Small-vessel vasculitis leading to severe acute kidney injury after ipilimumab: a case report.

Immune checkpoint inhibitors are effective monoclonal antibodies used in cancer treatment, particularly in metastatic melanoma. They target proteins responsible for cancer cells evading the immune system. However, their use can lead to immune-related adverse events, with the skin and gastrointestinal tract being commonly affected. Kidney involvement is rarer, with interstitial nephritis being the most common manifestation. In a unique case, kidney biopsy-proven small-vessel vasculitis with arteriolar immune deposition was observed following ipilimumab administration.

Diagnostic accuracy and clinical impact of MRI-based technologies for patients with non-alcoholic fatty liver disease: systematic review and economic evaluation.

Background: Magnetic resonance imaging-based technologies are non-invasive diagnostic tests that can be used to assess non-alcoholic fatty liver disease. Objectives: The study objectives were to assess the diagnostic test accuracy, clinical impact and cost-effectiveness of two magnetic resonance imaging-based technologies (LiverMultiScan and magnetic resonance elastography) for patients with non-alcoholic fatty liver disease for whom advanced fibrosis or cirrhosis had not been diagnosed and who had indeterminate results from fibrosis testing, or for whom transient elastography or acoustic radiation force impulse was unsuitable, or who had discordant results from fibrosis testing. Data sources: The data sources searched were MEDLINE, MEDLINE Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Database of Controlled Trials, Database of Abstracts of Reviews of Effects and the Health Technology Assessment. Methods: A systematic review was conducted using established methods. Diagnostic test accuracy estimates were calculated using bivariate models and a summary receiver operating characteristic curve was calculated using a hierarchical model. A simple decision-tree model was developed to generate cost-effectiveness results. Results: The diagnostic test accuracy review (13 studies) and the clinical impact review (11 studies) only included one study that provided evidence for patients who had indeterminate or discordant results from fibrosis testing. No studies of patients for whom transient elastography or acoustic radiation force impulse were unsuitable were identified. Depending on fibrosis level, relevant published LiverMultiScan diagnostic test accuracy results ranged from 50% to 88% (sensitivity) and from 42% to 75% (specificity). No magnetic resonance elastography diagnostic test accuracy data were available for the specific population of interest. Results from the clinical impact review suggested that acceptability of LiverMultiScan was generally positive. To explore how the decision to proceed to biopsy is influenced by magnetic resonance imaging-based technologies, the External Assessment Group presented cost-effectiveness analyses for LiverMultiScan plus biopsy versus biopsy only. Base-case incremental cost-effectiveness ratio per quality-adjusted life year gained results for seven of the eight diagnostic test strategies considered showed that LiverMultiScan plus biopsy was dominated by biopsy only; for the remaining strategy (Brunt grade ≥2), the incremental cost-effectiveness ratio per quality-adjusted life year gained was £1,266,511. Results from threshold and scenario analyses demonstrated that External Assessment Group base-case results were robust to plausible variations in the magnitude of key parameters. Limitations: Diagnostic test accuracy, clinical impact and cost-effectiveness data for magnetic resonance imaging-based technologies for the population that is the focus of this assessment were limited. Conclusions: Magnetic resonance imaging-based technologies may be useful to identify patients who may benefit from additional testing in the form of liver biopsy and those for whom this additional testing may not be necessary. However, there is a paucity of diagnostic test accuracy and clinical impact data for patients who have indeterminate results from fibrosis testing, for whom transient elastography or acoustic radiation force impulse are unsuitable or who had discordant results from fibrosis testing. Given the External Assessment Group cost-effectiveness analyses assumptions, the use of LiverMultiScan and magnetic resonance elastography for assessing non-alcoholic fatty liver disease for patients with inconclusive results from previous fibrosis testing is unlikely to be a cost-effective use of National Health Service resources compared with liver biopsy only. Study registration: This study is registered as PROSPERO CRD42021286891. Funding: Funding for this study was provided by the Evidence Synthesis Programme of the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 10. See the NIHR Journals Library website for further project information.

