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Study Design: Review article. Objectives: A narrative review of the literature on the current advances and limitations in quality and safety improvement initiatives in spine surgery. Methods: A comprehensive literature search was performed using Ovid MEDLINE focusing on 3 preidentified concepts: (1) quality and safety improvement, (2) reporting of outcomes and adverse events, and (3) prediction model and practice guidelines. The search was conducted under appropriate subject headings and using relevant text words. Articles were screened, and manuscripts relevant to this discussion were included in the narrative review. Results: Quality and safety improvement remains a major research focus attracting investigators from the global spine community. Multiple databases and registries have been developed for the purpose of generating data and monitoring the progress of quality and safety improvement initiatives. The development of various prediction models and clinical practice guidelines has helped shape the care of spine patients in the modern era. With the reported success of exemplary programs initiated by the Northwestern and Seattle Spine Team, other quality and safety improvement initiatives are anticipated to follow. However, despite these advancements, the reporting metrics for outcomes and adverse events remain heterogeneous in the literature. Conclusion: Constant surveillance and continuous improvement of the quality and safety of spine treatments is imperative in modern health care. Although great advancement has been made, issues with reporting outcomes and adverse events persist, and improvement in this regard is certainly needed.

Servitization – der Begriff kennzeichnet wie kein anderer die aktuellen Veranderungen. Seit Jahren wachst der Dienstleistungsanteil am BSP, wandeln sich die Bedurfnisse von Verbrauchern und Unternehmen. Der grundlegende Trend ist der Wunsch zu nutzen und nicht zu besitzen. Globalisierung und Digitalisierung beschleunigen diesen Trend. Wir Menschen leben in der Shared Economy schon langer – wahrend der DIY-Handwerker die Bormaschine im Baumarkt ausleiht, nutzt der Profi-Handwerker die Hilti und das Bauunternehmen den Kompressor von Kaeser oder Boge auf Basis neuer Geschaftsmodelle – z. B. auf Zeit oder nach Menge. Was sind die Erfolgsfaktoren dieser neuen Zeit? Wie wandeln sich Unternehmen zu Dienstleistern? Was ist in einer so komplexen und schnelllebigen Zeit das Ziel? Nur das Unternehmen, das seine Kunden kennt und alle Aktivitaten auf sie ausrichtet, liefert die vom Kunden erwarteten Ergebnisse – und das Team schafft erganzend begeisternde Kundenkontakte. Loyale Kunden sind das Ziel. Customer Centricity, Service Excellence und eine gute Servicekultur, die intern und extern die gewunschte Customer Experience (CX) schafft, sind die Hebel fur ein herausragendes Miteinander im Team und fur nachhaltige Erfolge im Markt. Der folgende Beitrag beschreibt, was verandert werden muss, welche Bedeutung dabei Customization, Personalization und Servitization haben, warum ETC und ISS ServiceCompass die richtigen Tools fur diese Transformation sind und wie diese Werkzeuge fur die erfolgreiche Business Transformation zum Erreichen von Kundenzentrierung und Customer Service Excellence eingesetzt werden mussen.

Sin financiación 22.673 JCR (2019) Q1, 2/138 Cardiac & Cardiovascular Systems 5.883 SJR (2019) Q1, 4/362 Cardiology and Cardiovascular Medicine No data IDR 2019 UEM

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

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

Background The treatment of oligometastatic (≤5 metastases) spinal disease has trended toward ablative therapies, yet to the authors' knowledge little is known regarding the prognosis of patients presenting with oligometastatic spinal disease and the value of this approach. The objective of the current study was to compare the survival and clinical outcomes of patients with cancer with oligometastatic spinal disease with those of patients with polymetastatic (>5 metastases) disease. Methods The current study was an international, multicenter, prospective study. Patients who were admitted to a participating spine center with a diagnosis of spinal metastases and who underwent surgical intervention and/or radiotherapy between August 2013 and May 2017 were included. Data collected included demographics, overall survival, local control, and treatment information including surgical, radiotherapy, and systemic therapy details. Health-related quality of life (HRQOL) measures included the EuroQOL 5 dimensions 3-level questionnaire (EQ-5D-3L), the 36-Item Short Form Health Survey (SF-36v2), and the Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ). Results Of the 393 patients included in the current study, 215 presented with oligometastatic disease and 178 presented with polymetastatic disease. A significant survival advantage of 90.1% versus 77.3% at 3 months and 77.0% versus 65.1% at 6 months from the time of treatment was found for patients presenting with oligometastatic disease compared with those with polymetastatic disease. It is important to note that both groups experienced significant improvements in multiple HRQOL measures at 6 months after treatment, with no differences in these outcome measures noted between the 2 groups. Conclusions The treatment of oligometastatic disease appears to offer a significant survival advantage compared with polymetastatic disease, regardless of treatment choice. HRQOL measures were found to improve in both groups, demonstrating a palliative benefit for all treated patients.

Knowledge of environments used during early life history and movement patterns of Bighead Carp (Hypophthalmichthys nobilis) and Silver Carp (H. molitrix), collectively termed bigheaded carps, in the Upper Mississippi River (UMR) would be valuable for informing control measures to limit further population expansion and impacts of these species. Lock and Dam 19 (LD19) is a high-head dam on the UMR that delineates downriver areas where bigheaded carps are well established from upriver pools where these species are less abundant and evidence of reproduction and recruitment are limited. Principal natal environments supporting recruitment of emerging bigheaded carp populations in the UMR are unknown. The objectives of this study were to (1) infer environments occupied during early-life stages by bigheaded carps collected in UMR Pools 19–21 during 2013–2014 using otolith microchemistry and stable isotope analyses, and (2) use early-life environment assignments and capture location to identify individuals that passed through LD19. Differences in multivariate water chemistry signatures (Sr:Ca, Ba:Ca and δ18O) among the UMR, its tributaries, and the Missouri and Middle Mississippi rivers enabled development of a classification model for inferring early-life environment of bigheaded carps. Multiple sources of recruits, including from tributaries, have contributed to upriver expansion of bigheaded carps in the UMR. Sustainable control of bigheaded carps upstream of LD19 will likely require efforts to control local recruitment and immigration from downriver. The frequency of bigheaded carps collected in Pool 19 that were downstream of LD19 during early life suggests that bigheaded carps upstream of LD19 still predominantly consisted of immigrants from downriver during 2013–2014. Otolith chemistry provides an approach for assessing the extent to which changes in abundance of bigheaded carps upstream of LD19 are associated with local recruitment or immigration from downriver.

