Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression.

How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissue-specific expression of the human long noncoding RNA LINK-A in mouse mammary glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48-polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb and p53, and sensitized mammary gland tumors to immune checkpoint blockers. Patients with programmed ccll death protein-1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels and downregulated PLC components. Hence we demonstrate lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which provides the basis for developing combinational immunotherapy treatment regimens and early TNBC prevention.

Hypoxia Reduction Sensitizes Refractory Cancers to Immunotherapy.

In order to fuel their relentless expansion, cancers must expand their vasculature to augment delivery of oxygen and essential nutrients. The disordered web of irregular vessels that results, however, leaves gaps in oxygen delivery that foster tumor hypoxia. At the same time, tumor cells increase their oxidative metabolism to cope with the energetic demands of proliferation, which further worsens hypoxia due to heightened oxygen consumption. In these hypoxic, nutrient-deprived environments, tumors and suppressive stroma evolve to flourish while antitumor immunity collapses due to a combination of energetic deprivation, toxic metabolites, acidification, and other suppressive signals. Reversal of cancer hypoxia thus has the potential to increase the survival and effector function of tumor-infiltrating T cells, as well as to resensitize tumors to immunotherapy. Early clinical trials combining hypoxia reduction with immune checkpoint blockade have shown promising results in treating patients with advanced, metastatic, and therapeutically refractory cancers.

Outcomes following tibiotalocalcaneal arthrodesis using a solid posterior offset intramedullary nail in 44 patients with a minimum 30-month follow-up.

BACKGROUND: Tibiotalocalcaneal arthrodesis is frequently performed by foot and ankle surgeons in the management of complex ankle and hindfoot pathology. In this study, the authors describe the clinical and radiological outcomes of tibiotalocalcaneal arthrodesis using a solid posterior offset hindfoot arthrodesis nail. METHODS: Forty-four consecutive patients underwent tibiotalocalcaneal arthrodesis by a single surgeon operating in two centers. Clinical and radiological outcomes were assessed preoperatively and at 6-month, 12-month and final follow-up (mean 47 months). Clinical outcomes were assessed with VAS, AOFAS and MOXFQ scores. Serial radiographs were used to assess union at each follow-up visit. RESULTS: Forty-four patients attended 12-month and final follow-up (mean 47 months). A total of 44 (100%) ankle joints and 44 (100%) subtalar joints were completely united at 12-month follow-up. The VAS score improved significantly from a mean of 6.5 preoperatively to a mean of 0.98 at final follow-up (P = <0.0001). AOFAS score improved significantly from a mean of 36.4 preoperatively to a mean of 73 at final follow-up (P = <0.0001). MOXFQ score improved significantly from a mean of 44.5 preoperatively to a mean of 12.7 at final follow-up (P = <0.0001). The mean change in frontal plane alignment was 5.7 degrees (P = 0.005). A total of 6 patients (13.6%) had an adverse event during the course of the study. CONCLUSIONS: Tibiotalocalcaneal arthrodesis with a solid posterior offset hindfoot arthrodesis nail is a safe and effective surgical option for patients with severe ankle and hindfoot pathology. It has a high union rate, low complication rate and significantly improves clinical outcomes.

Bilateral first metatarsophalangeal joint arthrodesis: An investigation of functional, surgical and radiological outcomes.

BACKGROUND: First metatarsophalangeal joint (MTPJ) arthrodesis is a commonly utilised procedure. In this study, the authors aim to explore functional outcomes of patients undergoing nonsynchronous bilateral first MTPJ arthrodesis under the care of a single surgeon using a compression screw/locking plate construct. METHODS: This is a prospectively collected, retrospectively analysed case series of fifty five patients who underwent bilateral nonsynchronous first MTPJ arthrodesis. Clinical and radiological outcomes were assessed preoperatively and at a minimum of two years postoperatively. Clinical outcomes were assessed using the Foot and Ankle Outcome Score (FAOS), the Self-Reported Foot and Ankle Score (SEFAS) and the Sports Questionnaire version 1 (SQ). Postoperative radiographs were used to assess evidence of union and compare both hallux valgus and intermetatarsal angles. Removal of hardware, revision surgery and correction of deformities were also recorded. RESULTS: Fifty five patients were included in the study. There was statistically significant improvements in all five facets of the FAOS (p value < 0.05). The mean postoperative SEFAS was 45.1. In total, patients participated in thirteen different sporting activities. This represented 92 patient specific activities preoperatively and 104 postoperatively. The most common activities were walking, cycling and swimming. Overall, 94.5% (N = 52) of the cohort were satisfied with their return to sport while 98.2% (N = 54) would recommend bilateral first MTPJ arthrodesis. Mean reductions in hallux valgus angles and intermetatarsal angles were noted at 18.87 and 4.69 degrees respectively. There was one non-union in the cohort which required revision surgery. One patient required removal of hardware. CONCLUSIONS: Bilateral first MTPJ arthrodesis is a safe and effective surgical option for patients with bilateral first MTPJ pathology. It has a high union rate, low complication rate and significantly improves clinical outcomes and allows patients reliably return to physical activities.