Non-alcoholic fatty liver disease includes a range of conditions that are caused by a build-up of fat in the liver, and not by alcohol consumption. This build-up of fat can cause inflammation. Persistent inflammation can cause scar tissue (fibrosis) to develop. It is important to identify patients with fibrosis because severe fibrosis can cause permanent liver damage (cirrhosis), which can lead to liver failure and liver cancer. In the National Health Service, patients with non-alcoholic fatty liver disease undergo tests to determine whether they have fibrosis. The test results are not always accurate and multiple tests can give conflicting results. Some of the tests may not be suitable for patients who have a very high body mass index. In the National Health Service, a liver biopsy may be offered to patients with inconclusive or conflicting test results or to those patients for whom other tests are unsuitable. However, liver biopsy is expensive, and is associated with side-effects such as pain and bleeding. Magnetic resonance imaging-based testing could be used as an extra test to help clinicians assess non-alcoholic fatty liver disease and identify patients who may need a liver biopsy. We assessed two magnetic resonance imaging-based diagnostic tests, LiverMultiScan and magnetic resonance elastography. LiverMultiScan is imaging software that is used alongside magnetic resonance imaging to measure markers of liver disease. Magnetic resonance elastography is used in some National Health Service centres to assess liver fibrosis; however, magnetic resonance elastography requires more equipment than just an magnetic resonance imaging scanner. We reviewed all studies examining how well LiverMultiScan and magnetic resonance elastography assess patients with non-alcoholic fatty liver disease. We also built an economic model to estimate the costs and benefits of using LiverMultiScan to identify patients who should be sent for a biopsy. Results from the model showed that LiverMultiScan may not provide good value for money to the National Health Service.

2023 UPDATE: Luso-Brazilian evidence-based guideline for the management of antidiabetic therapy in type 2 diabetes.

BACKGROUND: The management of antidiabetic therapy in people with type 2 diabetes (T2D) has evolved beyond glycemic control. In this context, Brazil and Portugal defined a joint panel of four leading diabetes societies to update the guideline published in 2020. METHODS: The panelists searched MEDLINE (via PubMed) for the best evidence from clinical studies on treating T2D and its cardiorenal complications. The panel searched for evidence on antidiabetic therapy in people with T2D without cardiorenal disease and in patients with T2D and atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or diabetic kidney disease (DKD). The degree of recommendation and the level of evidence were determined using predefined criteria. RESULTS AND CONCLUSIONS: All people with T2D need to have their cardiovascular (CV) risk status stratified and HbA1c, BMI, and eGFR assessed before defining therapy. An HbA1c target of less than 7% is adequate for most adults, and a more flexible target (up to 8%) should be considered in frail older people. Non-pharmacological approaches are recommended during all phases of treatment. In treatment naïve T2D individuals without cardiorenal complications, metformin is the agent of choice when HbA1c is 7.5% or below. When HbA1c is above 7.5% to 9%, starting with dual therapy is recommended, and triple therapy may be considered. When HbA1c is above 9%, starting with dual therapyt is recommended, and triple therapy should be considered. Antidiabetic drugs with proven CV benefit (AD1) are recommended to reduce CV events if the patient is at high or very high CV risk, and antidiabetic agents with proven efficacy in weight reduction should be considered when obesity is present. If HbA1c remains above target, intensification is recommended with triple, quadruple therapy, or even insulin-based therapy. In people with T2D and established ASCVD, AD1 agents (SGLT2 inhibitors or GLP-1 RA with proven CV benefit) are initially recommended to reduce CV outcomes, and metformin or a second AD1 may be necessary to improve glycemic control if HbA1c is above the target. In T2D with HF, SGLT2 inhibitors are recommended to reduce HF hospitalizations and mortality and to improve HbA1c. In patients with DKD, SGLT2 inhibitors in combination with metformin are recommended when eGFR is above 30 mL/min/1.73 m2. SGLT2 inhibitors can be continued until end-stage kidney disease.

Cost-utility Analysis of Evoke Closed-loop Spinal Cord Stimulation for Chronic Back and Leg Pain.