The Bengal Fan contains the most complete record of Himalayan climate and tectonics. As the largest fan system of the world it is fed by the Ganges-Brahmaputra river systems. International Ocean Discovery Program (IODP) Expedition 354 cored seven sites along an east-west core transect at 8°N in the lower Bengal Fan. We studied the Pleistocene sections of these sites to provide constraints on the depositional history of the last 1.25 Ma. Low-resolution bio- and magnetostratigraphic constraints identified two regionally-extensive hemipelagic units and intercalated turbidite deposits that provide a chronostratigraphic framework for the 320 km transect. Using a combination of lithostratigraphy and sediment physical properties that vary on orbital timescales, we tuned high-resolution data sets to the LR04 benthic δ18O isotope stack to obtain new constraints on the timing of depositional changes. Above the underlying Unit 1, which consists of Early to Middle Pleistocene turbiditic deposits, we divide four more units for the last 1.25 Ma: Unit 2, a Middle Pleistocene hemipelagic layer deposited at all sites from Marine Isotopic Stages (MIS) 37 to ∼17 (∼1.24–0.68 Ma) during the entire time of the Mid-Pleistocene Transition, when the Bengal Fan depocenter must have been distal to our transect; Unit 3, mostly turbidites with some intercalated hemipelgic sediments deposited from ∼MIS 16–∼13 (∼0.68–0.48 Ma), with sandy lithologies only found at the easternmost site on the west flank of the Ninetyeast Ridge; Unit 4, massive turbiditic sediments that started to dominate deposition with the Mid-Brunhes Transition (∼MIS 12) until MIS 7/8 (∼0.48–0.25 Ma), when the channel-levee system was focused east of the 85°E basement ridge at 8°N; and Unit 5, a Late Pleistocene hemipelagic layer at the top that spans MIS 7/8–1 (∼0.25 Ma to present) while the turbidite deposition was focused west of the 85°E basement ridge at 8°N. We find evidence that, on these timescales, deposition across the lower Bengal Fan changed with the evolution of Pleistocene climate, monsoon and sea-level history and hence responded to external controls on sediment accumulation and fan architecture rather than only fan-internal, autocyclic mechanisms.

Two post hoc analyses in self-identified black and white patients with hypertension evaluated the angiotensin II receptor blocker azilsartan medoxomil (AZL-M) and the fixed-dose combination of AZL-M with chlorthalidone (AZL-M/CLD) versus the ARB olmesartan (OLM) and the OLM fixed-dose combination with hydrochlorothiazide (OLM/HCTZ). One analysis pooled 1,610 patients from two 6-week randomized controlled trials to compare once daily AZL-M 40 mg, AZL-M 80 mg, OLM 40 mg, and placebo. The second analysis included 1,020 patients from a 12-week randomized controlled trial to compare once daily AZL-M/CLD 40/25 mg, AZL-M/CLD 80/25 mg, and OLM/HCTZ 40/25 mg. Efficacy end points were 24-hour mean ambulatory and clinic systolic and diastolic blood pressure (SPB/DBP) and the percentage of patients achieving clinic SBP/DBP targets. Treatment with AZL-M 80 mg lowered mean clinic SBP by 12.5 mm Hg (p

BACKGROUND In response to the call by the World Health Organisation to reduce premature deaths from non-communicable diseases by 25% by the year 2025 (25×25), the Pan-African Society of Cardiology (PASCAR), in partnership with several organisations, including the World Heart Federation, have developed an urgent 10-point action plan to improve detection, treatment and control of hypertension in Africa. Priority six of this action plan is to promote a task-shifting/task-sharing approach in the management of hypertension. AIM This capacity-building initiative aims to enhance the knowledge, skills and core competences of primary healthcare physicians in the management of hypertension and related complications. METHODS In a collaborative approach with the International Society of Hypertension, the British and Irish Hypertension Society, the Public Health Foundation of India and the Centre for Chronic Disease Control, the PASCAR hypertension taskforce held a continental faculty meeting in Kenya on 25 and 26 February 2018 to review and discuss a process of effective contextualisation and implementation of the Indian hypertension management course on the African continent. RESULTS A tailored African course in terms of evidence-based learning, up-to-date curriculum and on-the-job training was developed with a robust monitoring and evaluation strategy. The course will be offered on a modular basis with a judicious mix of case studies, group discussions and contact sessions, with great flexibility to accommodate participants' queries. CONCLUSIONS Hypertension affects millions of people in Africa and if left untreated is a major cause of heart disease, kidney disease and stroke. CCMH-Africa will train in the next 10 years, 25 000 certified general physicians and 50 000 nurses, capable of adequately managing uncomplicated hypertension, thereby freeing the few available specialists to focus on severe or complicated cases.

Numerous studies show promise for cell-based tissue engineering strategies aiming to repair painful intervertebral disc (IVD) degeneration. However, clinical translation to human IVD repair is slow. In the present study, the regenerative potential of an autologous nucleus pulposus (NP)-cell-seeded thermoresponsive hyaluronic acid hydrogel in human lumbar IVDs was assessed under physiological conditions. First, agarose-encased in vitro constructs were developed, showing greater than 90 % NP cell viability and high proteoglycan deposition within HA-pNIPAM hydrogels following 3 weeks of dynamic loading. Second, a bovine-induced IVD degeneration model was used to optimise and validate T1ρ magnetic resonance imaging (MRI) for detection of changes in proteoglycan content in isolated intact IVDs. Finally, isolated intact human lumbar IVDs were pre-scanned using the established MRI sequence. Then, IVDs were injected with HA-pNIPAM hydrogel alone or autologous NP-cell-seeded. Next, the treated IVDs were cultured under cyclic dynamic loading for 5 weeks. Post-treatment T1ρ values were significantly higher as compared to pre-treatment scans within the same IVD and region of interest. Histological evaluation of treated human IVDs showed that the implanted hydrogel alone accumulated proteoglycans, while those that contained NP cells also displayed neo-matrix-surrounded cells within the gel. The study indicated a clinical potential for repairing early degenerative human IVDs using autologous cells/hydrogel suspensions. This unique IVD culture set-up, combined with the long-term physiological culture of intact human IVDs, allowed for a more clinically relevant evaluation of human tissue repair and regeneration, which otherwise could not be replicated using the available in vitro and in vivo models.

