patient comprehension. The purpose of this study was to investigate patient satisfaction with treatment outcomes after surgery and/or radiotherapy for spinal metastases and to evaluate how health‐related quality of life (HRQOL) is related to patient satisfaction. Methods Patients with spinal metastases treated with surgery and/or radiotherapy were enrolled in a prospective, international, observational study. Demographic, histologic, treatment, and HRQOL data were collected. HRQOL was evaluated with the Numeric Rating Scale pain score, the 3‐level version of the EuroQol 5‐Dimension (EQ‐5D‐3L) instrument, and the Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ2.0). Patient satisfaction was derived from the SOSGOQ2.0 at 6, 12, and 26 weeks after treatment. Patients were classified as satisfied, neutral, or dissatisfied. Results Twelve weeks after treatment, 183 of the surgically treated patients (84%) were satisfied, and only 11 (5%) were dissatisfied; in contrast, 101 of the patients treated with radiotherapy alone (77%) were satisfied, and only 7 (5%) were dissatisfied. Significant improvements in pain, physical function, mental health, social function, leg function, and EQ‐5D were associated with satisfaction after surgery. Satisfaction after radiotherapy was associated with significant improvements in pain, mental health, and overall SOSGOQ2.0 scores. Dissatisfaction after treatment was associated with lower baseline values for leg strength and lower social functioning scores for surgically treated patients and with lower social functioning scores and being single for patients treated with radiotherapy. Conclusions High levels of satisfaction with treatment outcomes are observed after surgery and/or radiotherapy for spinal metastases. Posttreatment satisfaction is associated with significant improvements in pain and different dimensions of HRQOL., High levels of satisfaction with treatment outcomes are observed after surgery and/or radiotherapy for spinal metastases. Posttreatment satisfaction is associated with significant improvements in pain and different dimensions of health‐related quality of life.

Initial studies of catheter-based renal denervation (RDN) for uncontrolled HTN using radiofrequency ablation in the main renal arteries showed that RDN was effective in lowering office blood pressure (BP). However, the first randomized sham-controlled trial, SYMPLICITY-HTN-3, did not show significantly lower office or 24-h ambulatory systolic BP compared with sham treatment. Subsequent studies in both animals and humans demonstrated the potential importance of more distal and branch renal artery radiofrequency ablation, and a second-generation multielectrode system became available. Two recent randomized sham-controlled trials in patients not taking antihypertensive drugs (SPYRAL HTN-OFF MED) or continuing to take drugs (SPYRAL HTN-ON MED) performed RDN with the second-generation radiofrequency ablation system using an ablation protocol that included treatment of the distal renal artery as well as the branch renal arteries. These studies showed that RDN significantly reduced office and 24-h ambulatory BP compared with sham treatment. Another recent randomized sham-controlled trial in patients not receiving medications showed that RDN with catheter-based ultrasound (RADIANCE-HTN SOLO) applied in just the main renal arteries significantly lowered daytime ambulatory and office BP compared with sham treatment. These trials have renewed clinical and scientific interest in defining the appropriate role of RDN in hypertension treatment. In addition, other important issues will need to be addressed in the future such as the development of tests to determine the extent of RDN at the time of the procedure and the potential of renal nerve fibers to regain their patency at some later stage following the ablation procedure.