OBJECTIVES: The effectiveness of Evoke closed-loop spinal cord stimulation (CL-SCS), a novel modality of neurostimulation, has been demonstrated in a randomized controlled trial (RCT). The objective of this cost-utility analysis was to develop a de novo economic model to estimate the cost-effectiveness of Evoke CL-SCS when compared with open-loop SCS (OL-SCS) for the management of chronic back and leg pain. METHODS: A decision tree followed by a Markov model was used to estimate the costs and outcomes of Evoke CL-SCS versus OL-SCS over a 15-year time horizon from the UK National Health Service perspective. A "high-responder" health state was included to reflect improved levels of SCS pain reduction recently reported. Results are expressed as incremental cost per quality-adjusted life year (QALY). Deterministic and probabilistic sensitivity analysis (PSA) was conducted to assess uncertainty in the model inputs. RESULTS: Evoke CL-SCS was estimated to be the dominant treatment strategy at ~5 years postimplant (ie, it generates more QALYs while cost saving compared with OL-SCS). Probabilistic sensitivity analysis showed that Evoke CL-SCS has a 92% likelihood of being cost-effective at a willingness to pay threshold of £20,000/QALY. Results were robust across a wide range of scenario and sensitivity analyses. DISCUSSION: The results indicate a strong economic case for the use of Evoke CL-SCS in the management of chronic back and leg pain with or without prior spinal surgery with dominance observed at ~5 years.

Predicting patient-reported outcomes following lumbar spine surgery: development and external validation of multivariable prediction models.

BACKGROUND: This study aimed to develop and externally validate prediction models of spinal surgery outcomes based on a retrospective review of a prospective clinical database, uniquely comparing multivariate regression and random forest (machine learning) approaches, and identifying the most important predictors. METHODS: Outcomes were change in back and leg pain intensity and Core Outcome Measures Index (COMI) from baseline to the last available postoperative follow-up (3-24 months), defined as minimal clinically important change (MCID) and continuous change score. Eligible patients underwent lumbar spine surgery for degenerative pathology between 2011 and 2021. Data were split by surgery date into development (N = 2691) and validation (N = 1616) sets for temporal external validation. Multivariate logistic and linear regression, and random forest classification and regression models, were fit to the development data and validated on the external data. RESULTS: All models demonstrated good calibration in the validation data. Discrimination ability (area under the curve) for MCID ranged from 0.63 (COMI) to 0.72 (back pain) in regression, and from 0.62 (COMI) to 0.68 (back pain) in random forests. The explained variation in continuous change scores spanned 16%-28% in linear, and 15%-25% in random forests regression. The most important predictors included age, baseline scores on the respective outcome measures, type of degenerative pathology, previous spinal surgeries, smoking status, morbidity, and duration of hospital stay. CONCLUSIONS: The developed models appear robust and generalisable across different outcomes and modelling approaches but produced only borderline acceptable discrimination ability, suggesting the need to assess further prognostic factors. External validation showed no advantage of the random forest approach.

Evidence-based consensus guidelines on patient selection and trial stimulation for spinal cord stimulation therapy for chronic non-cancer pain.

Spinal cord stimulation (SCS) has demonstrated effectiveness for neuropathic pain. Unfortunately, some patients report inadequate long-term pain relief. Patient selection is emphasized for this therapy; however, the prognostic capabilities and deployment strategies of existing selection techniques, including an SCS trial, have been questioned. After approval by the Board of Directors of the American Society of Regional Anesthesia and Pain Medicine, a steering committee was formed to develop evidence-based guidelines for patient selection and the role of an SCS trial. Representatives of professional organizations with clinical expertize were invited to participate as committee members. A comprehensive literature review was carried out by the steering committee, and the results organized into narrative reports, which were circulated to all the committee members. Individual statements and recommendations within each of seven sections were formulated by the steering committee and circulated to members for voting. We used a modified Delphi method wherein drafts were circulated to each member in a blinded fashion for voting. Comments were incorporated in the subsequent revisions, which were recirculated for voting to achieve consensus. Seven sections with a total of 39 recommendations were approved with 100% consensus from all the members. Sections included definitions and terminology of SCS trial; benefits of SCS trial; screening for psychosocial characteristics; patient perceptions on SCS therapy and the use of trial; other patient predictors of SCS therapy; conduct of SCS trials; and evaluation of SCS trials including minimum criteria for success. Recommendations included that SCS trial should be performed before a definitive SCS implant except in anginal pain (grade B). All patients must be screened with an objective validated instrument for psychosocial factors, and this must include depression (grade B). Despite some limitations, a trial helps patient selection and provides patients with an opportunity to experience the therapy. These recommendations are expected to guide practicing physicians and other stakeholders and should not be mistaken as practice standards. Physicians should continue to make their best judgment based on individual patient considerations and preferences.

