Evaluation of "appropriate use criteria" for surgical decision-making in lumbar degenerative spondylolisthesis. A controlled, multicentre, prospective observational study.

INTRODUCTION: Selecting patients with lumbar degenerative spondylolisthesis (LDS) for surgery is difficult. Appropriate use criteria (AUC) have been developed to clarify the indications for LDS surgery but have not been evaluated in controlled studies. METHODS: This prospective, controlled, multicentre study involved 908 patients (561 surgical and 347 non-surgical controls; 69.5 ± 9.7y; 69% female), treated as per normal clinical practice. Their appropriateness for surgery was afterwards determined using the AUC. They completed the Core Outcome Measures Index (COMI) at baseline and 12 months' follow-up. Multiple regression adjusting for confounders evaluated the influence of appropriateness designation and treatment received on the 12-month COMI and achievement of MCIC (≥ 2.2-point-reduction). RESULTS: As per convention, appropriate (A) and uncertain (U) groups were combined for comparison with the inappropriate (I) group. For the adjusted 12-month COMI, the benefit of surgery relative to non-surgical care was not significantly greater for the A/U than the I group (p = 0.189). There was, however, a greater treatment effect of surgery for those with higher baseline COMI (p = 0.035). The groups' adjusted probabilities of achieving MCIC were: 83% (A/U, receiving surgery), 71% (I, receiving surgery), 50% (A/U, receiving non-surgical care), and 32% (I, receiving non-surgical care). CONCLUSIONS: A/U patients receiving surgery had the highest chances of achieving MCIC, but the AUC were not able to identify which patients had a greater treatment effect of surgery relative to non-surgical care. The identification of other characteristics that predict a greater treatment effect of surgery, in addition to baseline COMI, is required to improve decision-making.

Transmission-Based Vertebrae Strength Probe Development: Far Field Probe Property Extraction and Integrated Machine Vision Distance Validation Experiments.

We are developing a transmission-based probe for point-of-care assessment of vertebrae strength needed for fabricating the instrumentation used in supporting the spinal column during spinal fusion surgery. The device is based on a transmission probe whereby thin coaxial probes are inserted into the small canals through the pedicles and into the vertebrae, and a broad band signal is transmitted from one probe to the other across the bone tissue. Simultaneously, a machine vision scheme has been developed to measure the separation distance between the probe tips while they are inserted into the vertebrae. The latter technique includes a small camera mounted to the handle of one probe and associated fiducials printed on the other. Machine vision techniques make it possible to track the location of the fiducial-based probe tip and compare it to the fixed coordinate location of the camera-based probe tip. The combination of the two methods allows for straightforward calculation of tissue characteristics by exploiting the antenna far field approximation. Validation tests of the two concepts are presented as a precursor to clinical prototype development.

Diverse segments of the US public underestimate the environmental concerns of minority and low-income Americans.

In a nationally representative survey experiment, diverse segments of the US public underestimated the environmental concerns of nonwhite and low-income Americans and misperceived them as lower than those of white and more affluent Americans. Moreover, both whites and nonwhites and higher- and lower-income respondents associated the term "environmentalist" with whites and the well-educated, suggesting that shared cultural stereotypes may drive these misperceptions. This environmental belief paradox-a tendency to misperceive groups that are among the most environmentally concerned and most vulnerable to a wide range of environmental impacts as least concerned about the environment-was largely invariant across demographic groups and also extended to the specific issue of climate change. Suggesting these beliefs are malleable, exposure to images of a racially diverse (vs. nondiverse) environmental organization in an embedded randomized experiment reduced the perceived gap between whites' and nonwhites' environmental concerns and strengthened associations between nonwhites and the category "environmentalists" among minority respondents. These findings suggest that stereotypes about others' environmental attitudes may pose a barrier to broadening public engagement with environmental initiatives, particularly among populations most vulnerable to negative environmental impacts.

Myeloid ERK5 deficiency suppresses tumor growth by blocking protumor macrophage polarization via STAT3 inhibition.