Sauger Sander canadensis, Walleye Sander vitreus, and Smallmouth Bass Micropterus dolomieu, are important sportfish in the four main stem Missouri River reservoirs in South Dakota: Lakes Oahe, Sharpe, Francis Case, and Lewis and Clark. However, native Sauger populations, once assumed to be stable, may be in decline. To identify temporal trends and potential interspecific mechanisms affecting Sauger populations, we examined their long-term abundance trends in standard gillnet surveys and angler catch and harvest trends in long-term creel surveys. We also used a robust design occupancy model to examine changes in within-lake distribution of this species. There are concerns regarding the effects of Walleye and Smallmouth Bass on Sauger, so we also described the population trends of these potential competitors. Standard gillnet surveys indicated declining abundance of both Sauger and Walleye in Lakes Oahe and Sharpe. Sauger abundance has trended down in Lewis and Clark, but upward in Francis Case. Conversely, Walleye abundance trends declined in Francis Case and increased in Lewis and Clark. Occupancy (ψ̂) of Sauger declined in all four reservoirs, indicating a contracting distribution throughout the reservoirs. Walleye occupancy remained ∼1.0. Smallmouth Bass occupancy increased in the three reservoirs with sufficient data for analysis, excluding Lewis and Clark Lake. Smallmouth Bass exhibited steady increases in angler catch and harvest, as well as abundance in long-term gillnet surveys, suggesting expanding and increasing populations. Habitat alteration is hypothesized to be a major driver of the Sauger occupancy and abundance declines. However, Walleye and Smallmouth Bass interactions could also be contributing to observed declines of native Sauger.

Piezoceramics are widely‐used in high‐power applications, whereby the material is driven in the vicinity of the resonance frequency with high electric fields. Evaluating material's performance at these conditions requires the consideration of inherent nonlinearity, anisotropy, and differences between individual vibration modes. In this work, the relation between electromechanical properties at large vibration velocity and the utilized vibration mode is investigated for a prototype hard piezoceramic. The nonlinear behavior is determined using a combined three‐stage pulse drive method, which enables the analysis of resonant and antiresonant conditions and the calculation of electromechanical parameters. The deviations of coupling coefficients, compliances, and piezoelectric coefficients at high‐power drive were found to be strongest for the transverse length vibration mode. Differences in the mechanical quality factors were observed only between the planar and transverse length modes, which were rationalized by the different strain distribution profiles and the contribution of different loss tensor components. In addition, the influence of the measurement configuration was investigated and a correction method is proposed. The differences between vibration modes are further confirmed by heat generation measurements under continuous drive, which revealed that the strongest heat generation appears in the radial mode, while transverse and longitudinal length modes show similar temperature increase.

Background Stress is associated with an increased prevalence of anxiety and depression. Repeated social defeat (RSD) stress in mice increases the release of monocytes from the bone marrow that are recruited to the brain by microglia. These monocytes enhance inflammatory signaling and augment anxiety. Moreover, RSD promotes stress sensitization, in which exposure to acute stress 24 days after cessation of RSD causes anxiety recurrence. The purpose of this study was to determine whether microglia were critical to stress sensitization and exhibited increased reactivity to subsequent acute stress or immune challenge. Methods Mice were exposed to RSD, microglia were eliminated by colony-stimulating factor 1 receptor antagonism (PLX5622) and allowed to repopulate, and responses to acute stress or immune challenge (lipopolysaccharide) were determined 24 days after RSD sensitization. Results Microglia maintained a unique messenger RNA signature 24 days after RSD. Moreover, elimination of RSD-sensitized microglia prevented monocyte accumulation in the brain and blocked anxiety recurrence following acute stress (24 days). When microglia were eliminated prior to RSD and repopulated and mice were subjected to acute stress, there was monocyte accumulation in the brain and anxiety in RSD-sensitized mice. These responses were unaffected by microglial elimination/repopulation. This may be related to neuronal sensitization that persisted 24 days after RSD. Following immune challenge, there was robust microglial reactivity in RSD-sensitized mice associated with prolonged sickness behavior. Here, microglial elimination/repopulation prevented the amplified immune reactivity ex vivo and in vivo in RSD-sensitized mice. Conclusions Microglia and neurons remain sensitized weeks after RSD, and only the immune reactivity component of RSD-sensitized microglia was prevented by elimination/repopulation.