Effectiveness and Safety of Intrathecal Drug Delivery Systems for the Management of Cancer Pain: A Systematic Review and Meta-Analysis.

OBJECTIVES: Intrathecal drug delivery systems (IDDS) and spinal cord stimulation (SCS) have been proposed and assessed for the management of cancer pain; however, such treatments remain underused. We conducted a systematic review to evaluate the effectiveness and safety of IDDS and SCS for cancer pain. MATERIALS AND METHODS: Electronic databases MEDLINE, CENTRAL, EMBASE, and WikiStim were searched from 1988 to March 2021. Randomized controlled trials and observational studies of adults with pain related to cancer or its treatment who received an implantable IDDS or SCS were eligible for inclusion. The primary outcome of the review was change in pain intensity from baseline to the last available follow-up, measured using a visual analog scale or numerical rating scale. The protocol for this review is registered on PROSPERO (CRD42021240717). RESULTS: A total of 22 studies (24 reports) included a total of 3043 participants who received either IDDS or SCS for cancer pain. Eight studies reporting data for 405 participants with an IDDS could be included in the meta-analysis of pain intensity that showed a statistically significant reduction at the latest posttreatment follow-up time compared with baseline (mean difference [MD], -3.31; 95% CI, -4.18 to -2.45; p < 0.001). Six studies reporting data for 325 participants with an IDDS could be included in the meta-analysis of pain intensity that showed a statistically significant reduction up to one month after treatment compared with baseline (MD, -3.53; 95% CI, -4.06 to -3.00; p < 0.001). A meta-analysis including studies of participants with either an IDDS or an SCS device showed similar results. Improvements in other outcomes following implantation of IDDS also were observed. Postdural puncture headache was the most reported complication, whereas urinary retention, nausea, and vomiting were commonly reported side effects. CONCLUSION: Our findings suggest that IDDS is effective in reducing pain intensity for patients with cancer pain when compared with pretreatment.

Ziconotide for the Management of Cancer Pain: A Budget Impact Analysis.

OBJECTIVES: Recent recommendations on starting dose, smaller dose increments, and longer intervals between dose increase have the potential to increase the safety of ziconotide administration in addition to improving its value for money. Ziconotide is not routinely commissioned in England, with one of the concerns being whether it represents the best use of resources. The aim of this project is to conduct a budget impact analysis to estimate the costs or savings associated with the changes in ziconotide dosage in addition to its use in combination with morphine for the management of cancer pain. MATERIALS AND METHODS: An open, Markov-like cohort decision analytic model was developed to estimate the budget impact of ziconotide in combination with morphine (ziconotide combination therapy) vs morphine monotherapy through intrathecal drug delivery (ITDD) for the management of cancer pain. The perspective adopted was that of the UK National Health Service, with a five-year time horizon. Sensitivity analyses were conducted to evaluate different scenarios. RESULTS: Ziconotide combination therapy was more expensive than treatment with morphine monotherapy. The total costs of ziconotide combination therapy and morphine monotherapy for the first year were £395,748 and £136,628 respectively. The estimated five-year cumulative budget impact of treatment with ziconotide combination therapy for the five-year time horizon was £2,487,539, whereas that of morphine monotherapy was £913,804. The additional costs in any of the first five years are below the resource impact significance level of £1 million for medical technologies in England. CONCLUSIONS: The results of this budget impact analysis suggest that although a combination of intrathecal ziconotide in combination with morphine is associated with higher costs to the health care system in England, the incremental costs are not significant. Routine commissioning of ziconotide alone or in combination with morphine would provide an alternative for a population with limited ITDD treatment options.

Gradation of Clinical Holistic Response as New Composite Outcome to Evaluate Success in Spinal Cord Stimulation Studies for Pain.