Owing to the prevalence of tumor-associated macrophages (TAMs) in cancer and their unique influence upon disease progression and malignancy, macrophage-targeted interventions have attracted notable attention in cancer immunotherapy. However, tractable targets to reduce TAM activities remain very few and far between because the signaling mechanisms underpinning protumor macrophage phenotypes are largely unknown. Here, we have investigated the role of the extracellular-regulated protein kinase 5 (ERK5) as a determinant of macrophage polarity. We report that the growth of carcinoma grafts was halted in myeloid ERK5-deficient mice. Coincidentally, targeting ERK5 in macrophages induced a transcriptional switch in favor of proinflammatory mediators. Further molecular analyses demonstrated that activation of the signal transducer and activator of transcription 3 (STAT3) via Tyr705 phosphorylation was impaired in erk5-deleted TAMs. Our study thus suggests that blocking ERK5 constitutes a treatment strategy to reprogram macrophages toward an antitumor state by inhibiting STAT3-induced gene expression.

Discovery of a Gatekeeper Residue in the C-Terminal Tail of the Extracellular Signal-Regulated Protein Kinase 5 (ERK5).

The extracellular signal-regulated protein kinase 5 (ERK5) is a non-redundant mitogen-activated protein kinase (MAPK) that exhibits a unique C-terminal extension which comprises distinct structural and functional properties. Here, we sought to elucidate the significance of phosphoacceptor sites in the C-terminal transactivation domain of ERK5. We have found that Thr732 acted as a functional gatekeeper residue controlling C-terminal-mediated nuclear translocation and transcriptional enhancement. Consistently, using a non-bias quantitative mass spectrometry approach, we demonstrated that phosphorylation at Thr732 conferred selectivity for binding interactions of ERK5 with proteins related to chromatin and RNA biology, whereas a number of metabolic regulators were associated with full-length wild type ERK5. Additionally, our proteomic analysis revealed that phosphorylation of the Ser730-Glu-Thr732-Pro motif could occur independently of dual phosphorylation at Thr218-Glu-Tyr220 in the activation loop. Collectively, our results firmly establish the significance of C-terminal phosphorylation in regulating ERK5 function. The post-translational modification of ERK5 on its C-terminal tail might be of particular relevance in cancer cells where ERK5 has be found to be hyperphosphoryated.

Exploring the Role of PGC-1α in Defining Nuclear Organisation in Skeletal Muscle Fibres.

Muscle fibres are multinucleated cells, with each nucleus controlling the protein synthesis in a finite volume of cytoplasm termed the myonuclear domain (MND). What determines MND size remains unclear. In the present study, we aimed to test the hypothesis that the level of expression of the transcriptional coactivator PGC-1α and subsequent activation of the mitochondrial biogenesis are major contributors. Hence, we used two transgenic mouse models with varying expression of PGC-1α in skeletal muscles. We isolated myofibres from the fast twitch extensor digitorum longus (EDL) and slow twitch diaphragm muscles. We then membrane-permeabilised them and analysed the 3D spatial arrangements of myonuclei. In EDL muscles, when PGC-1α is over-expressed, MND volume decreases; whereas, when PGC-1α is lacking, no change occurs. In the diaphragm, no clear difference was noted. This indicates that PGC-1α and the related mitochondrial biogenesis programme are determinants of MND size. PGC-1α may facilitate the addition of new myonuclei in order to reach MND volumes that can support an increased mitochondrial density. J. Cell. Physiol. 232: 1270-1274, 2017. © 2016 Wiley Periodicals, Inc.

When does deprivation motivate future-oriented thinking? The case of climate change.

Pepper & Nettle overstate cross-domain evidence of present-oriented thinking among lower-socioeconomic-status (SES) groups and overlook key social and contextual drivers of temporal decision making. We consider psychological research on climate change - a quintessential intertemporal problem that implicates inequities and extrinsic mortality risk - documenting more future-oriented thinking among low- compared to high-SES groups.

Core outcome domains for clinical trials in non-specific low back pain.