Testing the hierarchy of predictability in grassland restoration across a gradient of environmental severity.

Ecological restoration is critical for recovering degraded ecosystems but is challenged by variable success and low predictability. Understanding which outcomes are more predictable and less variable following restoration can improve restoration effectiveness. Recent theory asserts that the predictability of outcomes would follow an order from most to least predictable from coarse to fine community properties (physical structure > taxonomic diversity > functional composition > taxonomic composition) and that predictability would increase with more severe environmental conditions constraining species establishment. We tested this "hierarchy of predictability" hypothesis by synthesizing outcomes along an aridity gradient with 11 grassland restoration projects across the United States. We used 1829 vegetation monitoring plots from 227 restoration treatments, spread across 52 sites. We fit generalized linear mixed-effects models to predict six indicators of restoration outcomes as a function of restoration characteristics (i.e., seed mixes, disturbance, management actions, time since restoration) and used variance explained by models and model residuals as proxies for restoration predictability. We did not find consistent support for our hypotheses. Physical structure was among the most predictable outcomes when the response variable was relative abundance of grasses, but unpredictable for total canopy cover. Similarly, one dimension of taxonomic composition related to species identities was unpredictable, but another dimension of taxonomic composition indicating whether exotic or native species dominated the community was highly predictable. Taxonomic diversity (i.e., species richness) and functional composition (i.e., mean trait values) were intermittently predictable. Predictability also did not increase consistently with aridity. The dimension of taxonomic composition related to the identity of species in restored communities was more predictable (i.e., smaller residuals) in more arid sites, but functional composition was less predictable (i.e., larger residuals), and other outcomes showed no significant trend. Restoration outcomes were most predictable when they related to variation in dominant species, while those responding to rare species were harder to predict, indicating a potential role of scale in restoration predictability. Overall, our results highlight additional factors that might influence restoration predictability and add support to the importance of continuous monitoring and active management beyond one-time seed addition for successful grassland restoration in the United States.

Functional Capabilities After First Metatarsal Phalangeal Joint Arthrodesis Using a Locking Plate and Compression Screw Construct.

Arthrodesis of the first metatarsal phalangeal joint (MTPJ) is a widely utilized surgical procedure for a wide array of metatarsal pathologies. This study aims to explore the functional limitations following first MTPJ arthrodesis, overall satisfaction and patient's abilities to achieve activities of daily living (ADL). This prospective cohort study assessed functional limitations as well as footwear and lifestyle restrictions using several questionnaires. One hundred and three participants who had a first MTPJ arthrodesis under the care of a single surgeon were recruited. Pre- and postoperative patient-reported outcome measures were recorded. The American Orthopaedic Foot and Ankle Score (AOFAS) and the Manchester-Oxford Foot Questionnaire were also used to further examine functional status. Hallux valgus angle (HVA) and intermetatarsal angle (IMA) were compared using preoperative and postoperative weightbearing radiographs and successful fusion was recorded. Complications were documented and are discussed in detail. The duration of follow-up was more than 12 months. There was one nonunion in the cohort while 2 patients experienced delay to fusion. Approximately 97% of patients were very satisfied with the procedure and their ability to achieve ADLs post operatively. A further 82.5% of patients were able to return to wearing nonadaptive footwear. The mean reduction in HVA and IMA was 21.78° and 6.84°, respectively. This study demonstrates the safe and successful use of a compression screw/locking plate construct for arthrodesis of the first MTPJ. Furthermore, the study provides clear evidence of high levels of functionality after the procedure with statistically significant differences (p value <.05) in all 4 facets of the AOFAS questionnaire as well as several notable differences in activity levels and footwear restrictions pre and postoperatively.

