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Abstract The investigation of triggers causing the onset and intensification of Northern Hemisphere Glaciation (NHG) during the late Pliocene is essential for understanding the global climate system, with important implications for projecting future climate changes. Despite their critical roles in the global climate system, influences of land-ocean interactions on high-latitude ice sheets remain largely unexplored. Here, we present a high-resolution Asian dust record from Ocean Drilling Program Site 1208 in the North Pacific, which lies along the main route of the westerlies. Our data indicate that atmosphere-land-ocean interactions affected aeolian dust emissions through modulating moisture and vegetation in dust source regions, highlighting a critical role of terrestrial systems in initiating the NHG as early as 3.6 Myr ago. Combined with additional multi-proxy and model results, we further show that westerly wind strength was enhanced, mainly at low-to-middle tropospheric levels, during major glacial events at about 3.3 and 2.7 Myr ago. We suggest that coupled responses of Earth’s surface dynamics and atmospheric circulation in the Plio-Pleistocene likely involved feedbacks related to changes in paleogeography, ocean circulation, and global climate.

Degenerative cervical myelopathy (DCM) is the leading cause of spinal cord dysfunction in adults, representing substantial morbidity and significant financial and resource burdens. Typically, patients with progressive DCM will eventually receive surgical treatment. Nonetheless, despite advancements in pharmacotherapeutics, evidence for pharmacological therapy remains limited. Health professionals from various fields would find interest in pharmacological agents that could benefit patients with mild DCM or enhance surgical outcomes. This review aims to consolidate all clinical and experimental evidence on the pharmacological treatment of DCM. We conducted a comprehensive narrative review that presents all pharmacological agents that have been investigated for DCM treatment in both humans and animal models. Riluzole exhibits effectiveness solely in rat models, but not in treating mild DCM in humans. Cerebrolysin emerges as a potential neuroprotective agent for myelopathy in animals but had contradictory results in clinical trials. Limaprost alfadex demonstrates motor function improvement in animal models and exhibits promising outcomes in a small clinical trial. Glucocorticoids not only fail to provide clinical benefits but may also lead to adverse events. Cilostazol, anti-Fas ligand antibody, and Jingshu Keli display promise in animal studies, while erythropoietin, granulocyte colony-stimulating factor and limaprost alfadex exhibit potential in both animal and human research. Existing evidence mainly rests on weak clinical data and animal experimentation. Current pharmacological efforts target ion channels, stem cell differentiation, inflammatory, vascular, and apoptotic pathways. The inherent nature and pathogenesis of DCM offer substantial prospects for developing neurodegenerative or neuroprotective therapies capable of altering disease progression, potentially delaying surgical intervention, and optimizing outcomes for those undergoing surgical decompression.

Abstract We document an apparent downward displacement of the Matuyama‐Brunhes magnetic reversal by ∼20 m at Scotia Sea International Ocean Discovery Program Site U1538 (Pirie Basin) by comparison with the well‐defined paleomagnetic record at nearby Site U1537 (Dove Basin). Detailed stratigraphic correlation between the two sites is possible due to similar lithologic variations. However, the two sites have distinctly different porewater geochemistry. Notably, Site U1538 indicates a greater demand for electron acceptors to oxidize organic carbon and Fe2+ enrichment below the depth of SO42− depletion. Magnetic parameters indicate enrichment of an authigenic magnetic mineral with strong remanence properties around the depth of SO42− depletion (∼46 m at Site U1538) relative to magnetic parameters at correlative depths at Site U1537. Fe2+ enrichment below the depth of SO42− depletion is not predicted based on the energetically favorable order of electron acceptors for microbial respiration but is documented here and in other depositional settings. This indicates Fe2+ production exceeds the production of H2S by SO42− reduction, providing a geochemical environment that favors the production and preservation of ferrimagnetic remanence‐bearing iron sulfides over paramagnetic pyrite and, thus, a mechanism for deep chemical remanent magnetization acquisition at depths of tens of meters. The influence of authigenic ferrimagnetic iron sulfides on paleomagnetic signals can be difficult to demonstrate with magnetic properties alone; therefore, this finding has implications for evaluating the fidelity of magnetostratigraphic records with complementary geochemical data. Such situations should be considered in other depositional environments with similar porewater Fe2+ accumulation below the SO42− reduction depth.