Fish recruitment is complex, regulated by environmental factors that induce high mortality early in life. Additionally, age-0 fish can be difficult to sample, making recruitment difficult to detect. We used a robust design occupancy model to evaluate the effects of biotic (age-0 and adult common carp (Cyprinus carpio), bluegill (Lepomis macrochirus), walleye (Sander vitreus), and northern pike (Esox lucius) relative abundance, prey availability, age-0 carp length) and abiotic (water level, temperature) factors on age-0 carp occupancy, detection, and extinction in 13 lakes in South Dakota, USA, for July–April 2008–2010. Age-0 carp occupancy decreased with increasing adult carp abundance and increased with increasing water levels. Age-0 carp detection probability was high during summer (>0.75) but decreased in fall and spring (0.34). Most lakes were occupied in July but overwinter extinction probability was high (59%), resulting in 51% occupancy probability by April. Other environmental factors were not supported, suggesting they had little effect on reproduction and survival. Our results indicate reproduction was universally successful but difficult to detect and that overwinter mortality often resulted in recruitment failure.

Aims Studies have shown a non-linear relationship between systolic blood pressure (SBP) and diastolic blood pressure (DBP) and outcomes, with increased risk observed at both low and high blood pressure (BP) levels. We hypothesized that the BP-risk association is different in individuals with and without diabetes at high cardiovascular risk. Methods and results We identified patients with (N = 11 487) or without diabetes (N = 19 450), from 30 937 patients, from 133 centres in 44 countries with a median follow-up of 56 months in the ONTARGET/TRANSCEND studies. Patients had a prior history of stroke, myocardial infarction (MI), peripheral artery disease, or were high-risk diabetics. Patients in ONTARGET had been randomized to ramipril 10 mg daily, telmisartan 80 mg daily, or the combination of both. Patients in TRANSCEND were ACE intolerant and randomized to telmisartan 80 mg daily or matching placebo. We analysed the association of mean achieved in-trial SBP and DBP with the composite outcome of cardiovascular death, MI, stroke and hospitalization for congestive heart failure (CHF), the components of the composite, and all-cause death. Data were analysed by Cox regression and restricted cubic splines, adjusting for risk markers including treatment allocation and accompanying cardiovascular treatments. In patients with diabetes, event rates were higher across the whole spectrum of SBP and DBP compared with those without diabetes (P Conclusion High on treatment BP levels (≥160 or ≥90 mmHg) are associated with increased risk of cardiovascular outcomes and death. Also low levels ( Clinical trial registration http://clinicaltrials.gov.Unique identifier: NCT00153101.

Complying with the demands of drinking water supply whilst minimizing environmental impact poses a great challenge in water management. This study investigates the potential of withdrawal management of drinking water reservoirs to alleviate the disruption of the river continuum by a reservoir dam with respect to temperature and discharge. The aim is the identification of an optimal withdrawal strategy to provide a near‐natural discharge temperature and flow for the downstream river without jeopardizing drinking water production. First, we identify the applicability of new withdrawal regimes for raw water security and downstream river demands. Second, we search for an ideal withdrawal regime in scenario simulations using a numerical reservoir model (“General Lake Model”). The scenarios on a drinking water reservoir in Germany demonstrate that we are able to derive an optimized reservoir management. The numerical model is provided for operators as a simple and efficient tool for optimizing the withdrawal strategy within reservoir management.

Zoledronate (Zol) is a bone-preserving/ anti-tumoral drug that is widely used for the treatment of many cancers including spinal bone metastases. High systemic Zol doses required to elicit an adequate effect in the spine often lead to significant side effects, limiting its prolonged use and effectiveness. Here, we aim to provide an alternative strategy to locally deliver Zol at the tumor site. We show that nanoporous 3D-printed scaffolds can be loaded with Zol and possess the ability to release Zol (10-28%) over a sustained period. Additionally, we demonstrate that Zol-impregnated scaffolds, mostly Gel Lay, impair the proliferation of the prostate cancer cell line LAPC4 and the prostate-induced bone metastasis cells in vitro. 3D-printed nanoporous polymers offer a novel and versatile opportunity for potential local delivery of drugs in future clinical settings. These polymers can decrease systemic exposure and related side effects of Zol while at the same time concentrating the drug effect at the tumor site thereby inhibiting tumor proliferation. Also, these scaffolds could be co-printed or coupled with other materials to produce custom implants that offer better structural support for bone growth at the tumor site following resection.