PURPOSE: Inconsistent reporting of outcomes in clinical trials of patients with non-specific low back pain (NSLBP) hinders comparison of findings and the reliability of systematic reviews. A core outcome set (COS) can address this issue as it defines a minimum set of outcomes that should be reported in all clinical trials. In 1998, Deyo et al. recommended a standardized set of outcomes for LBP clinical research. The aim of this study was to update these recommendations by determining which outcome domains should be included in a COS for clinical trials in NSLBP. METHODS: An International Steering Committee established the methodology to develop this COS. The OMERACT Filter 2.0 framework was used to draw a list of potential core domains that were presented in a Delphi study. Researchers, care providers and patients were invited to participate in three Delphi rounds and were asked to judge which domains were core. A priori criteria for consensus were established before each round and were analysed together with arguments provided by panellists on importance, overlap, aggregation and/or addition of potential core domains. The Steering Committee discussed the final results and made final decisions. RESULTS: A set of 280 experts was invited to participate in the Delphi; response rates in the three rounds were 52, 50 and 45%. Of 41 potential core domains presented in the first round, 13 had sufficient support to be presented for rating in the third round. Overall consensus was reached for the inclusion of three domains in this COS: 'physical functioning', 'pain intensity' and 'health-related quality of life'. Consensus on 'physical functioning' and 'pain intensity' was consistent across all stakeholders, 'health-related quality of life' was not supported by the patients, and all the other domains were not supported by two or more groups of stakeholders. Weighting all possible argumentations, the Steering Committee decided to include in the COS the three domains that reached overall consensus and the domain 'number of deaths'. CONCLUSIONS: The following outcome domains were included in this updated COS: 'physical functioning', 'pain intensity', 'health-related quality of life' and 'number of deaths'. The next step for the development of this COS will be to determine which measurement instruments best measure these domains.

Racial attitudes and visual cues in political judgments: support for Obama during the 2008 presidential election.

The present longitudinal study examined the complex role of race-including racial attitudes and visual representations of race-in White Americans' responses to Obama during the 2008 U.S. presidential election. Consistent with prior research, participants who perceived Obama as darker skinned were less likely to vote for him and generally evaluated Obama less positively. It is important to note, however, that these effects were stronger among Whites with more egalitarian expressed racial attitudes. Moreover, this pattern occurred over and above effects of political orientation and remained stable over a 2-month period, including pre- and postelection. Implications of these findings for understanding the complex and persistent influence of race in politics are considered.

Climate change and health equity: A research agenda for psychological science.

Climate change poses unique and substantial threats to public health and well-being, from heat stress, flooding, and the spread of infectious disease to food and water insecurity, conflict, displacement, and direct health hazards linked to fossil fuels. These threats are especially acute for frontline communities. Addressing climate change and its unequal impacts requires psychologists to consider temporal and spatial dimensions of health, compound risks, as well as structural sources of vulnerability implicated by few other public health challenges. In this review, we consider climate change as a unique context for the study of health inequities and the roles of psychologists and health care practitioners in addressing it. We conclude by discussing the research infrastructure needed to broaden current understanding of these inequities, including new cross-disciplinary, institutional, and community partnerships, and offer six practical recommendations for advancing the psychological study of climate health equity and its societal relevance. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Evaluation of the Clinical and Radiographic Degenerative Spondylolisthesis (CARDS) classification system as a guide to surgical technique selection.