Resource pulses are found in a variety of ecosystems and are becoming a prevailing theme in ecology. However, limited information is available regarding how recipient ecosystem productivity influences effects of resource pulses. Our objective was to compare the abundance, stability, and food web responses of nutrients and primary producers and consumers in oligotrophic versus eutrophic aquatic mesocosms receiving resource pulses of decaying fish. Nutrient availability and primary producer and consumer abundance were generally different between trophic states and pulsed treatments. Nitrate decreased and phytoplankton increased as a result of the pulse, whereas total Kjeldahl nitrogen, copepods, and total zooplankton increased following the pulse in oligotrophic but not eutrophic mesocosms. Gastropod density was higher in non-pulsed oligotrophic compared to pulsed eutrophic mesocosms but was not affected by the pulse within a trophic state. Despite temporal variation of all parameters, ecosystem stability was not affected by the pulse. Several differences in δ15N and δ13C values were also observed between biota in oligotrophic and eutrophic mesocosms, but only amphipod δ13C values in eutrophic mesocosms were depleted by the pulse. Overall, our results indicate that recipient ecosystem productivity is an important factor regulating the effects of resource pulses, with implications for ecosystems and food web structure.

Ferroelectric materials find application in numerous electronic devices and are continuously enabling the development of new technologies. Their versatility is intimately related to the unique property to switch the polarization with electric fields. However, the switching mechanisms in polycrystalline ferroelectric materials remain insufficiently understood. Here we reveal that switching in ferroelectric/ferroelastic materials consists of a sequence of individual events, separated into three regimes: rapid movement of non-180° domain walls, main switching phase with 180° and non-180° switching events, and creep-like non-180° domain wall movement. The determination of the mechanisms was enabled by a novel measurement approach, simultaneously tracking the time dynamics of switched polarization, macroscopic strain, and structural changes. Time-resolved in situ synchrotron diffraction allowed direct insight into the non-180° domain wall dynamics and lattice strains and gave evidence for strong time correlation of non-180° switching events in different grains of the polycrystalline material. The obtained results open new opportunities for targeted manipulation of individual switching events and tuning of material's functional properties.

We conducted a multidisciplinary study to provide the stratigraphic and palaeoclimatic context of monsoonal rainfall dynamics and their responses to orbital forcing for the Bay of Bengal. Using sediment lightness we established an age model at orbital resolution for International Ocean Discovery Programme (IODP) Core U1452C-1H that covers the last 200 ka in the lower Bengal Fan. The low-resolution δ18O of G. sacculifer is consistent with global δ18O records, at least for major glacial-to-interglacial transitions. The variability of total organic carbon, total nitrogen, and the δ13C composition of organic matter indicate the marine origin of organic matter. Marine primary productivity likely increased during insolation minima, indicative for an enhanced NE monsoon during glacials and stadials. Pristine insolation forcing is also documented for wet-bulk density, red-green color variability, and grain-size variations, indicating that darker and coarser-grained material deposited at higher sedimentation rates during insolation minima. Stronger NE monsoon likely amplified ocean-atmosphere interactions over the Indian Ocean, leading to stronger upwelling through shoaling the thermocline, and higher delivery of sediment to the Bay of Bengal due to higher soil erosion on land. In addition, lower glacial and stadial sea levels as well as stronger westward surface circulation favored delivery of coarser-grained fluvial material to the lower Bengal Fan. At the same time the stronger NE monsoon might have increased the aeolian supply. Total inorganic carbon, the Ca/Ti ratio, and biogenic silica vary dominantly on obliquity frequencies, suggesting mobilization and transport of lithogenic material primarily during lowered sea levels and/or higher influence of the Northern Hemisphere westerlies on the dust transport from the Tibetan Plateau. The close resemblance of sediment lightness and the climate record of Antarctic ice cores over multiple glacial cycles indicate close relationship between high southern latitude and tropical Asian climate through shifts in position of the Intertropical Convergence Zone. The Bengal Fan monsoonal record shows very clear and strict responses to insolation forcing in the lower part from ~200 ka to the Younger Toba Tuff during Marine Isotope Stage (MIS) 7 – 5, and less distinct response patterns after deposition of the ash during MIS 4 – 2, consistent with low-amplitude changes in insolation.

Copyright © 2018 by the American Society of Plastic Surgeons. Background: Soft-tissue complications often dictate the success of limb salvage and the overall outcome of open fractures. Based on prior work at the R Adams Cowley Shock Trauma Center, the authors hypothesize that wounds larger than 200 cm2 are associated with a greater likelihood of both flap-related reoperation and wound complications among patients requiring soft-tissue reconstruction with a rotational flap or free tissue transfer. Methods: This study was a secondary analysis of Fluid Lavage in Open Wounds trial data that included all patients who received a rotational or free tissue flap transfer for an open fracture. The primary outcome was flap-related reoperation within 12 months of injury. The secondary outcome was wound complication, which included events treated operatively or nonoperatively. Multivariable logistic regression was used to assess the association between wound size and outcomes, adjusting for confounders. Results: Seventeen percent of the 112 patients required a flap-related reoperation. A wound size greater than 200 cm2 was not associated with reoperation in an unadjusted model (p = 0.64) or adjusting for Gustilo type (p = 0.70). The sample had an overall wound complication rate of 47.3 percent. Patients with a wound size of greater than 200 cm2 were three times more likely to experience wound complications (OR, 3.05; 95 percent CI, 1.08 to 8.62; p = 0.04) when adjusting for moderate to severe wound contamination and wound closure in the operating room. Conclusion: The findings of this study demonstrate that wound surface area is an integral determinant for wound complication following soft-tissue flap treatment, but found no association between wound surface area and flap-related reoperation rates.