Abstract High-resolution ice core records from coastal Antarctica are particularly useful to inform our understanding of environmental changes and their drivers. Here, we present a decadally resolved record of sea-salt sodium (a proxy for open-ocean area) and non-sea salt calcium (a proxy for continental dust) from the well-dated Roosevelt Island Climate Evolution (RICE) core, focusing on the time period between 40–26 ka BP. The RICE dust record exhibits an abrupt shift towards a higher mean dust concentration at 32 ka BP. Investigating existing ice-core records, we find this shift is a prominent feature across Antarctica. We propose that this shift is linked to an equatorward displacement of Southern Hemisphere westerly winds. Subsequent to the wind shift, data suggest a weakening of Southern Ocean upwelling and a decline of atmospheric CO2 to lower glacial values, hence making this shift an important glacial climate event with potentially important insights for future projections.

Background and Objectives: Hyponatraemia increases the morbidity and mortality risks of orthopaedic patients. When undergoing spine surgery, hyponatraemic patients have high risks of pneumonia and of staying in hospital for up to 1 day longer compared with non-hyponatraemic patients. This study aims to assess the occurrence of adverse events among patients with pre-operative hyponatraemia after undergoing lumbar surgery. Materials and Methods: A retrospective cohort study was conducted. Patients who underwent spinal surgery in 2011 to 2013 were identified from the American College of Surgeons National Surgical Quality Improvement Program database. Multivariate analysis was conducted to demonstrate the difference in post-operative complication rates between hyponatraemic patients and normonatraemic patients. Post-operative adverse events, need for blood transfusion and length of stay were considered as clinical outcome data. Results: A total of 58,049 patients were included; pre-operatively, 55,012 (94.8%) were normonatraemic and 3037 (5.2%) were hyponatraemic. Multivariate analysis showed that hyponatraemic patients had higher rates of adverse events, blood transfusions and urinary tract infections. Specifically, 632 (20.8%) hyponatraemic patients developed adverse events, compared with 6821 (12.4%) normonatraemic patients; the hyponatraemic patients received transfusions, compared with 6821 (7.4%) normonatraemic patients; and 97 (3.2%) hyponatraemic patients developed urinary tract infections, compared with 715 (1.3%) normonatraemic patients. Finally, an extended length of stay beyond 6 days occurred in 604 (19.9%) hyponatraemic patients, compared with 4676 (8.5%) normonatraemic patients. Conclusions: Our study identified an association between pre-operative hyponatraemia and post-operative adverse events in spinal surgery patients. However, it is unclear whether hyponatraemia caused the higher adverse event rate.

Abstract The economic repercussions of waiting for lumbar disc surgery have not been well studied. The primary goal of this study was to perform a cost-consequence analysis of patients receiving early vs late surgery for symptomatic disc herniation from a societal perspective. Secondarily, we compared patient factors and patient-reported outcomes. This is a retrospective analysis of prospectively collected data from the CSORN registry. A cost-consequence analysis was performed where direct and indirect costs were compared, and different outcomes were listed separately. Comparisons were made on an observational cohort of patients receiving surgery less than 60 days after consent (short wait) or 60 days or more after consent (long wait). This study included 493 patients with surgery between January 2015 and October 2021 with 272 patients (55.2%) in the short wait group and 221 patients (44.8%) classified as long wait. There was no difference in proportions of patients who returned to work at 3 and 12-months. Time from surgery to return to work was similar between both groups (34.0 vs 34.9 days, p = 0.804). Time from consent to return to work was longer in the longer wait group corresponding to an additional $11,753.10 mean indirect cost per patient. The short wait group showed increased healthcare usage at 3 months with more emergency department visits (52.6% vs 25.0%, p

ObjectivesThis study aimed to examine whether preoperative cervical muscle size, composition, and asymmetry from magnetic resonance imaging (MRI) can predict post-operative outcomes in patients with degenerative cervical myelopathy (DCM).MethodsA total of 171 patients with DCM were included. Relative total cross-sectional area (RCSA), functional CSA (fat-free area, FCSA), ratio of FCSA/CSA (fatty infiltration) and asymmetry of the multifidus (MF) and semispinalis cervicis (SCer) together (MF + SCer), and cervical muscle as a group (MF, SCer, semispinalis capitis, and splenius capitis) were obtained from T2-weighted axial MR images at the mid-disk, at the level of maximum cord compression and the level below. Univariate and multivariate linear regression analyses were used to assess the relationship between baseline cervical muscle measurements of interest with the modified Japanese Orthopedic Association (mJOA), Nurick Classification, Neck Disability Index (NDI), and SF-36 health survey at 6-month and 12-month post-surgery.ResultsLower RCSA of MF + SCer, less CSA MF + SCer asymmetry and greater FCSA/CSA for the cervical muscle group (e.g., less fatty infiltration), and younger age were significant predictors of higher mJOA scores (e.g., less disability) at 6-month and 12-month post-surgery (all p