INTRODUCTION: The most prominent outcome measurement in the field of neuromodulation is pain relief. Nevertheless, the number of studies that rely on composite outcomes has increased. The aims of this study are twofold: (1) to evaluate which measures are important to include in a composite outcome and (2) to develop this new composite outcome to evaluate the degree of being a clinical holistic responder with a corresponding minimal clinical important difference (MCID). MATERIALS AND METHODS: Data from patients with persistent spinal pain syndrome type 2 treated with High-Dose Spinal Cord Stimulation (HD-SCS) were used. Pain intensity for low back and leg pain, disability, health-related quality of life, medication use, and patient satisfaction were measured at baseline and after 12 months of HD-SCS. Exploratory and Confirmatory Factor Analyses were used to evaluate which measures should be included in the composite outcome. Anchor-based and distribution-based methods were applied to determine the MCID of the newly developed outcome measurement. RESULTS: A three-factor model was the most appropriate for this data set, in which leg pain intensity, EQ5D VAS, and disability had the largest loading on these factors. A clinical holistic outcome was created with a total score ranging from 0 (=better [no pain, no disability, and perfect health status]) to 300 (=worse [maximal pain, maximal disability, and worst health status]). The MCID value based on an absolute change score from baseline up to 12 months of HD-SCS was 87.97. When calculating with percentage changes, a MCID value of 48.4% was revealed. CONCLUSIONS: This new composite outcome evaluating the degree of deviation from being a holistic responder is a step toward a meaningful, overall outcome assessment for patients who are treated with SCS. Further studies to evaluate the psychometric properties and the generalizability toward other patient populations still need to be performed.

Health-related quality of life in persons post-COVID-19 infection in comparison to normative controls and chronic pain patients.

The Coronavirus disease 2019 (COVID-19) pandemic exerted a tremendous pressure on the healthcare system, people's social life, mental health and financial status with profound implications for the general population. The exact impact of the pandemic on the overall physical, mental and social wellbeing of COVID-19 infection survivors on the long term has not yet been explored in a thorough way. Based on the reporting of persistent pain, fatigue and dyspnea symptoms by these survivors, it is our hypothesis that their quality of life will be extremely impacted, as is observed in patients with chronic pain. Therefore, the first aim of this study was to perform an in-depth evaluation of the quality of life of post-COVID-19 infected persons. The second aim was to compare the quality of life of these persons with a normative population and with patients with chronic pain. Health-related quality of life, as a measure for a person's overall physical, mental, and social wellbeing, was measured with the 3-level EQ5D in 547 post-COVID-19 infected persons. These data were compared to reference data from normal population records for Belgium and to data from patients with chronic pain after spinal surgery with two-way analyses of variance. In total, 89.58% of the post-COVID-19 infected persons reported pain/discomfort and 82.45% indicated limitations when performing usual activities, when evaluated 287 days (SD: 150) after the infection. Self-care was preserved in most post-COVID-19 persons, whereby only 13.16% indicated problems. The mean EQ5D-3L index score was 0.57 (SD: 0.23) and EQ5D VAS mean score was 56.6 (SD: 18.2). The mean index score for the normative population was significantly higher than for COVID-19 infected persons [mean difference of 0.31 (95% from 0.29 to 0.33), p < 0.01] while the mean score of chronic pain patients was significantly lower than the score of COVID-19 infected persons [mean difference of -0.31 (95% from -0.29 to -0.33), p < 0.01]. Compared to age-and sex adjusted reference data, health-related quality of life of persons with long COVID is severely impacted. In relation to patients with chronic pain after spinal surgery, the quality of life of post-COVID-19 infected persons seemed to be better. Clinical trial registration: https://www.clinicaltrials.gov/, identifier: NCT04912778.

The Influence of Schmorl Nodes in Spinal Sagittal Balance in Young Adults / A Influência dos nódulos de Schmorl no equilíbrio sagital de adultos jovens

Abstract Objectives The present study aims to characterize the spinal balance (SB) in young adults with Schmorl nodes (SN). Methods A cross-sectional study was conducted on a sample of 47 young adults. Lumbar magnetic resonance imaging (MRI) was used to divide the patients into an SN group and a control group. Standing full spine radiographs were used to compare the spinopelvic SB parameters between groups: sagittal vertical axis, thoracic kyphosis, lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS). Results The LL and SS values were significantly lower in patients with SN when compared with the control group (54.5° versus 64.3°; 36.2° versus 41.4°, respectively). No significant differences were observed for the other parameters. Significant correlations were found in both groups between LL and SS; PI and PT; and PI and SS. Conclusions Young adults with SN have associated SB modifications, particularly lower LL and SS values, when compared with a control group. This flatter profile resembles that observed in patients with lower back pain and early disc pathology. We believe that SNs are relevant clinical findings that should prompt the study of the SB of a patient, as it may uncover variations associated with early disc degeneration. Level of Evidence III