Summary Background Previous catheter-based renal denervation studies have reported variable efficacy results. We aimed to evaluate safety and blood pressure response after renal denervation or sham control in patients with uncontrolled hypertension on antihypertensive medications with drug adherence testing. Methods In this international, randomised, single-blind, sham-control, proof-of-concept trial, patients with uncontrolled hypertension (aged 20–80 years) were enrolled at 25 centres in the USA, Germany, Japan, UK, Australia, Austria, and Greece. Eligible patients had an office systolic blood pressure of between 150 mm Hg and 180 mm Hg and a diastolic blood pressure of 90 mm Hg or higher; a 24 h ambulatory systolic blood pressure of between 140 mm Hg and 170 mm Hg at second screening; and were on one to three antihypertensive drugs with stable doses for at least 6 weeks. Patients underwent renal angiography and were randomly assigned to undergo renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were masked to randomisation assignments. The primary efficacy endpoint was blood pressure change from baseline (measured at screening visit two), based on ambulatory blood pressure measurements assessed at 6 months, as compared between treatment groups. Drug surveillance was used to assess medication adherence. The primary analysis was done in the intention-to-treat population. Safety events were assessed through 6 months as per major adverse events. This trial is registered with ClinicalTrials.gov, number NCT02439775, and follow-up is ongoing. Findings Between July 22, 2015, and June 14, 2017, 467 patients were screened and enrolled. This analysis presents results for the first 80 patients randomly assigned to renal denervation (n=38) and sham control (n=42). Office and 24 h ambulatory blood pressure decreased significantly from baseline to 6 months in the renal denervation group (mean baseline-adjusted treatment differences in 24 h systolic blood pressure −7·0 mm Hg, 95% CI −12·0 to −2·1; p=0·0059, 24 h diastolic blood pressure −4·3 mm Hg, −7·8 to −0·8; p=0.0174, office systolic blood pressure −6·6 mm Hg, −12·4 to −0·9; p=0·0250, and office diastolic blood pressure −4·2 mm Hg, −7·7 to −0·7; p=0·0190). The change in blood pressure was significantly greater at 6 months in the renal denervation group than the sham-control group for office systolic blood pressure (difference −6·8 mm Hg, 95% CI −12·5 to −1·1; p=0·0205), 24 h systolic blood pressure (difference −7·4 mm Hg, −12·5 to −2·3; p=0·0051), office diastolic blood pressure (difference −3·5 mm Hg, −7·0 to −0·0; p=0·0478), and 24 h diastolic blood pressure (difference −4·1 mm Hg, −7·8 to −0·4; p=0·0292). Evaluation of hourly changes in 24 h systolic blood pressure and diastolic blood pressure showed blood pressure reduction throughout 24 h for the renal denervation group. 3 month blood pressure reductions were not significantly different between groups. Medication adherence was about 60% and varied for individual patients throughout the study. No major adverse events were recorded in either group. Interpretation Renal denervation in the main renal arteries and branches significantly reduced blood pressure compared with sham control with no major safety events. Incomplete medication adherence was common. Funding Medtronic.

Mercury contamination in aquatic ecosystems is a concern due to health risks of consuming fish. Fish mercury concentrations are highly variable and influenced by a range of environmental factors. However, seasonal variation in mercury levels are typically overlooked when monitoring fish mercury concentrations, establishing consumption advisories, or creating accumulation models. Temporal variation in sampling could bias mercury concentration estimates of accumulation potential. Thus, the objectives of this study were to first evaluate seasonal variation of largemouth bass (Micropterus salmoides) axial muscle mercury concentration from two Iowa, USA impoundments. Second, we conducted a meta-analysis to evaluate if seasonal variation in mercury concentration is dependent upon mean mercury concentration, waterbody type, or fish trophic level or mean length. Largemouth bass were collected four times between May and October (24–36 fish per month) from Twelve Mile (2013) and Red Haw (2014) lakes. Largemouth bass axial muscle mercury concentrations were variable within and between lakes, ranging from undetectable (

There have been concerns that treatment of overactive bladder with β3 -adrenoceptor agonists may potentially have detrimental cardiovascular (CV) side effects. We evaluated the CV safety of mirabegron, a β3 -adrenoceptor agonist, alone and in combination therapy with the antimuscarinic agent solifenacin. The SYNERGY trial was a multinational, multicenter, randomized, double-blind, parallel-group, placebo and active-controlled phase 3 trial. Patients were randomized to receive solifenacin 5 mg + mirabegron 50 mg (combination 5 + 50 mg), solifenacin 5 mg + mirabegron 25 mg (combination 5 + 25 mg), solifenacin 5 mg monotherapy, mirabegron 25 mg monotherapy, mirabegron 50 mg monotherapy, or placebo for a 12-week double-blind treatment period. A total of 3398 patients were included in the study. Mean changes from baseline to the end of therapy in ECG parameters were similar across treatment groups, although there was an increase in heart rate of 1 beat/minute in the mirabegron treatment groups. There were no clinically meaningful differences in change from baseline in QTcF between monotherapies and placebo and between monotherapies and combination therapy. There were very few major CV events: 1 of 853 (0.1%) with a nonfatal myocardial infarction in the combination 5 + 25 mg group, 2 of 848 (0.2%) with a nonfatal stroke in the combination 5 + 50 mg group, and no events in the other groups. This CV safety analysis of the combination of mirabegron and solifenacin showed rates of CV events comparable with those for monotherapy treatments based on assessments of vital signs, electrocardiograms, and adjudicated CV events.

Background: Azilsartan medoxomil (AZL-M), an angiotensin II receptor blocker, has been developed in fixed-dose combinations (FDCs) with chlorthalidone (CTD). Objective/methods: We compared FDCs of AZL-M/CTD 20/12.5 mg once daily titrated to 40/25 mg if needed or AZL-M/CTD 40/12.5 mg once daily titrated to 80/25 mg if needed with an olmesartan medoxomil (OLM)-hydrochlorothiazide (HCTZ) 20/12.5 mg FDC once daily titrated to 40/25 mg if needed in a randomized, double-blind, 8-week study of 1085 participants with clinic SBP 160–190 mmHg and DBP 119 mmHg or less. Titration to higher doses occurred at week 4 if BP was at least 140/90 mmHg (≥130/80 mmHg if diabetes or chronic kidney disease). The primary endpoint was change from baseline in clinic SBP; 24-h ambulatory BP monitoring was also measured. Results: Greater reductions in clinic SBP from a baseline of 165 mmHg were observed (P