BACKGROUND CONTEXT: The role of fusion in degenerative spondylolisthesis (DS) is controversial. The Clinical and Radiographic Degenerative Spondylolisthesis (CARDS) classification system was developed to assist surgeons in surgical technique selection based on individual patient characteristics. This system has not been clinically validated as a guide to surgical technique selection. PURPOSE: The purpose of this study was to determine if outcomes vary with different surgical techniques across the CARDS categories. STUDY DESIGN/SETTING: Prospective cohort study performed at one Swiss and one American spine center. PATIENT SAMPLE: Five hundred eight patients with DS undergoing surgical treatment. OUTCOME MEASURES: Core Outcomes Measure Index (COMI) at 3 months and 12 months postoperatively. METHODS: Patients undergoing surgery for DS were enrolled at 2 institutions and classified according to the CARDS system using dynamic radiographs. The Core Outcome Measure Index (COMI) was completed preoperatively, and 3 and 12 months postoperatively. Surgical technique was classified as uninstrumented (decompression alone or decompression with uninstrumented fusion) or instrumented (decompression with pedicle screw instrumentation with or without interbody fusion). Unadjusted analyses and mixed effect models compared COMI scores between the two surgery technique groups (uninstrumented vs instrumented), stratified by CARDS category over time. Reoperation rates were also compared between the surgery technique groups stratified by CARDS category. Partial funding was given through NASS grant for clinical research. RESULTS: Five hundred five out of 508 patients enrolled in the study had sufficient data to be classified according to CARDS. Seven percent were classified as CARDS A, 28% as CARDS B, 48% as CARDS C, and 17% as CARDS D (CARDS A most "stable," CARDS D least "stable"). One hundred and thirty-three patients (26%) underwent decompression alone, 30 (6%) underwent decompression and uninstrumented fusion, 42 (8%) underwent decompression and posterolateral instrumented fusion, and 303 (60%) underwent decompression with posterolateral and interbody instrumented fusion. Patients in the least "stable" categories tended to be less likely to be treated with an uninstrumented technique (CARDS D 19% vs 32% for the other categories, p=.10). There were no significant differences in 3 or 12-month COMI scores between surgical technique groups stratified by CARDS category in the unadjusted or adjusted analyses. In the unadjusted analyses, there was a trend towards less improvement in 12-month COMI change score in the CARDS D patients in the uninstrumented group compared to the instrumented group (-2.7 vs -4.1, p=.10). Reoperation rates were not significantly different between the surgical technique groups stratified by CARDS category. CONCLUSIONS: In general, outcomes for uninstrumented and instrumented surgical techniques were similar across the CARDS categories. Surgeons likely took factors included in CARDS into account during surgical technique selection. This resulted in a low number of CARDS D (n=15) patients being treated with uninstrumented techniques, which limited the statistical power of this analysis. As such, this study does not validate CARDS as a useful classification system for surgical technique selection in DS.

Integration of High-Throughput Imaging and Multiparametric Metabolic Profiling Reveals a Mitochondrial Mechanism of Tenofovir Toxicity.

Nephrotoxicity is a major cause of kidney disease and failure in drug development, but understanding of cellular mechanisms is limited, highlighting the need for better experimental models and methodological approaches. Most nephrotoxins damage the proximal tubule (PT), causing functional impairment of solute reabsorption and systemic metabolic complications. The antiviral drug tenofovir disoproxil fumarate (TDF) is an archetypal nephrotoxin, inducing mitochondrial abnormalities and urinary solute wasting, for reasons that were previously unclear. Here, we developed an automated, high-throughput imaging pipeline to screen the effects of TDF on solute transport and mitochondrial morphology in human-derived RPTEC/TERT1 cells, and leveraged this to generate realistic models of functional toxicity. By applying multiparametric metabolic profiling-including oxygen consumption measurements, metabolomics, and transcriptomics-we elucidated a highly robust molecular fingerprint of TDF exposure. Crucially, we identified that the active metabolite inhibits complex V (ATP synthase), and that TDF treatment causes rapid, dose-dependent loss of complex V activity and expression. Moreover, we found evidence of complex V suppression in kidney biopsies from humans with TDF toxicity. Thus, we demonstrate an effective and convenient experimental approach to screen for disease relevant functional defects in kidney cells in vitro, and reveal a new paradigm for understanding the pathogenesis of a substantial cause of nephrotoxicity.

Mapping the purple menace: spatiotemporal distribution of purple loosestrife (Lythrum salicaria) along roadsides in northern New York State.

Purple loosestrife (Lythrum salicaria L.) is an invasive, herbaceous plant, frequently found in wetlands, creating monoculture stands, resulting in intensive management strategies in central New York, Ontario, and Quebec. The goal of this study was to identify the extent of infestations and to investigate factors that promote the spread of purple loosestrife. We attempted to answer several questions regarding level of infestation, connection to mowing, and influence of culverts. During flowering season in July and August, 2017-2019, we mapped infestations along 150 km (93 miles) of state highway between the Adirondack Park and the St. Lawrence River using the ESRI Collector app. The results of our preliminary analysis revealed significant increase in the number of plants (P < 0.001). In addition, a linear correlation analysis demonstrated a higher loosestrife density with an increase in plant species richness and a decrease in the distance to the closest infestation and wetland (P < 0.001 each). We found no statistical evidence that mowing promotes the spread of loosestrife. As expected, there were more individual infestations in highway ditches, but larger and denser infestations in wetlands (P = 0.003 in 2019). Culverts enable purple loosestrife to spread underneath highways and should be managed to prevent spread.