Tumor hypermetabolism confers resistance to immunotherapy.

Advances in our understanding of tumor immune biology and development of cancer immunotherapies have led to improved outcomes for patients that suffer from aggressive cancers such as metastatic melanoma. Despite these advances, a significant proportion of patients still fail to benefit, and as a result, attention has shifted to understanding how cancer cells escape immune destruction. Of particular interest is the metabolic landscape of the tumor microenvironment, as recent studies have demonstrated how both competition for essential nutrients and depletion of specific amino acids can promote T cell dysfunction. Here, we will discuss the major energetic pathways engaged by both T cells and cancer cells, metabolic substrates present in the tumor microenvironment, and emerging therapeutic strategies that seek to improve T cell metabolic fitness and bolster the antitumor immune response.

New Hope for Therapeutic Cancer Vaccines in the Era of Immune Checkpoint Modulation.

The driver and passenger mutations accumulated in the process of malignant transformation offer an adequate spectrum of immune visible alterations to the cellular proteome and resulting peptidome to render these cancers targetable-and, in theory, rejectable-by the host T cell immune response. In addition, cancers often overexpress tissue-specific and developmental antigens to which immune tolerance is incomplete. Sometimes, virally transferred oncogenes drive malignant transformation and remain expressed throughout the cancer. Despite this state of antigenic sufficiency, cancer grows progressively and overcomes all efforts of the host immune system to contain it. While therapeutic cancer vaccination can mobilize high frequencies of tumor-specific T cells, these responses remain subject to intratumoral attenuation. Antibody modulation of T cell function through checkpoint blockade or costimulatory activation can restore survival, proliferation, and effector function to these tumor-infiltrating T cells and convert otherwise subtherapeutic vaccines into potentially curative cancer immunotherapeutics.

Mycobacterium porcinum Skin and Soft Tissue Infections After Vaccinations - Indiana, Kentucky, and Ohio, September 2018-February 2019.

During December 2018-February 2019, a multistate investigation identified 101 patients with vaccination-associated adverse events among an estimated 940 persons in Kentucky, Indiana, and Ohio who had received influenza; hepatitis A; pneumococcal; or tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines at the workplace during September 11-November 28, 2018. These vaccines had been administered by staff members of a third-party health care company contracted by 24 businesses. Company A provided multiple vaccine types during workplace vaccination events across 54 locations in these adjoining states. Injection-site wound isolates from patients yielded Mycobacterium porcinum, a nontuberculous mycobacteria (NTM) species in the Mycobacterium fortuitum group; subtyping using pulsed-field gel electrophoresis of all 28 available isolates identified two closely related clusters. Site visits to company A and interviews with staff members identified inadequate hand hygiene, improper vaccine storage and handling, lack of appropriate medical record documentation, and lack of reporting to the Vaccine Adverse Event Reporting System (VAERS). Vaccination-associated adverse events can be prevented by training health care workers responsible for handling or administering vaccines in safe vaccine handling, administration, and storage practices, timely reporting of any suspected vaccination-associated adverse events to VAERS, and notifying public health authorities of any adverse event clusters.

Discovery of IACS-8803 and IACS-8779, potent agonists of stimulator of interferon genes (STING) with robust systemic antitumor efficacy.

Activation of the stimulator of interferon genes (STING) pathway by both exogenous and endogenous cytosolic DNA results in the production of interferon beta (IFN-ß) and is required for the generation of cytotoxic T-cell priming against tumor antigens. In the clinical setting, pharmacological stimulation of the STING pathway has the potential to synergize with immunotherapy antibodies by boosting anti-tumor immune responses. We report the discovery of two highly potent cyclic dinucleotide STING agonists, IACS-8803 and IACS-8779, which show robust activation of the STING pathway in vitro and a superior systemic anti-tumor response in the B16 murine model of melanoma when compared to one of the clinical benchmark compounds.

Biodiversity Recovery and Transformation Impacts for Wetland Biodiversity.