Objective Mounting evidence indicates that stress influences the experience of pain. Exposure to psychosocial stress disrupts bi-directional communication pathways between the central nervous system and peripheral immune system, and can exacerbate the frequency and severity of pain experienced by stressed subjects. Repeated social defeat (RSD) is a murine model of psychosocial stress that recapitulates the immune and behavioral responses to stress observed in humans, including activation of stress-reactive neurocircuitry and increased pro-inflammatory cytokine production. It is unclear, however, how these stress-induced neuroimmune responses contribute to increased pain sensitivity in mice exposed to RSD. Here we used a technique of regional analgesia with local anesthetics in mice to block the development of mechanical allodynia during RSD. We next investigated the degree to which pain blockade altered stress-induced neuroimmune activation and depressive-like behavior. Methods Following development of a mouse model of regional analgesia with discrete sensory blockade over the dorsal-caudal aspect of the spine, C57BL/6 mice were divided into experimental groups and treated with Ropivacaine (0.08%), Liposomal Bupivacaine (0.08%), or Vehicle (0.9% NaCl) prior to exposure to stress. This specific region was selected for analgesia because it is the most frequent location for aggression-associated pain due to biting during RSD. Mechanical allodynia was assessed 12 h after the first, third, and sixth day of RSD after resolution of the sensory blockade. In a separate experiment, social avoidance behavior was determined after the sixth day of RSD. Blood, bone marrow, brain, and spinal cord were collected for immunological analyses after the last day of RSD in both experiments following behavioral assessments. Results RSD increased mechanical allodynia in an exposure-dependent manner that persisted for at least one week following cessation of the stressor. Mice treated with either Ropivacaine or Liposomal Bupivacaine did not develop mechanical allodynia following exposure to stress, but did develop social avoidance behavior. Neither drug affected stress-induced activation of monocytes in the bone marrow, blood, or brain. Neuroinflammatory responses developed in all treatment groups, as evidenced by elevated IL-1β mRNA levels in the brain and spinal cord after RSD. Conclusions In this study, psychosocial stress was associated with increased pain sensitivity in mice. Development of mechanical allodynia with RSD was blocked by regional analgesia with local anesthetics, Ropivacaine or Liposomal Bupivacaine. Despite blocking mechanical allodynia, these anesthetic interventions did not prevent neuroimmune activation or social avoidance associated with RSD. These data suggest that stress-induced neuroinflammatory changes are not associated with increased sensitivity to pain following RSD. Thus, blocking peripheral nociception was effective in inhibiting enhanced pain signaling without altering stress-induced immune or behavioral responses.

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.

Resource pulses provide short-duration, large-magnitude resources that influence ecosystem productivity, structure, and function. However, little empirical evidence is available evaluating how lake ecosystems respond to varying resource pulse magnitudes. We used mesocosms inoculated with primary producers and consumers to compare resource pulses of 0, 25, 50, 100, and 250 kg/ha of common carp Cyprinus carpio to simulate post-winterkill fish biomass in shallow lakes. Ecosystem responses to a gradient of resource pulse magnitudes typically had the greatest effects on nutrient availability and primary producers with fewer detectable effects for consumers. Total phosphorus, total Kjeldahl nitrogen, nitrate, phytoplankton, and periphyton productions increased as a result of the resource pulse, whereas copepods were the only consumer observed to elicit a positive response. In contrast, pulse magnitude had little effect on ecosystem stability, trophic position, or energy flow, potentially due to the low biomass of pulse magnitudes introduced. Resource pulses of moderate or large size generally increased nutrient availability and primary productivity while decreasing water clarity, suggesting that resource pulses can be an important factor influencing shallow eutrophic lakes but that effects may not be proportional to pulse size.

Landscape alterations can alter fish occurrence and abundance in wetlands. By increasing turbidity in wetland ponds, fishes can induce a shift from a clear- to a turbid-water state, resulting in reduced plant and amphibian abundance. In 2012, a drought reduced water levels and eliminated fishes from many wetlands of the prairie-pothole region (PPR) in the Midwestern United States. Our study objective was to evaluate if fish eliminations were associated with changes in wetland condition. A one-way ANOVA was used to compare the magnitude of change in parameters indicative of wetland condition (turbidity, plant cover and taxon richness, and tiger-salamander (Ambystoma tigrinum) biomass and numerical abundance) from 29 Iowa PPR wetlands between 2010 and 2011 (pre-drought) and 2014–2015 (post-drought) among wetlands where 1) all fishes were eliminated 2) large-bodied fishes were eliminated, 3) small-bodied fishes were eliminated, 4) fishes were retained, and 5) fishes were never detected. Turbidity decreased and plant cover increased more where large-bodied fishes were eliminated compared to the other groups. Changes in tiger-salamander biomass and abundance and plant-taxon richness were not different among groups. Results indicate that wetlands can shift from a turbid- to a clear-water state following drought and elimination of large-bodied fishes.

Macroinvertebrates are often excluded from wetland monitoring because samples collected using a conventional 500-μm mesh sieve are time consuming to process. To facilitate increased cost-effectiveness of obtaining macroinvertebrate data, influence of sieve mesh size on relationships between macroinvertebrate and environmental variables was evaluated in 27 prairie pothole wetlands. Benthic and water-column samples were washed through sieves with mesh sizes of 6 mm, 4 mm, 2 mm, and 500 μm, and macroinvertebrate numerical densities and taxon richness were quantified. Influence of particulate matter was evaluated by washing invertebrates through sieves before and after removal of this material from samples, and calculating differences in density and taxon richness. Regardless of sieve mesh size and particulate matter abundance, macroinvertebrate taxon richness exclusive of taxa occurring in all wetlands (planorbid snails, oligochaetes, leeches, chironomids) was positively correlated with plant cover, and negatively correlated with turbidity and fish biomass (p ≤ 0.05).Use of a 6-mm mesh sieve reduced sample volume by 35% and processing time by 54% relative to the 500-μm mesh sieve. Results suggest that reliance on taxon richness metrics and a sieve with 6-mm mesh will reduce macroinvertebrate sampling costs while still generating data that reflect wetland condition.