Sedimentary ancient DNA can indicate ecosystem-wide changes. Here, the authors show association between warm phases and high diatom abundance in the Antarctic Scotia Sea, in addition to presenting ancient eukaryote sedimentary DNA spanning the last approximately 1 million years.

Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here, we demonstrated that multidrug-resistant CLL cells in vivo exhibited apoptosis restriction at a pre-mitochondrial level due to insufficient activation of the Bax and Bak (Bax/Bak) proteins. Co-immunoprecipitation analyses with selective BH domain antagonists revealed that the pleiotropic proapoptotic protein (Bim) was prevented from activating Bax/Bak by “switching” interactions to other upregulated antiapoptotic proteins (Mcl-1, Bcl-xL, Bcl-2). Hence, treatments that bypass Bax/Bak restriction are required to deplete these resistant cells in patients. Protein phosphatase 2A (PP2A) contributes to oncogenesis and treatment resistance. We observed that small-molecule activator of PP2A (SMAP) induced cytotoxicity in multiple cancer cell lines and CLL samples, including multidrug-resistant leukemia and lymphoma cells. The SMAP (DT-061) activated apoptosis in multidrug-resistant CLL cells through induction of mitochondrial permeability transition pores, independent of Bax/Bak. DT-061 inhibited the growth of wild-type and Bax/Bak double-knockout, multidrug-resistant CLL cells in a xenograft mouse model. Collectively, we discovered multidrug-resistant CLL cells in patients and validated a pharmacologically tractable pathway to deplete this reservoir.

Limitations of bone defect reconstruction include poor bone healing and osteointegration with acrylic cements, lack of strength with bone putty/paste, and poor osteointegration. Tissue engineering aims to bridge these gaps through the use of bioactive implants. However, there is often a risk of infection and biofilm formation associated with orthopedic implants, which may develop anti-microbial resistance. To promote bone repair while also locally delivering therapeutics, 3D-printed implants serve as a suitable alternative. Soft, nanoporous 3D-printed filaments made from a thermoplastic polyurethane and polyvinyl alcohol blend, LAY-FOMM and LAY-FELT, have shown promise for drug delivery and orthopedic applications. Here, we compare 3D printability and sustained antibiotic release kinetics from two types of commercial 3D-printed porous filaments suitable for bone tissue engineering applications. We found that both LAY-FOMM and LAY-FELT could be consistently printed into scaffolds for drug delivery. Further, the materials could sustainably release Tetracycline over 3 days, independent of material type and infill geometry. The drug-loaded materials did not show any cytotoxicity when cultured with primary human fibroblasts. We conclude that both LAY-FOMM and LAY-FELT 3D-printed scaffolds are suitable devices for local antibiotic delivery applications, and they may have potential applications to prophylactically reduce infections in orthopedic reconstruction surgery.

Current materials used to fill bone defects (ceramics, cement) either lack strength or do not induce bone repair. The use of biodegradable polymers such as PLA may promote patient healing by stimulating the production of new bone in parallel with a controlled degradation of the scaffold. This project aims to determine the design parameters maximising scaffold mechanical performance in such materials. Starting from a base cylindrical model of 10 mm height and of outer and inner diameters of 10 and 4 mm, respectively, 27 scaffolds were designed. Three design parameters were investigated: pore distribution (crosswise, lengthwise, and eccentric), pore shape (triangular, circular, and square), and pore size (surface area of 0.25 mm2, 0.5625 mm2, and 1 mm2). Using the finite element approach, a compressive displacement (0.05 mm/s up to 15% strain) was simulated on the models and the resulting scaffold stiffnesses (N/mm2) were compared. The models presenting good mechanical behaviors were further printed along two orientations: 0° (cylinder sitting on its base) and 90° (cylinder laying on its side). A total of n = 5 specimens were printed with PLA for each of the retained models and experimentally tested using a mechanical testing machine with the same compression parameters. Rigidity and yield strength were evaluated from the experimental curves. Both numerically and experimentally, the highest rigidity was found in the model with circular pore shape, crosswise pore distribution, small pore size (surface area of 0.25 mm2), and a 90° printing orientation. Its average rigidity reached 961 ± 32 MPa from the mechanical testing and 797 MPa from the simulation, with a yield strength of 42 ± 1.5 MPa. The same model with a printing orientation of 0° resulted in an average rigidity of 515 ± 7 MPa with a yield strength of 32 ± 1.6 MPa. Printing orientation and pore size were found to be the most influential design parameters on rigidity. The developed design methodology should accelerate the identification of effective scaffolds for future in vitro and in vivo studies.