Life Cycle Assessment (LCA) methods for land use take both occupation and transformation impacts into account. However, for wetlands and impacts from water consumption, it is so far not possible to account for transformation impacts. It is our goal to close this research gap, by determining wetland recovery times and developing characterization factors for transformation. To do this, we conducted a meta-analysis of 59 studies analyzing biodiversity recovery in wetlands subject to passive and active restoration. Generalized linear models were fitted to the biodiversity data and age, along with other wetland characteristics (such as elevation, latitude, or climate class), and were used as predictor variables. The results indicate that elevation, latitude, type of wetland, and restoration method have the strongest effect on recovery speed. Recovery times vary from less than one year to a maximum of 107 years with passive restoration and 105 years with active restoration. Corresponding transformation characterization factors vary between 10-14 and 10-2 species-eq·year2/m3. Finally, recognizing the relevance of this work to real-world policy issues beyond LCA, we discuss the implications of our estimated restoration times on the feasibility of "biodiversity offsetting". Offsetting utilizes restoration to replace biodiversity value lost due to development impacts. Our work can help stakeholders make informed decisions on whether offsetting represents a legitimate policy option in a particular context.

Unique potential of 4-1BB agonist antibody to promote durable regression of HPV+ tumors when combined with an E6/E7 peptide vaccine.

Antibody modulation of T-cell coinhibitory (e.g., CTLA-4) or costimulatory (e.g., 4-1BB) receptors promotes clinical responses to a variety of cancers. Therapeutic cancer vaccination, in contrast, has produced limited clinical benefit and no curative therapies. The E6 and E7 oncoproteins of human papilloma virus (HPV) drive the majority of genital cancers, and many oropharyngeal tumors. We discovered 15-19 amino acid peptides from HPV-16 E6/E7 for which induction of T-cell immunity correlates with disease-free survival in patients treated for high-grade cervical neoplasia. We report here that intranasal vaccination with these peptides and the adjuvant alpha-galactosylceramide elicits systemic and mucosal T-cell responses leading to reduced HPV(+) TC-1 tumor growth and prolonged survival in mice. We hypothesized that the inability of these T cells to fully reject established tumors resulted from suppression in the tumor microenvironment which could be ameliorated through checkpoint modulation. Combining this E6/E7 peptide vaccine with checkpoint blockade produced only modest benefit; however, coadministration with a 4-1BB agonist antibody promoted durable regression of established genital TC-1 tumors. Relative to other therapies tested, this combination of vaccine and α4-1BB promoted the highest CD8(+) versus regulatory FoxP3(+) T-cell ratios, elicited 2- to 5-fold higher infiltration by E7-specific CTL, and evoked higher densities of highly cytotoxic TcEO (T cytotoxic Eomesodermin) CD8 (>70-fold) and ThEO (T helper Eomesodermin) CD4 (>17-fold) T cells. These findings have immediate clinical relevance both in terms of the direct clinical utility of the vaccine studied and in illustrating the potential of 4-1BB antibody to convert therapeutic E6/E7 vaccines already in clinical trials into curative therapies.

Expanding Kenya's protected areas under the Convention on Biological Diversity to maximize coverage of plant diversity.

Biodiversity is highly valuable and critically threatened by anthropogenic degradation of the natural environment. In response, governments have pledged enhanced protected-area coverage, which requires scarce biological data to identify conservation priorities. To assist this effort, we mapped conservation priorities in Kenya based on maximizing alpha (species richness) and beta diversity (species turnover) of plant communities while minimizing economic costs. We used plant-cover percentages from vegetation surveys of over 2000 plots to build separate models for each type of diversity. Opportunity and management costs were based on literature data and interviews with conservation organizations. Species richness was predicted to be highest in a belt from Lake Turkana through Mount Kenya and in a belt parallel to the coast, and species turnover was predicted to be highest in western Kenya and along the coast. Our results suggest the expanding reserve network should focus on the coast and northeastern provinces of Kenya, where new biological surveys would also fill biological data gaps. Meeting the Convention on Biological Diversity target of 17% terrestrial coverage by 2020 would increase representation of Kenya's plant communities by 75%. However, this would require about 50 times more funds than Kenya has received thus far from the Global Environment Facility.

Forest restoration: a global dataset for biodiversity and vegetation structure.