Resumo Objetivos O presente estudo tem como objetivo caracterizar o equilíbrio sagital (SB, na sigla em inglês) espinhal em adultos jovens com nódulos de Schmorl (NS). Métodos Este é um estudo transversal de uma amostra composta por 47 adultos jovens. Ressonância magnética (RM) lombar foi usada para separar os pacientes em um grupo com NS e um grupo controle. Radiografias da coluna vertebral em pé foram usadas para comparar os parâmetros espinopélvicos do SB entre os grupos: eixo vertical sagital, cifose torácica, lordose lombar (LL), incidência pélvica (PI, na sigla em inglês), inclinação pélvica (PT, na sigla em inglês) e inclinação sacral (SS, na sigla em inglês). Resultados Os valores de LL e SS foram significativamente menores nos pacientes com NS em comparação com o grupo controle (54,5° versus 64,3°; 36,2° versus 41,4°, respectivamente). Não foram observadas diferenças significativas nos demais parâmetros. Os dois grupos apresentaram correlações significativas entre LL e SS, PI e PT e PI e SS. Conclusões Adultos jovens com NS apresentam modificações associadas ao SB, principalmente valores menores de LL e SS, em comparação com o grupo controle. Este perfil mais plano assemelha-se ao observado em pacientes com lombalgia e patologia discal em estágio inicial. Acreditamos que o NS seja um achado clínico relevante que deve levar ao estudo do SB de um paciente por poder revelar variações associadas aos primeiros estágios de degeneração discal. Nível de Evidência III

Rationale and Recent Advances in Targeted Drug Delivery for Cancer Pain: Is It Time to Change the Paradigm?

BACKGROUND: Cancer pain prevalence remains high with more than 60% of patients with advanced cancer experiencing cancer-related pain. The undertreatment of pain due to concerns of opioid dependence or diversion, as well as the potential effect of opioids on tumor neogenesis, add to the suffering among cancer populations. OBJECTIVES: The aim of this narrative review was to assess evidence on the effectiveness, safety, cost-effectiveness, and advances of Intrathecal (IT) Drug Delivery Systems (IDDS) for the management of cancer pain. STUDY DESIGN: The present review was performed by searching for articles indexed in PubMed, MEDLINE, SciELO, Google Scholar, and Scopus. METHODS: Studies were included if they investigated patients with chronic cancer-related pain treated with IDDS and assessed experienced pain. We performed a narrative synthesis. RESULTS: IDDS have demonstrated efficacy in relieving cancer pain even in the challenging treatment of head and neck cancer pain. IDDS is also associated with a large reduction in serum opioid concentrations limiting adverse effects. When combined with other analgesics commonly used in the spinal space, but not systemically, pain relief may be dramatically improved. Advances in IT drug diffusion, including mixtures created with pharmaceutical compounding, improve the safety and accuracy of this therapy. IDDS is cost-effective and safe yet remains underutilized in this patient population. LIMITATIONS: Despite numerous clinical studies, only a small number of randomized trials have been conducted to evaluate the effectiveness of IDDS for cancer pain. CONCLUSIONS: This article presents an overview of the current state of evidence on the effectiveness, safety, cost-effectiveness, and advances of IDDS for the management of cancer pain. Despite current evidence, IDDS remains underutilized for people with cancer pain. Potential areas to facilitate its use are discussed. A shift in the paradigm of cancer pain treatment should be considered given the undertreatment rate, lack of benefits, and considerable risks associated with oral opioid medication in many patients who suffer from chronic cancer pain.

Predictors of Pain and Disability Outcomes Following Spinal Surgery for Chronic Low Back and Radicular Pain: A Systematic Review.