Background: While considered the mainstay of treatment for specific bone metastases, ZA is used predominantly to treat osteolytic lesions. The purpose of this network meta-analysis is to compare ZA to other treatment options in its ability to improve specific clinical outcomes in patients with bone metastases secondary to any primary tumor. Methods: PubMed, Embase and Web of Science were systematically searched from inception to May 5th, 2022. Keywords used were solid tumor, lung neoplasm, kidney neoplasm, breast neoplasm, prostate neoplasm, ZA and bone metastasis. Every randomized controlled trial and non-randomized quasi-experimental study of systemic ZA administration for patients with bone metastases and any comparator were included. A Bayesian network meta-analysis was done on the primary outcomes including number of SREs, time to developing a first on-study SRE, overall survival, and disease progression-free survival. Secondary outcome was pain at 3, 6 and 12 months after treatment. Results: Our search yielded 3861 titles with 27 meeting inclusion criteria. For the number of SRE, ZA in combination with chemotherapy or hormone therapy was statistically superior to placebo (OR 0.079; 95 % CrI: 0.022–0.27). For the time to the first on study SRE, the relative effectiveness of ZA 4 mg was statistically superior to placebo (HR 0.58; 95 % CrI:0.48–0.77). At 3 and 6 months, ZA 4 mg was significantly superior to placebo for reducing pain with a SMD of −0.85 (95 % CrI:-1.6, −0.0025) and −2.6 (95 % CrI:-4.7, −0.52) respectively. Conclusions: This systematic review shows the benefits of ZA in decreasing the incidence of SREs, increasing the time to the first on-study SRE, and reducing the pain level at 3 and 6 months.

A new high-resolution record for the Antarctic Zone shows persistent anti-phasing of high interglacial ocean productivity and high glacial dust deposition, suggesting a close inter-hemispheric coupling of cryosphere, ocean and atmosphere.

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.

Abstract Background Guidelines recommend physical activity to reduce cardiovascular (CV) events. The association between physical activity and progression of chronic kidney disease (CKD) with and without diabetes is unknown. We assessed the association of self-reported physical activity with renal and CV outcomes in high-risk patients aged ≥ 55 years over a median follow-up of 56 months in post-hoc analysis of a previously randomized trial program. Methods Analyses were done with Cox regression analysis, mixed models for repeated measures, ANOVA and χ2-test. 31,312 patients, among them 19,664 with and 11,648 without diabetes were analyzed. Results Physical activity was inversely associated with renal outcomes (doubling of creatinine, end-stage kidney disease (ESRD)) and CV outcomes (CV death, myocardial infarction, stroke, heart failure hospitalization). Moderate activity (at least 2 times/week to every day) was associated with lower risk of renal outcomes and lower incidence of new albuminuria (p

The collection of fish eggs is a commonly used technique for monitoring invasive carp. Genetic identification is the most trusted method for identifying fish eggs but is expensive and slow. Recent work suggests random forest models could provide an inexpensive method for identifying invasive carp eggs based on morphometric egg characteristics. While random forests provide accurate predictions, they do not produce a simple formula for obtaining new predictions. Instead, individuals must have knowledge of the R coding language, limiting the individuals who can use the random forests for resource management. We present WhoseEgg: a web-based point-and-click application that allows non-R users to access random forests via a point and click interface to rapidly identify fish eggs with an objective of detecting invasive carp (Bighead, Grass, and Silver Carp) in the Upper Mississippi River basin. This article provides an overview of WhoseEgg, an example application, and future research directions.