Associations between Homelessness and Alzheimer's Disease and Related Dementia: A Systematic Review.

The homeless population in the United States is rapidly aging, with a parallel increase in Alzheimer's disease and related dementia (ADRD). During an evolving pandemic that jeopardizes employment and housing, assessing the relationship between ADRD and homelessness is critical since the latter is potentially intervenable. The objective of this study is to review the literature and determine whether there is an association between homelessness and dementia risk. A systematic review of existing studies was conducted through PubMED, SCOPUS, and EMBASE among others. Of the 228 results found, nine met inclusion criteria. Homeless studies mainly centered on veteran populations (n = 6/9). There is a complex relationship suggesting homelessness as a risk for and consequence of ADRD but also co-occurrence with psychiatric disorders, substance abuse, and traumatic injuries. Future studies should employ enumeration surveys with modular longitudinal tracking and measure social determinants of health, discrimination, chronic stress, and mood disorders.

Plant vs. Kidney: Evaluating Nephrotoxicity of Botanicals with the Latest Toxicological Tools.

Botanicals can cause nephrotoxicity via numerous mechanisms, including disrupting renal blood flow, damaging compartments along the nephron, and obstructing urinary flow. While uncommon, there are various reports of botanical-induced nephrotoxicity in the literature, such as from aristolochia (Aristolochia spp.) and rhubarb (Rheum spp.). However, at present, it is a challenge to assess the toxic potential of botanicals because their chemical composition is variable due to factors such as growing conditions and extraction techniques. Therefore, selecting a single representative sample for an in vivo study is difficult. Given the increasing use of botanicals as dietary supplements and herbal medicine, new approach methodologies (NAMs) are needed to evaluate the potential for renal toxicity to ensure public safety. Such approaches include in vitro models that use layers of physiological complexity to emulate the in vivo microenvironment, enhance the functional viability and differentiation of cell cultures, and improve sensitivity to nephrotoxic insults. Furthermore, computational tools such as physiologically based pharmacokinetic (PBPK) modeling can add confidence to these tools by simulating absorption, distribution, metabolism, and excretion. The development and implementation of NAMs for renal toxicity testing will allow specific mechanistic data to be generated, leading to a better understanding of the nephrotoxic potential of botanicals.

Challenges and adaptations to public involvement with marginalised groups during the COVID-19 pandemic: commentary with illustrative case studies in the context of patient safety research.

Patient and public involvement (PPI) is integral to research on patient safety in the NIHR Greater Manchester Patient Safety Translational Research Centre (NIHR GMPSTRC), and is central to our patient safety research within our theme focusing on people in marginalised groups. Due to the impact of COVID-19, researchers had to adapt how they do PPI. For marginalised groups, remote working and digital adaptations (the key adaptations made in accessing and utilising health services in the United Kingdom during COVID-19) can potentially lead to further marginalisation of people already marginalised and provide new barriers to others. This editorial showcases three case examples of PPI with marginalised groups during COVID-19, these are with: (1) adults with vision impairments, (2) adults and carers with lived experience of self-harm and/ or suicide and (3) adults with lived experience of homelessness. In these case examples, we focus on challenges relating to key aspects of PPI during the pandemic. First, setting up a PPI advisory group and secondly maintaining relationships and effective PPI with a pre-existing advisory group. We contrast these examples using more traditional ways of 'doing PPI' i.e. involving public contributors in various stages of the research cycle, with a more fully 'co-produced' approach to research when developing a new patient safety intervention. Important considerations for PPI with marginalised groups during COVID-19 include: how to avoid exacerbating the digital divide when using video conferencing for PPI, the need for enhanced awareness around flexibility and resources, and the value of working closely with specialist charities to enable adaptations that are sensitive to the changed circumstances and needs of PPI contributors.