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.

Summary Background Endovascular renal denervation reduces blood pressure in patients with mild-to-moderate hypertension, but its efficacy in patients with true resistant hypertension has not been shown. We aimed to assess the efficacy and safety of endovascular ultrasound renal denervation in patients with hypertension resistant to three or more antihypertensive medications. Methods In a randomised, international, multicentre, single-blind, sham-controlled trial done at 28 tertiary centres in the USA and 25 in Europe, we included patients aged 18–75 years with office blood pressure of at least 140/90 mm Hg despite three or more antihypertensive medications including a diuretic. Eligible patients were switched to a once daily, fixed-dose, single-pill combination of a calcium channel blocker, an angiotensin receptor blocker, and a thiazide diuretic. After 4 weeks of standardised therapy, patients with daytime ambulatory blood pressure of at least 135/85 mm Hg were randomly assigned (1:1) by computer (stratified by centres) to ultrasound renal denervation or a sham procedure. Patients and outcome assessors were masked to randomisation. Addition of antihypertensive medications was allowed if specified blood pressure thresholds were exceeded. The primary endpoint was the change in daytime ambulatory systolic blood pressure at 2 months in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov , NCT02649426 . Findings Between March 11, 2016, and March 13, 2020, 989 participants were enrolled and 136 were randomly assigned to renal denervation (n=69) or a sham procedure (n=67). Full adherence to the combination medications at 2 months among patients with urine samples was similar in both groups (42 [82%] of 51 in the renal denervation group vs 47 [82%] of 57 in the sham procedure group; p=0·99). Renal denervation reduced daytime ambulatory systolic blood pressure more than the sham procedure (−8·0 mm Hg [IQR –16·4 to 0·0] vs –3·0 mm Hg [–10·3 to 1·8]; median between-group difference –4·5 mm Hg [95% CI –8·5 to –0·3]; adjusted p=0·022); the median between-group difference was –5·8 mm Hg (95% CI –9·7 to –1·6; adjusted p=0·0051) among patients with complete ambulatory blood pressure data. There were no differences in safety outcomes between the two groups. Interpretation Compared with a sham procedure, ultrasound renal denervation reduced blood pressure at 2 months in patients with hypertension resistant to a standardised triple combination pill. If the blood pressure lowering effect and safety of renal denervation are maintained in the long term, renal denervation might be an alternative to the addition of further antihypertensive medications in patients with resistant hypertension. Funding ReCor Medical.

Background: The aim of this review is to investigate current uses of fibrinogen as a tool to reduce operative and postoperative blood loss in different surgical fields especially orthopedic spine surgery. This is a systematic review. Methods: MEDLINE (via Ovid 1946 to June 1, 2020) and Embase (via Ovid 1947 to June 1, 2020) were searched using the keywords “fibrinogen”, “surgery”, and “spine” for relevant studies. The search strategy used text words and relevant indexing to identify articles discussing the use of fibrinogen to control surgical blood loss. Results: The original literature search yielded 407 articles from which 68 duplications were removed. Three hundred thirty-nine abstracts and titles were screened. Results were separated by surgical specialties. Conclusions: Multiple studies have looked at the role of fibrinogen for acute bleeding in the operative setting. The current evidence regarding the use of fibrinogen concentrate in spine surgery is promising but limited, even though this is a field with the potential for severe hemorrhage. Further trials are required to understand the utility of fibrinogen concentrate as a first-line therapy in spine surgery and to understand the importance of target fibrinogen levels and subsequent dosing and administration to allow recommendations to be made in this field.

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.