Theoretical models indicate that photoevaporative and magnetothermal winds play a crucial role in the evolution and dispersal of protoplanetary disks and affect the formation of planetary systems. However, it is still unclear what wind-driving mechanism is dominant or if both are at work, perhaps at different stages of disk evolution. Recent spatially resolved observations by Fang et al. of the [O i ] 6300 Å spectral line, a common disk wind tracer in TW Hya, revealed that about 80% of the emission is confined to the inner few astronomical units of the disk. In this work, we show that state-of-the-art X-ray-driven photoevaporation models can reproduce the compact emission and the line profile of the [O i ] 6300 Å line. Furthermore, we show that the models also simultaneously reproduce the observed line luminosities and detailed spectral profiles of both the [O i ] 6300 Å and the [Ne ii ] 12.8 μ m lines. While MHD wind models can also reproduce the compact radial emission of the [O i ] 6300 Å line, they fail to match the observed spectral profile of the [O i ] 6300 Å line and underestimate the luminosity of the [Ne ii ] 12.8 μ m line by a factor of 3. We conclude that, while we cannot exclude the presence of an MHD wind component, the bulk of the wind structure of TW Hya is predominantly shaped by a photoevaporative flow.

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.

Abstract Background Exercise is a common approach for the management of patients with chronic non-specific low back pain (LBP). However, there is no clear mechanistic evidence or consensus on what type of exercise is more effective than others. While considerable evidence suggests a link between lumbar muscle health (e.g., atrophy and fatty infiltration) with functional deficits, it is unknown whether exercises targeting the lumbar spine can lead to noticeable improvements in muscle health and functional outcomes. The primary aim of this study is to compare the effect of combined motor control and isolated strengthening lumbar exercises (MC + ILEX) versus a general exercise group (GE) on multifidus muscle morphology (size and composition). Secondary aims include assessing the effect of the interventions on overall paraspinal muscle health, pain and disability, as well as psychological factors as possible effect modifiers. Methods A total of 50 participants with chronic non-specific LBP and moderate to severe disability, aged between 18 and 60, will be recruited from the local orthopaedic clinics and university community. Participants will be randomised (1:1) to either the MC + ILEX or GE group. Participants will undergo 24 individually supervised exercise sessions over a 12-week period. The primary outcome will be multifidus morphology (atrophy) and composition (fatty infiltration). Secondary outcomes will be muscle function (e.g., % thickness change during contraction), morphology, lumbar extension strength, pain intensity and disability. Potential treatment effect modifiers including maladaptive cognitions (fear of movement, catastrophizing), anxiety, depression, physical activity, and sleep quality will also be assessed. All measurements will be obtained at baseline, 6-week and 12-week; self-reported outcomes will also be collected at 24-week. Between-subjects repeated measure analysis of variance will be used to examine the changes in paraspinal muscle morphology over the different time points. Linear mixed models will be used to assess whether baseline scores can modify the response to the exercise therapy treatment. Discussion The results of this study will help clarify which of these two common interventions promote better results in terms of overall paraspinal muscle heath, back pain, disability and psychological factors in adults with chronic LBP. Trial registration NTCT04257253 , registered prospectively on February 5, 2020.

Abstract 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 p16 INK4a , 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 p16 INK4a 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.

Purpose Event-based clinical outcome trials have shown limited evidence to support guidelines recommendations to lower blood pressure (BP) to

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

Cerca de una cuarta parte de los adultos tienen hipertensión, el principal factor de riesgo de muerte (inclusive la causada por cardiopatía y accidente cerebrovascular). Existen políticas eficaces que podrían ayudar a las personas a elegir opciones saludables para prevenir el aumento de la presión arterial; si se las aplicara plenamente, se podría evitar en gran medida el desarrollo de hipertensión. La hipertensión es fácil de detectar y tratar, PERO solo alrededor de 50% de los adultos que presentan dicha afección son conscientes de su situación y solamente 1 de cada 7 de ellos recibe el tratamiento adecuado. La prevención y el control de la hipertensión es el mecanismo principal para prevenir y controlar las enfermedades no transmisibles y un modelo para evitar otros riesgos de presentar dichas enfermedades. La adopción de un modo de vida saludable y el tratamiento farmacológico efectivo podrían prevenir y controlar la hipertensión en la mayoría de las personas si se implementaran de manera sistemática en la población; en todos los entornos es posible aplicar intervenciones sencillas, que pueden usarse para mejorar la atención primaria. Es urgente adoptar medidas sostenidas para introducir cambios eficaces en las políticas públicas y los sistemas de salud pública con miras a prevenir y controlar la hipertensión.