The National Institute of Health Research (NIHR) Greater Manchester Patient Safety Translational research Centre (GMPSTRC) carries out research to improve patient safety. We work in partnership with patients and members of the public to plan, manage, design, and carry out the research. This is labelled as patient and public involvement. A key area of GMPSTRC research focuses on people who may be marginalised from healthcare and potentially suffer increased patient safety risks relative to the general population. COVID-19 impacted on research in multiple ways, notably how researchers work with members of the public. Remote working via the use of internet enabled technology has now become more commonplace, although this raises concerns about digital exclusion and how to address barriers when face-to-face PPI is not possible. This article showcases three examples of how researchers and public contributors with lived experience have adapted to working together during the COVID-19 pandemic. These case examples are: (1) setting up a public involvement group for developing an intervention to reduce medication errors for adults with vision impairments; (2) working with a pre-existing group of public contributors who are adults and carers with lived experience of self-harm and/or suicide; and (3) working with a charity called Groundswell who train and support researchers with lived experience of homelessness. Challenges during COVID-19 have been making video conferencing meetings accessible to members who have a range of different needs, and addressing the digital divide by allowing members flexibility in how they contribute to research. The article provides examples of how these challenges were addressed.

Inhibiting ERK5 overcomes breast cancer resistance to anti-HER2 therapy by targeting the G1/S cell cycle transition.

Targeting the human epidermal growth factor receptor 2 (HER2) became a landmark in the treatment of HER2-driven breast cancer. Nonetheless, the clinical efficacy of anti-HER2 therapies can be short-lived and a significant proportion of patients ultimately develop metastatic disease and die. One striking consequence of oncogenic activation of HER2 in breast cancer cells is the constitutive activation of the extracellular-regulated protein kinase 5 (ERK5) through its hyperphosphorylation. In this study, we sought to decipher the significance of this unique molecular signature in promoting therapeutic resistance to anti-HER2 agents. We found that a small-molecule inhibitor of ERK5 suppressed the phosphorylation of the retinoblastoma protein (RB) in HER2 positive breast cancer cells. As a result, ERK5 inhibition enhanced the anti-proliferative activity of single-agent anti-HER2 therapy in resistant breast cancer cell lines by causing a G1 cell cycle arrest. Moreover, ERK5 knockdown restored the anti-tumor activity of the anti-HER2 agent lapatinib in human breast cancer xenografts. Taken together, these findings support the therapeutic potential of ERK5 inhibitors to improve the clinical benefit that patients receive from targeted HER2 therapies.

Ethics, morality, and the psychology of climate justice.

Climate change is increasingly understood as a social justice issue by academics, policymakers, and the public; however, the nature of these perceptions and their implications for cooperation and decision-making have only recently begun to receive empirical attention. We review emerging empirical work that suggests that morality and justice perceptions can serve as both a bridge and a barrier to cooperation around climate change and highlight two critical areas for future development, identifying psychological processes that promote and impede climate vulnerability and that enhance equity in the design and implementation of climate solutions. We argue that conceptualizing climate justice as a multidimensional process addressing both social and structural barriers can stimulate new psychological research and help align disparate approaches within the social sciences.

The extracellular-regulated protein kinase 5 (ERK5) enhances metastatic burden in triple-negative breast cancer through focal adhesion protein kinase (FAK)-mediated regulation of cell adhesion.

There is overwhelming clinical evidence that the extracellular-regulated protein kinase 5 (ERK5) is significantly dysregulated in human breast cancer. However, there is no definite understanding of the requirement of ERK5 in tumor growth and metastasis due to very limited characterization of the pathway in disease models. In this study, we report that a high level of ERK5 is a predictive marker of metastatic breast cancer. Mechanistically, our in vitro data revealed that ERK5 was critical for maintaining the invasive capability of triple-negative breast cancer (TNBC) cells through focal adhesion protein kinase (FAK) activation. Specifically, we found that phosphorylation of FAK at Tyr397 was controlled by a kinase-independent function of ERK5. Accordingly, silencing ERK5 in mammary tumor grafts impaired FAK phosphorylation at Tyr397 and suppressed TNBC cell metastasis to the lung without preventing tumor growth. Collectively, these results establish a functional relationship between ERK5 and FAK signaling in promoting malignancy. Thus, targeting the oncogenic ERK5-FAK axis represents a promising therapeutic strategy for breast cancer exhibiting aggressive clinical behavior.