We present a new workflow for the localization of seismic events which is based on a diffraction stacking approach. In order to address the effects from complex source radiation patterns, we suggest to compute diffraction stacking from a characteristic function (CF) instead of stacking the original waveform data. A new CF, which is called in the following mAIC (modified from Akaike Information Criterion) is proposed. We demonstrate that both P- and S-wave onsets can be detected accurately. To avoid cross-talk between P and S waves due to inaccurate velocity models, we separate the P and S waves from the mAIC function by making use of polarization attributes. Then, the final image function is represented by the largest eigenvalue as a result of the covariance analysis between P-and S-image functions. Results from synthetic experiments show that the proposed diffraction stacking provides reliable results. The workflow of the diffraction stacking method was finally applied to local earthquake data from Sumatra, Indonesia. Recordings from a temporary network of 42 stations deployed for nine months around the Tarutung pull-apart basin were analysed. The seismic event locations resulting from the diffraction stacking method align along a segment of the Sumatran Fault. A more complex distribution of seismicity is imaged within and around the Tarutung basin. Two lineaments striking N-S were found in the centre of the Tarutung basin which support independent results from structural geology.

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.

OBJECTIVEThe aim of this study was to evaluate the anatomical and surgical risk factors for screw-related facet joint violation at the superior level in lumbar fusion.METHODSThe authors conducted a retrospective review of a consecutive series of posterior lumbar instrumented fusions performed by a single surgeon. Inclusion criteria were primary lumbar fusion of 1 or 2 levels for degenerative disorders. The following variables were analyzed as possible risk factors: surgical technique (percutaneous vs open screw placement), depth of surgical field, degree of anterior slippage of the superior level, pedicle and facet angle, and facet degeneration of the superior level. Postoperative CT scans were evaluated by 2 independent reviewers. Axial, sagittal, and coronal views were reviewed. Pedicle screws were graded as intra-articular if they clearly interposed between the superior and inferior facet joints of the superior level. Multivariate logistic regression analyses were conducted to assess the factors associated with this complication.RESULTSOne hundred thirty-one patients were included. Interobserver reliability for facet joint violation assessment was high (κ = 0.789). The incidence of superior facet joint violation was 12.59% per top-level screw (33 of 262 proximal screws). The rate of facet violation was 28.0% in the percutaneous technique group (14 of 50 patients) and 12.3% in the open surgery group (10 of 81 patients) (OR 2.26, 95% CI 1.09–4.21; p = 0.024). In multivariate logistic regression analysis, independent predictors of facet violation were percutaneous screw placement (adjusted OR 3.31, 95% CI 1.42–7.73; p = 0.006), right-side pedicle screw (adjusted OR 3.14, 95% CI 1.29–7.63; p = 0.011), and facet angle > 45° (adjusted OR 10.95, 95% CI 4.64–25.84; p < 0.0001).CONCLUSIONSThe incidence of facet joint violation was higher in percutaneous minimally invasive than in open technique for posterior lumbar spine surgery. Also, coronal orientation of the facet joint is a significant risk factor independent of the surgical technique.

Catheter-based renal denervation is a new approach to treat hypertension via modulation of the renal sympathetic nerves. Although nonrandomized and small, open-label randomized studies resulted in significant reductions in office blood pressure 6months after renal denervation with monopolar radiofrequency catheters, the first prospective, randomized, sham-controlled study (Symplicity HTN-3) failed to meet its blood pressure efficacy end point. New clinical trials with new catheters have since been designed to address the limitations of earlier studies. Accordingly, the RADIANCE-HTN and REQUIRE studies are multicenter, blinded, randomized, sham-controlled trials designed to assess the blood pressure-lowering efficacy of the ultrasound-based renal denervation system (Paradise) in patients with established hypertension either on or off antihypertensive medications, is designed to evaluate patients in 2 cohorts-SOLO and TRIO, in the United States and Europe. The SOLO cohort includes patients with essential hypertension, at low cardiovascular risk, and either controlled on 1 to 2 antihypertensive medications or uncontrolled on 0 to 2 antihypertensive medications. Patients undergo a 4-week medication washout period before randomization to renal denervation (treatment) or renal angiogram (sham). The TRIO cohort includes patients with hypertension resistant to at least 3 antihypertensive drugs including a diuretic. Patients will be stabilized on a single-pill, triple-antihypertensive-drug combination for 4weeks before randomization to treatment or sham. Reduction in daytime ambulatory systolic blood pressure (primary end point) will be assessed at 2months in both cohorts. A predefined medication escalation protocol, as needed for blood pressure control, is implemented between 2 and 6months in both cohorts by a study staff member blinded to the randomization process. At 6months, daytime ambulatory blood pressure and antihypertensive treatment score will be assessed. REQUIRE is designed to evaluate patients with resistant hypertension on standard of care medication in Japan and Korea. Reduction in 24-hour ambulatory systolic blood pressure will be assessed at 3months (primary end point). Both studies are enrolling patients, and their results are expected in 2018.

Summary Background Early studies suggest that radiofrequency-based renal denervation reduces blood pressure in patients with moderate hypertension. We investigated whether an alternative technology using endovascular ultrasound renal denervation reduces ambulatory blood pressure in patients with hypertension in the absence of antihypertensive medications. Methods RADIANCE-HTN SOLO was a multicentre, international, single-blind, randomised, sham-controlled trial done at 21 centres in the USA and 18 in Europe. Patients with combined systolic–diastolic hypertension aged 18–75 years were eligible if they had ambulatory blood pressure greater than or equal to 135/85 mm Hg and less than 170/105 mm Hg after a 4-week discontinuation of up to two antihypertensive medications and had suitable renal artery anatomy. Patients were randomised (1:1) to undergo renal denervation with the Paradise system (ReCor Medical, Palo Alto, CA, USA) or a sham procedure consisting of renal angiography only. The randomisation sequence was computer generated and stratified by centres with randomised blocks of four or six and permutation of treatments within each block. Patients and outcome assessors were blinded to randomisation. The primary effectiveness endpoint was the change in daytime ambulatory systolic blood pressure at 2 months in the intention-to-treat population. Patients were to remain off antihypertensive medications throughout the 2 months of follow-up unless specified blood pressure criteria were exceeded. Major adverse events included all-cause mortality, renal failure, an embolic event with end-organ damage, renal artery or other major vascular complications requiring intervention, or admission to hospital for hypertensive crisis within 30 days and new renal artery stenosis within 6 months. This study is registered with ClinicalTrials.gov, number NCT02649426. Findings Between March 28, 2016, and Dec 28, 2017, 803 patients were screened for eligibility and 146 were randomised to undergo renal denervation (n=74) or a sham procedure (n=72). The reduction in daytime ambulatory systolic blood pressure was greater with renal denervation (−8·5 mm Hg, SD 9·3) than with the sham procedure (−2·2 mm Hg, SD 10·0; baseline-adjusted difference between groups: −6·3 mm Hg, 95% CI −9·4 to −3·1, p=0·0001). No major adverse events were reported in either group. Interpretation Compared with a sham procedure, endovascular ultrasound renal denervation reduced ambulatory blood pressure at 2 months in patients with combined systolic–diastolic hypertension in the absence of medications. Funding ReCor Medical.