OBJECTIVES: Success rates of spinal surgeries to treat chronic back pain are highly variable and useable prognostic indicators are lacking. We aimed to identify and evaluate preoperative predictors of pain and disability after spinal surgery for chronic low back/leg pain. METHODS: Electronic database (01/1984-03/2021) and reference searches identified 2622 unique citations. Eligible studies included adults with chronic low back/leg pain lasting ≥3 months undergoing first elective lumbar spine surgery, and outcomes defined as change in pain (primary)/disability (secondary) after ≥3 months. We included 21 reports (6899 participants), 7 were judged to have low and 14 high risks of bias. We performed narrative synthesis and determined the quality of evidence (QoE). RESULTS: Better pain outcomes were associated with younger age, higher education, and no spinal stenosis (low QoE); lower preoperative pain, fewer comorbidities, lower pain catastrophizing, anxiety and depression (very low QoE); but not with symptom duration (moderate QoE), other sociodemographic factors (low QoE), disability, or sensory testing (very low QoE). More favorable disability outcomes were associated with preoperative sensory loss (moderate QoE); lower job-related resignation and neuroticism (very low QoE); but not with socioeconomic factors, comorbidities (low QoE), demographics, pain, or pain-related psychological factors (very low QoE). DISCUSSION: In conclusion, absence of spinal stenosis potentially predicts greater pain relief and preoperative sensory loss likely predicts reduction in disability. Overall, QoE for most identified associations was low/very low.

Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion.

AIMS/HYPOTHESIS: Imbalances in glucose metabolism are hallmarks of clinically silent prediabetes (defined as impaired fasting glucose and/or impaired glucose tolerance) representing dysmetabolism trajectories leading to type 2 diabetes. CD26/dipeptidyl peptidase 4 (DPP4) is a clinically proven molecular target of diabetes-controlling drugs but the DPP4 gene control of dysglycaemia is not proven. METHODS: We dissected the genetic control of post-OGTT and insulin release responses by the DPP4 gene in a Portuguese population-based cohort of mainly European ancestry that comprised individuals with normoglycaemia and prediabetes, and in mouse experimental models of Dpp4 deficiency and hyperenergetic diet. RESULTS: In individuals with normoglycaemia, DPP4 single-nucleotide variants governed glycaemic excursions (rs4664446, p=1.63x10-7) and C-peptide release responses (rs2300757, p=6.86x10-5) upon OGTT. Association with blood glucose levels was stronger at 30 min OGTT, but a higher association with the genetic control of insulin secretion was detected in later phases of the post-OGTT response, suggesting that the DPP4 gene directly senses glucose challenges. Accordingly, in mice fed a normal chow diet but not a high-fat diet, we found that, under OGTT, expression of Dpp4 is strongly downregulated at 30 min in the mouse liver. Strikingly, no genetic association was found in prediabetic individuals, indicating that post-OGTT control by DPP4 is abrogated in prediabetes. Furthermore, Dpp4 KO mice provided concordant evidence that Dpp4 modulates post-OGTT C-peptide release in normoglycaemic but not dysmetabolic states. CONCLUSIONS/INTERPRETATION: These results showed the DPP4 gene as a strong determinant of post-OGTT levels via glucose-sensing mechanisms that are abrogated in prediabetes. We propose that impairments in DPP4 control of post-OGTT insulin responses are part of molecular mechanisms underlying early metabolic disturbances associated with type 2 diabetes.

Systematic Review and Meta-Analysis of Predictors of Return to Work After Spinal Surgery for Chronic Low Back and Leg Pain.

Spinal surgeries to treat chronic low back pain (CLBP) have variable success rates, and despite the significant personal and socioeconomic implications, we lack consensus for prognostic factors. This systematic review and meta-analysis evaluated the evidence for preoperative predictors of return to work (RTW) after spinal surgery for CLBP. We searched electronic databases and references (January 1984 to March 2021), screened 2,622 unique citations, and included 8 reports (5 low and 3 high risk-of-bias) which involved adults with ≥3 months duration of CLBP with/without leg pain undergoing first elective lumbar surgery with RTW assessed ≥3 months later. Narrative synthesis and meta-analysis where possible found that individuals less likely to RTW were older (odds ratio [OR] = .58; 95% confidence interval [CI]: 0.46-0.72), not working before surgery, had longer sick leave (OR = .95; 95% CI: 0.93-0.97), higher physical workload, legal representation (OR = .61; 95% CI: 0.53-0.71), psychiatric comorbidities and depression (moderate quality-of-evidence, QoE), and longer CLBP duration and opioid use (low QoE), independent of potential confounders. Low quality and small number of studies limit our confidence in other associations. In conclusion, RTW after spinal surgery for CLBP likely depends on sociodemographic and affective psychological factors, and potentially also on symptom duration and opioid use. PERSPECTIVE: This systematic review and meta-analysis synthesizes and evaluates existing evidence for preoperative predictors of return to work after spinal surgery for chronic low back pain. Demonstrated associations between return to work and sociodemographic, health-related, and psychological factors can inform clinical decision-making and guide further research.