Cerca de ¼ dos adultos têm hipertensão arterial, que é o fator de risco isolado mais importante para morte (incluídas as mortes por cardiopatia e acidente vascular cerebral). Existem políticas eficazes que poderiam facilitar escolhas pessoais saudáveis para evitar a elevação da pressão arterial e, se plenamente implementadas, podem prevenir a ocorrência da hipertensão arterial. É fácil rastrear e tratar a hipertensão, MAS somente cerca de 50% dos adultos hipertensos estão cientes de sua condição, e apenas cerca de 1 em cada 7 é tratado adequadamente. A prevenção e controle da hipertensão é o principal mecanismo de prevenção e controle das doenças não transmissíveis e um modelo para outros riscos de doenças não transmissíveis. Tratamentos eficazes com mudanças de estilo de vida e medicamentos poderiam prevenir e controlar a hipertensão arterial na maioria das pessoas se aplicados sistematicamente à população; as intervenções simples são viáveis em todos os ambientes e podem melhorar a atenção primária. É necessária a ação continuada e urgente a fim de obter mudanças efetivas nas políticas públicas e no sistema de saúde para prevenir e controlar a hipertensão arterial.

Bone is a frequent site of tumor metastasis. The bone–tumor microenvironment is heterogeneous and complex in nature. Such complexity is compounded by relations between metastatic and bone cells influencing their sensitivity/resistance to chemotherapeutics. Standard chemotherapeutics may not show efficacy for every patient, and new therapeutics are slow to emerge, owing to the limitations of existing 2D/3D models. We previously developed a 3D interface model for personalized therapeutic screening, consisting of an electrospun poly lactic acid mesh activated with plasma species and seeded with stromal cells. Tumor cells embedded in an alginate-gelatin hydrogel are overlaid to create a physiologic 3D interface. Here, we applied our 3D model as a migration assay tool to verify the migratory behavior of different patient-derived bone metastasized cells. We assessed the impact of two different chemotherapeutics, Doxorubicin and Cisplatin, on migration of patient cells and their immortalized cell line counterparts. We observed different migratory behaviors and cellular metabolic activities blocked with both Doxorubicin and Cisplatin treatment; however, higher efficiency or lower IC50 was observed with Doxorubicin. Gene expression analysis of MDA-MB231 that migrated through our 3D hybrid model verified epithelial–mesenchymal transition through increased expression of mesenchymal markers involved in the metastasis process. Our findings indicate that we can model tumor migration in vivo, in line with different cell characteristics and it may be a suitable drug screening tool for personalized medicine approaches in metastatic cancer treatment.

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.

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 detected via increased alkaline phosphatase activity (6-fold and 1.5-fold, respectively) and mineralized matrix deposition (14-fold and 5-fold, respectively) in vitro. Furthermore, we evaluated in vivo compatibility, biosafety and bone repair potential in a rat femur window defect model. 100M+β-TCP implants 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.

Abstract 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.

Spheroids are recognized for resembling the important characteristics of natural tumors in cancer research. However, the lack of controllability of the spheroid size, form, and density in conventional spheroid culture methods reduces the reproducibility and precision of bioassay results and the assessment of drug-dose responses in spheroids. Nonetheless, the accurate prediction of cellular responses to drug compounds is crucial for developing new efficient therapeutic agents and optimizing existing therapeutic strategies for personalized medicine. We developed a surface-optimized PDMS microfluidic biochip to produce uniform and homogenous multicellular spheroids in a reproducible manner. This platform is surface optimized with 10% bovine serum albumin (BSA) to provide cell-repellent properties. Therefore, weak cell-surface interactions lead to the promotion of cell self-aggregations and the production of compact and uniform spheroids. We used a lung cancer cell line (A549), a co-culture model of lung cancer cells (A549) with (primary human osteoblasts, and patient-derived spine metastases cells (BML, bone metastasis secondary to lung). We observed that the behavior of cells cultured in three-dimensional (3D) spheroids within this biochip platform more closely reflects in vivo-like cellular responses to a chemotherapeutic drug, Doxorubicin, rather than on 24-well plates (two-dimensional (2D) model). It was also observed that the co-culture and patient-derived spheroids exhibited resistance to anti-cancer drugs more than the mono-culture spheroids. The repeatability of drug test results in this optimized platform is the hallmark of the reproducibility of uniform spheroids on a chip. This surface-optimized biochip can be a reliable platform to generate homogenous and uniform spheroids to study and monitor the tumor microenvironment and for drug screening.