Stand-alone cervical laminectomy for degenerative cervical myelopathy (DCM) has become increasingly rare due to risk of postlaminectomy kyphosis. This article discusses the biomechanics of cervical degeneration and how laminectomy effects spine stability, and summarizes relevant clinical studies to help guide surgical decision-making for the posterior treatment of DCM. Laminectomy and fusion remains a safe and efficacious treatment. Stand-alone laminectomy should only be used for a highly selected patient population with relative stiff lordotic cervical spines, using care to not disrupt facets and C2 and C7 muscle attachments.

As live release black bass (Micropterus spp.) tournaments increase in popularity, stress associated with live-well confinement may result in increased mortality rates. Variation in number of bass in tournament angler live-wells is common due to a suite of factors (e.g., regulations, number of anglers per boat, angler success), but the effect on delayed tournament mortality relative to other environmental factors is unknown. Largemouth bass Micropterus salmoides were collected and tagged following tournament weigh-ins (n = 80) and monthly electrofishing events (n = 15) in 2018 and 2019 at Brushy Creek Lake, Iowa, USA. A Cormack-Jolly-Seber model in Program MARK was used to evaluate the duration of reduced post-tournament survival (0–7 day) and the effects of number of bass per live-well (1–15 individuals) compared to environmental covariates (air and water temperature) and bass total length on post-tournament survival. Models indicated bass survival was reduced for three days following tournament capture and was negatively related to water temperature, number of bass in live-well, and number of initial tournament mortalities. Largest effects of all covariates on tournament survival occurred at high water temperatures but were reduced at cooler water temperatures. Daily survival probability ranged from 0.9792 (95 % CI: 0.9757, 0.9822) at 5.71 °C to 0.8927 (95 % CI: 0.8720, 0.9103) at 28.79 °C on day of tournament capture. Survival also decreased from 0.9819 (95 % CI: 0.9592, 0.9921) with one bass in the live-well to 0.9632 (95 % CI: 0.4167, 0.9990) with fifteen bass in the live-well. However, the effect number of bass in a live-well has on overall tournament survival is likely minimal due to the infrequency ten or more bass were confined per live-well. Our study provides information on the effect number of bass in a live-well has on post-release tournament survival while providing management insights to improve post-tournament survival for recreational bass fisheries.

Stocking walleye Sander virteus is a common management technique to supplement populations where natural reproduction is limited. However, numerous factors can influence the survival of fall stocked walleye including environmental conditions, predation, and stocked walleye total length (TL), condition, and foraging ability. The relative effects of these factors on survival of stocked walleye are challenging to evaluate and rarely assessed simultaneously. Our objective was to determine factors that influence survival rates of stocked fingerling walleye (98−287 mm TL) from stocking until ice cover in two Iowa systems (East Okoboji and West Okoboji) during fall 2015, 2016, and 2017 using mark-recapture techniques. Each fall, roughly 4000 stocked walleye were implanted with passive integrated transponder tags, stocked across both systems, and recaptured via boat electrofishing. Cormack-Jolly-Seber recapture models estimated walleye weekly apparent survival was negatively related to the weekly average proportion of walleye recovered from predator diets (β = −0.89; 95 % credibility interval = −1.74 to −0.03) and positively related to weekly average water temperatures (β = 2.62; 95 % credibility interval = 1.04–4.21). At an average fall water temperature (13.2 ℃), mean walleye apparent survival was 0.83 (95 % credibility interval = 0.75–0.91) when no walleye were recovered from predator diets and declined to 0.54 (95 % credibility interval = 0.28–0.84) when walleye comprised 60 % of predator diets. Between 41–97 % of stocked walleye were lost to apparent mortality from stocking through ice-up and survival was influenced by post-stocking predation rather than walleye body size or condition. Thus, strategies that minimize predation following stocking may result in the greatest improvements in walleye stocking success.

Supplemental Digital Content is available in the text., Background: Primary results of this prospective, open-label, multicenter trial suggested that alcohol-mediated renal denervation with perivascular injection of dehydrated alcohol using the Peregrine System Infusion Catheter safely reduces blood pressure (BP) in patients with resistant hypertension. To date, maintenance of the BP-lowering effect beyond 6 months using this novel technology has not been reported. This article describes the final, 12-month follow-up data on the safety and efficacy of alcohol-mediated renal denervation in these patients. Methods: Forty-five patients with resistant hypertension on a stable regimen of on average 5.1±1.5 antihypertensive medications underwent successful bilateral renal denervation using the Peregrine Catheter with alcohol as the neurolytic agent (0.6 mL per renal artery). Apart from 2 vascular access pseudoaneurysms (both without sequelae), no major procedural complications occurred. Results: At 12 months post-procedure, mean 24-hour ambulatory systolic and diastolic BP were reduced by 10 mm Hg (95% CI, −16 to −5) and 7 mm Hg (−10 to −3), respectively (P