Restoration initiatives are becoming increasingly applied around the world. Billions of dollars have been spent on ecological restoration research and initiatives, but restoration outcomes differ widely among these initiatives in part due to variable socioeconomic and ecological contexts. Here, we present the most comprehensive dataset gathered to date on forest restoration. It encompasses 269 primary studies across 221 study landscapes in 53 countries and contains 4,645 quantitative comparisons between reference ecosystems (e.g., old-growth forest) and degraded or restored ecosystems for five taxonomic groups (mammals, birds, invertebrates, herpetofauna, and plants) and five measures of vegetation structure reflecting different ecological processes (cover, density, height, biomass, and litter). We selected studies that (1) were conducted in forest ecosystems; (2) had multiple replicate sampling sites to measure indicators of biodiversity and/or vegetation structure in reference and restored and/or degraded ecosystems; and (3) used less-disturbed forests as a reference to the ecosystem under study. We recorded (1) latitude and longitude; (2) study year; (3) country; (4) biogeographic realm; (5) past disturbance type; (6) current disturbance type; (7) forest conversion class; (8) restoration activity; (9) time that a system has been disturbed; (10) time elapsed since restoration started; (11) ecological metric used to assess biodiversity; and (12) quantitative value of the ecological metric of biodiversity and/or vegetation structure for reference and restored and/or degraded ecosystems. These were the most common data available in the selected studies. We also estimated forest cover and configuration in each study landscape using a recently developed 1 km consensus land cover dataset. We measured forest configuration as the (1) mean size of all forest patches; (2) size of the largest forest patch; and (3) edge:area ratio of forest patches. Global analyses of the factors influencing ecological restoration success at both the local and landscape scale are urgently needed to guide restoration initiatives and to further develop restoration knowledge in a topic area of much contemporary interest.

Role of the tumor microenvironment in mature B-cell lymphoid malignancies.

The tumor microenvironment is the cellular and molecular environment in which the tumor exists and with which it continuously interacts. In B-cell lymphomas, this microenvironment is intriguing in that it plays critical roles in the regulation of tumor cell survival and proliferation, fostering immune escape as well as the development of treatment resistance. The purpose of this review is to summarize the proceedings of the Second Annual Summit on the Immune Microenvironment in Hematologic Malignancies that took place on September 11-12, 2014 in Dublin, Ireland. We provide a timely overview of the composition and biological relevance of the cellular and molecular microenvironment interface and discuss the role of interactions between the microenvironment and neoplastic cells in a variety of B-cell lymphomas. In addition, we focus on various novel therapeutic strategies that target the tumor microenvironment, including agents that modulate B-cell receptor pathways and immune-checkpoints, chimeric antigen receptor T cells and immunomodulatory agents.

How Well Does LCA Model Land Use Impacts on Biodiversity?--A Comparison with Approaches from Ecology and Conservation.

The modeling of land use impacts on biodiversity is considered a priority in life cycle assessment (LCA). Many diverging approaches have been proposed in an expanding literature on the topic. The UNEP/SETAC Life Cycle Initiative is engaged in building consensus on a shared modeling framework to highlight best-practice and guide model application by practitioners. In this paper, we evaluated the performance of 31 models from both the LCA and the ecology/conservation literature (20 from LCA, 11 from non-LCA fields) according to a set of criteria reflecting (i) model completeness, (ii) biodiversity representation, (iii) impact pathway coverage, (iv) scientific quality, and (v) stakeholder acceptance. We show that LCA models tend to perform worse than those from ecology and conservation (although not significantly), implying room for improvement. We identify seven best-practice recommendations that can be implemented immediately to improve LCA models based on existing approaches in the literature. We further propose building a "consensus model" through weighted averaging of existing information, to complement future development. While our research focuses on conceptual model design, further quantitative comparison of promising models in shared case studies is an essential prerequisite for future informed model choice.

Immune checkpoint combinations from mouse to man.

The discovery that antibody blockade of the T cell co-inhibitory receptor cytotoxic T lymphocyte-associated protein 4 (CTLA-4) can restore tumor immunity against many murine transplantable tumors leading to complete rejection of established cancer forever changed the field of immunotherapy. In more robust murine models as well as human cancer, however, CTLA-4 blockade alone can slow tumor growth and extend patient survival, but is rarely curative. Subsequent studies have revealed a large family of T cell immune checkpoint receptors which tumors engage to shield themselves from host immunity. As with CTLA-4, blockade of one of these additional inhibitory receptors, programmed death 1, has led to remarkable therapeutic responses against tumors of multiple lineages. Checkpoint monotherapy has demonstrated that durable, immune-mediated cures of established metastatic cancers are possible, yet the percentage of patients experiencing these outcomes remains low due to both redundant mechanisms of immune suppression in the tumor and limiting toxicity associated with some therapies. Thus, extending the curative potential of immunotherapy to a larger percentage of patients with a broader spectrum of malignancies will likely require combinations of co-inhibitory blockade and co-stimulatory activation designed to peel back multiple layers of tumor immune suppression while at the same time minimizing immune-mediated toxicity. As over a dozen T cell immune checkpoints and an additional dozen more co-stimulatory receptors have now been described, the challenge before us is to identify the most advantageous combinations of these agents based on the knowledge of their underlying biology and preclinical studies in murine tumor models.