Critical-size bone defects are those that will not heal without intervention and can arise secondary to trauma, infection, and surgical resection of tumors. Treatment options are currently limited to filling the defect with autologous bone, of which there is not always an abundant supply, or ceramic pastes that only allow for limited osteo-inductive and -conductive capacity. In this study we investigate the repair of bone defects using a 3D printed LayFomm scaffold. LayFomm is a polymer blend of polyvinyl alcohol (PVA) and polyurethane (PU). It can be printed using the most common method of 3D printing, fused deposition modeling, before being washed in water-based solutions to remove the PVA. This leaves a more compliant, micro-porous PU elastomer. In vitro analysis of dental pulp stem cells seeded onto macro-porous scaffolds showed their ability to adhere, proliferate and form mineralized matrix on the scaffold in the presence of osteogenic media. Subcutaneous implantation of LayFomm in a rat model showed the formation of a vascularized fibrous capsule, but without a chronic inflammatory response. Implantation into a mandibular defect showed significantly increased mineralized tissue production when compared to a currently approved bone putty. While their mechanical properties are insufficient for use in load-bearing defects, these findings are promising for the use of polyurethane scaffolds in craniofacial bone regeneration.

Abstract We investigate chronology and age uncertainty for the middle to upper Pleistocene lower Bengal Fan using a novel age‐depth modeling approach that factors lithostratigraphic, magnetostratigraphic, biostratigraphic, cyclostratigraphic, and seismic stratigraphic constraints, based on results from the International Ocean Discovery Program Expedition 354 Bengal Fan and analysis of the GeoB97‐020/027 seismic line. The initial chronostratigraphic framework is established using regionally extensive hemipelagic sediment units, and only age‐depth models of fan deposits that respect the superposition of channel‐levee systems between sites are accepted. In doing so, we reconstruct signals of regional sediment accumulation rate and lithogenic sediment input through the perspective of a two‐dimensional ~320 km transect at 8°N that are consistent with more distal and more ambiguous regional records. This chronology allows us to discuss the depositional history of the middle to upper Pleistocene lower Bengal Fan within the context of sea level, climate, and tectonic controls. We hypothesize, based on the timing of accumulation rate changes, that progradation and intensification of the Bengal Fan's channel‐levee system at 8°N was largely driven by increases in sea level amplitude during this time. However, it is also possible this progradation was influenced by changes in Pleistocene climate and increased Himalayan erosion rates, driving greater sediment flux to the fan.

Study DesignThis study was designed as a survey amongst Canadian spine surgeon to determine a scoring system to standardize pedicle screw placement assessment.PurposeThis study aimed to obtain and analyze the opinions of spine surgeons regarding the assessment of pedicle screw accuracy, with the goal of establishing clinical guidelines for interventions for malpositioned pedicle screws.Overview of LiteratureAccurate placement of pedicle screws is challenging, and misalignment can lead to various complications. To date, there is no recognized gold standard for assessing pedicle screw placement accuracy. The literature is lacking studies attempting to standardize pedicle screw placement accuracy assessment.MethodsA survey of the clinical methods and imaging criteria that are used for assessing pedicle screw placement accuracy was designed and sent to orthopedic and neurosurgery spine surgeons from the Canadian Spine Society for their anonymous participation.ResultsThirty-five surgeons completed the questionnaire. The most commonly used modalities for assessing pedicle screw position postoperatively were plain X-rays (97%) and computed tomography (CT, 97%). In both symptomatic and asymptomatic patients, the most and least worrisome breaches were medial and anterior breaches, respectively. The majority of surgeons tended not to re-operate on asymptomatic breaches. More than 60% of surgeons would re-operate on patients with new-onset pain and a ≤4-mm medial or inferior breach in both thoracic and lumbar regions. If a patient experienced sensory loss and a breach on CT, in either the thoracic or lumbar levels, 90% and 70% of the surgeons would re-operate for a medial breach and an inferior breach, respectively.ConclusionsPostoperative clinical presentation and imaging findings are crucial for interpreting aberrant pedicle screw placement. This study presents a preliminary scoring system for standardizing the classification of pedicle screws.