Study Design Retrospective cohort. Objectives To compare outcomes of minimally invasive surgery (MIS) vs open surgery (OPEN) for lumbar spinal stenosis (LSS) in patients with diabetes. Methods Patients with diabetes who underwent spinal decompression alone or with fusion for LSS within the Canadian Spine Outcomes and Research Network (CSORN) database were included. MIS vs OPEN outcomes were compared for 2 cohorts: (1) patients with diabetes who underwent decompression alone (N = 116; MIS n = 58 and OPEN n = 58), (2) patients with diabetes who underwent decompression with fusion (N = 108; MIS n = 54 and OPEN n = 54). Modified Oswestry Disability Index (mODI) and back and leg pain were compared at baseline, 6–18 weeks, and 1-year post-operation. The number of patients meeting minimum clinically important difference (MCID) or minimum pain/disability at 1-year was compared. Results MIS approaches had less blood loss (decompression alone difference 100 mL, P = .002; with fusion difference 244 mL, P < .001) and shorter length of stay (LOS) (decompression alone difference 1.2 days, P = .008; with fusion difference 1.2 days, P = .026). MIS compared to OPEN decompression with fusion had less patients experiencing adverse events (AEs) (difference 13 patients, P = .007). The MIS decompression with fusion group had lower 1-year mODI (difference 14.5, 95% CI [7.5, 21.0], P < .001) and back pain (difference 1.6, 95% CI [.6, 2.7], P = .002) compared to OPEN. More patients in the MIS decompression with fusion group exceeded MCID at 1-year for mODI (MIS 75.9% vs OPEN 53.7%, P = .028) and back pain (MIS 85.2% vs OPEN 70.4%, P = .017). Conclusions MIS approaches were associated with more favorable outcomes for patients with diabetes undergoing decompression with fusion for LSS.

The Bcl-2 inhibitor venetoclax (VEN) shows clinical activity in Chronic Lymphocytic Leukemia (CLL), and the response is potentiated when combined with the BTK inhibitor ibrutinib (IBR) (Portell et al. 2019; Tam et al. 2018). However, many VEN or VEN+IBR responses are incomplete and drug resistance develops in most cases. We previously noted that CLL cells exposed to microenvironmental agonists ex vivo exhibit resistance to VEN+IBR due to upregulation of multiple anti-apoptotic proteins (Jayappa et al. 2017). Here, we find in the circulation of CLL patients that activated (CD69Pos) leukemic B cells recently emigrated from the lymph node exhibit resistance to inhibitors of Bcl-2, Mcl-1, or Bcl-xL due to impaired activation of Bax/Bak proteins. Our molecular analysis suggests that multiple upregulated anti-apoptotic proteins (Mcl-1, Bcl-xL, and Bcl-2) swap for pro-apoptotic proteins (e.g. Bim) in these cells when subjected to single-drug treatments, leading to defective Bax/Bak activation resulting in resistance to drug induced apoptosis. A large-scale cell-based screen using small molecule agonist of Protein Phosphatase 2A (PP2A) (SMAP, TRC-382) revealed that blood cancer cell lines are highly sensitive to SMAP mediated activation of PP2A, a serine/threonine phosphatase known to regulate cell survival. A further pharmacologically optimized SMAP compound (DT061) showed activity even in leukemia cell lines or patient-derived CD69Pos CLL cells resistant to inhibitors of Bcl-2, Mcl-1, or Bcl-xL, suggesting PP2A activation can overcome apoptosis resistance. The PP2A activator DT061 induced apoptosis in these cells in the absence of Bax/Bak activation and was equally effective in an isogenic Bax/Bak double knockout cells, suggesting PP2A activation overcomes multi-drug resistance via induction of Bax/Bak-independent apoptosis. We next examined various Bax/Bak-independent apoptosis mechanisms using inhibitors, and found that inhibitors of mitochondrial permeability transition pores (mPTP) (NIM811 and cyclopsorin-A) blocked the DT061-induced apoptosis in CLL cells. Using the CalceinAM/CoCl2 assay, we noted that DT061 triggers mPTP opening in primary CLL cells, which was blocked by mPTP inhibitors, suggesting DT061 induces apoptosis via mPTP activation. In summary, microenvironmentally activated cancer cells displaying resistance to apoptosis due to defective Bax/Bak activation are found de novo in CLL patients. Reactivation of the tumor suppressive serine/threonine phosphatase by a series of small molecules (SMAPs) overcomes this resistance by inducing mPTP dependent apoptosis. Collectively, these findings demonstrate the existence of an anti-apoptotic multi-drug resistant pool of cancer cells in CLL patients, and validates a novel pharmaceutically tractable pathway to deplete this reservoir. Citation Format: Kallesh D. Jayappa, Caroline Farrington, Vicki L. Gordon, Shekhar Saha, Christopher Morris, Krista M. Isaac, Timothy P. Bender, Michael E. Williams, Craig A. Portell, Goutham Narla, Michael J. Weber. The PP2A activation using a small molecule agonist triggers apoptosis by releasing mitochondrial permeability transition pores in multi-drug resistant leukemic B cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 937.

Muskellunge Esox masquinongy is a popular species commonly introduced to warm-water reservoirs; however, little is known about seasonal habitat use and movement in these systems which may result in reservoir escapement and reduced Muskellunge abundance. Our objectives were to assess Muskellunge seasonal behaviors and quantify escapement and natural mortality to determine their effects on populations. Muskellunge captured from the lake and spillway were implanted with radio tags in Big Creek (n = 17) and Brushy Creek (n = 30) lakes, Iowa, USA beginning October 2016 and tracked through May 2019. Telemetry data were used to quantify depth at fish locations, movement rates, annual core and home ranges, and proportions of tagged Muskellunge using spillway approach areas. Telemetry encounter data were analyzed using a multi-state model with water temperature and reservoir water level covariates to estimate escapement and natural mortality. Muskellunge in Brushy Creek were located in deeper water than in Big Creek, but depth and movement were similar across seasons and behavior did not differ between fish captured in-lake and the spillway. Big Creek Muskellunge exhibited greater movements in spring, were located in shallow water and moved less in summer, and were found in deeper water during winter. Core and home ranges were similar between lakes and many tagged Muskellunge frequently used spillway approach areas during spring and summer. No escapement occurred from Big Creek (physical barrier on spillway) while weekly escapement probability from Brushy Creek (no barrier) was up to 0.13 and annual escapement ranged from 18 to 54 %. Escapement was greatest from May-August and increased with increasing weekly maximum reservoir level. Natural mortality was similar between systems, ranged from 15 to 18 % annually, and increased with water temperature. Our results suggest escapement can lead to greater loss of Muskellunge from reservoir populations than natural mortality and may be greater in spring and summer. However, escapement does not appear to be associated with fish behaviors.

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.