High-resolution assessment of land use impacts on biodiversity in life cycle assessment using species habitat suitability models.

Agricultural land use is a main driver of global biodiversity loss. The assessment of land use impacts in decision-support tools such as life cycle assessment (LCA) requires spatially explicit models, but existing approaches are either not spatially differentiated or modeled at very coarse scales (e.g., biomes or ecoregions). In this paper, we develop a high-resolution (900 m) assessment method for land use impacts on biodiversity based on habitat suitability models (HSM) of mammal species. This method considers potential land use effects on individual species, and impacts are weighted by the species' conservation status and global rarity. We illustrate the method using a case study of crop production in East Africa, but the underlying HSMs developed by the Global Mammals Assessment are available globally. We calculate impacts of three major export crops and compare the results to two previously developed methods (focusing on local and regional impacts, respectively) to assess the relevance of the methodological innovations proposed in this paper. The results highlight hotspots of product-related biodiversity impacts that help characterize the links among agricultural production, consumption, and biodiversity loss.

Is there any empirical support for biodiversity offset policy?

Biodiversity offsets are seen as a policy mechanism to balance development and conservation goals. Many offset schemes employ habitat restoration in one area to recreate biodiversity value that is destroyed elsewhere, assuming that recovery is timely and predictable. Recent research has challenged these assumptions on the grounds that restoration implies long time delays and a low certainty of success. To investigate these assertions, and to assess the strength of empirical support for offset policy, we used a meta-analytic approach to analyze data from 108 comparative studies of secondary growth (SG) and old-growth (OG) habitat (a total of 1228 SG sites and 716 OG reference sites). We extracted species checklists and calculated standardized response ratios for species richness, Fisher's alpha, Sorenson similarity, and Morisita-Horn similarity. We modeled diversity change with habitat age using generalized linear models and multi-model averaging, correcting for a number of potential explanatory variables. We tested whether (1) diversity of passively and actively restored habitat converges to OG values over time, (2) active restoration significantly accelerates this process, and (3) current offset policies are appropriate to the predicted uncertainties and time lags associated with restoration. The results indicate that in the best case, species richness converges to OG reference values within a century, species similarity (Sorenson) takes about twice as long, and assemblage composition (Morisita-Horn) up to an order of magnitude longer (hundreds to thousands of years). Active restoration significantly accelerates the process for all indices, but the inherently large time lags, uncertainty, and risk of restoration failure require offset ratios that far exceed what is currently applied in practice. Restoration offset policy therefore leads to a net loss of biodiversity, and represents an inappropriate use of the otherwise valuable tool of ecosystem restoration.

A comparison of available guidelines for the detection of cauda equina syndrome and assessing the need for further clinical guidance in Ireland.

The cauda equina syndrome (CES) is a rare but critical disorder, which can result in devastating motor weakness and sensory deficit, alongside often irreversible bladder, bowel and sexual dysfunction. In addition to the clinical burden of disease, this syndrome results in a disproportionately high medicolegal strain due to missed or delayed diagnoses. Despite being an emergency diagnosis, often necessitating urgent surgical decompression to treat, we believe there is a lack of clarity for clinicians in the current literature, with no published Irish guideline concerning screening or detection. The current study aims to identify and analyse appropriate guidelines in relation to CES screening which are available to clinicians in Ireland. The study design included a comprehensive literature review and comparison of existing guidelines. The review identified 13 sources of appropriate guidance for clinicians working in Ireland. These resources included textbooks, websites and guidelines developed in the UK. No Irish guidelines or advice were available on CES screening/treatment at the time of review. This review demonstrated the lack of consensus and guidance for clinicians in Ireland on how to effectively screen for CES, judge who requires further imaging and investigations and how to rule out the condition. A national consensus on thorough screening and prompt investigation for CES is necessary, and the formulation of new CES guidelines would be a welcome addition to what is available to clinicians currently.