Study DesignReliability study.PurposeTo examine the reliability of novice and experienced raters for measurements of the size and composition of the cervical extensor muscles using a thresholding technique.Overview of LiteratureAlthough some authors have reported on the dependability of magnetic resonance imaging (MRI) measurements of the cervical muscles, there remains some variability regarding intrarater and interrater reliabilities, and few studies have examined the associated measurement error. Whether the rater's experience noticeably influences the reliability and precision of such measurements has also not been examined.MethodsA sample of 10 patients with cervical pathologies was selected. Muscle cross-sectional area (CSA), functional cross-sectional area (FCSA), and signal intensity of the cervical extensor muscles were acquired from axial T2-weighted MRIs by a novice and an experienced rater. All measurements were obtained twice, at least 5 days apart, while the raters were blinded to all earlier measurements.ResultsInterrater reliability estimates (intraclass correlation coefficients) varied between 0.84 and 0.99 for the novice rater and between 0.94 and 0.99 for the experienced rater, indicating excellent reliability. The standard error of measurement for the novice rater was, however, noticeably higher for all cervical muscle measurements. Most of the interrater estimates showed excellent agreement with the exception of CSA measurement of the semispinalis cervicis at C4–C7 and FCSA measurement of the multifidus and semispinalis cervicis at C4–C7, which showed poor interrater reliability.ConclusionsThe proposed method of investigating cervical muscle measurements was highly reliable; however, novice raters should receive adequate training before using this method for diagnostic, research, and clinical purposes.

Study DesignRetrospective cohort study.PurposeThe purpose of this study was to assess the rate of blood transfusion after cervical fusion surgery, and its effect on complication rates.Overview of LiteratureCervical spine fusions have gained interest in the literature since these procedures are now ever more frequently being performed in an outpatient setting with few complications.MethodsThe American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was used to identify patients that underwent cervical fusion from 2010 to 2013. Multivariate regression analysis was used to determine postoperative complications associated with transfusion and cervical fusion.ResultsWe identified 11,588 patients who had cervical fusion between 2010 and 2013. The rate of blood transfusion following cervical fusion found to be 1.47%. All transfused patients were found to have increased risk of venous thromboembolism (TBE) (odds ratio [OR], 3.19; 95% confidence interval [95% CI], 1.16–8.77), myocardial infarction (MI) (OR, 9.12; 95% CI, 2.53–32.8), increased length of stay (LOS) (OR, 28.03; 95% CI, 14.28–55.01) and mortality (OR, 4.14; 95% CI, 1.44–11.93). Single level fusion had increased risk of TBE (OR, 3.37; 95% CI, 1.01–11.33), MI (OR, 10.5; 95% CI, 1.88–59.89), and LOS (OR, 14.79; 95% CI, 8.2–26.67). Multilevel fusion had increased risk of TBE (OR, 5.64; 95% CI, 1.15–27.6), surgical site infection (OR, 16.29; 95% CI, 3.34–79.49), MI (OR, 10.84; 95% CI, 2.01–58.55), LOS (OR, 26.56; 95% CI, 11.8–59.78), and mortality (OR, 10.24; 95% CI, 2.45–42.71). Patients who had anterior cervical discectomy and fusion surgery and received a transfusion had an increased risk of TBE (OR, 4.87; 95% CI, 1.04–22.82), surgical site infection (OR, 9.73; 95% CI, 2.14–44.1), MI (OR, 9.88; 95% CI, 1.87–52.2), increased LOS of more than 2 days (OR, 28.34; 95% CI, 13.79–58.21) and increase in mortality (OR, 6.3; 95% CI, 1.76–22.48). While, transfused patients who had posterior fusion surgery had increased risk of MI (OR, 10.45; 95% CI, 1.42–77.12) and increased LOS of more than 6 days (OR, 4.42; 95% CI, 2.68–7.29).ConclusionsOur results demonstrate that although cervical fusions can be done as outpatient procedures special precautions and investigations should be done for patients who receive transfusion after cervical fusion. These patients are demonstrated to have higher rate of MI, TBE, wound infection and mortality when compared to those who do not receive transfusion.