A risk-adjusted and anatomically stratified cohort comparison study of open surgery, endovascular techniques and medical management for juxtarenal aortic aneurysms-the UK COMPlex AneurySm Study (UK-COMPASS): a study protocol.

INTRODUCTION: In one-third of all abdominal aortic aneurysms (AAAs), the aneurysm neck is short (juxtarenal) or shows other adverse anatomical features rendering operations more complex, hazardous and expensive. Surgical options include open surgical repair and endovascular aneurysm repair (EVAR) techniques including fenestrated EVAR, EVAR with adjuncts (chimneys/endoanchors) and off-label standard EVAR. The aim of the UK COMPlex AneurySm Study (UK-COMPASS) is to answer the research question identified by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme: 'What is the clinical and cost-effectiveness of strategies for the management of juxtarenal AAA, including fenestrated endovascular repair?' METHODS AND ANALYSIS: UK-COMPASS is a cohort study comparing clinical and cost-effectiveness of different strategies used to manage complex AAAs with stratification of physiological fitness and anatomical complexity, with statistical correction for baseline risk and indication biases. There are two data streams. First, a stream of routinely collected data from Hospital Episode Statistics and National Vascular Registry (NVR). Preoperative CT scans of all patients who underwent elective AAA repair in England between 1 November 2017 and 31 October 2019 are subjected to Corelab analysis to accurately identify and include every complex aneurysm treated. Second, a site-reported data stream regarding quality of life and treatment costs from prospectively recruited patients across England. Site recruitment also includes patients with complex aneurysms larger than 55 mm diameter in whom an operation is deferred (medical management). The primary outcome measure is perioperative all-cause mortality. Follow-up will be to a median of 5 years. ETHICS AND DISSEMINATION: The study has received full regulatory approvals from a Research Ethics Committee, the Confidentiality Advisory Group and the Health Research Authority. Data sharing agreements are in place with National Health Service Digital and the NVR. Dissemination will be via NIHR HTA reporting, peer-reviewed journals and conferences. TRIAL REGISTRATION NUMBER: ISRCTN85731188.

The Influence of Missing Data on Disabilities in Patients Treated with High-Dose Spinal Cord Stimulation: A Tipping Point Sensitivity Analysis.

New waveforms have changed the field of Spinal Cord Stimulation (SCS) to optimize therapy outcomes, among which is High-Dose SCS (HD-SCS). Missing observations are often encountered when conducting clinical trials in this field. In this study, different approaches with varying assumptions were constructed to evaluate how conclusions may be influenced by these assumptions. The aim is to perform a tipping point sensitivity analysis to evaluate the influence of missing data on the overall conclusion regarding the effectiveness of HD-SCS on disability. Data from the Discover study were used, in which 185 patients with Failed Back Surgery Syndrome were included. Disability was evaluated before SCS and after 1, 3 and 12 months of HD-SCS. During the second, third and fourth visit, data from 130, 114 and 90 patients were available, respectively. HD-SCS resulted in a significant decrease in disability scores based on the analysis of observed data and with multiple imputations. The tipping point sensitivity analysis revealed that the shift parameter was 17. Thus, the conclusion concerning the time effect under a "missing at random" mechanism is robust when the shift parameter for the disability score is 17. From a clinical point of view, a shift of 17 points on disability is not very plausible. Therefore we tend to consider the conclusions drawn under "missing at random" as being robust.

A systematic review of health state utility values for thyroid cancer.

PURPOSE: Health state utility values are commonly used to inform economic evaluations and determine the cost-effectiveness of an intervention. The aim of this systematic review is to summarise the utility values available to represent the health-related quality of life (HRQoL) of patients with thyroid cancer. METHODS: Eight electronic databases were searched from January 1999 to April 2019 for studies which included assessment of HRQoL for patients with thyroid cancer. Utility estimates derived from multiple sources (EuroQol questionnaire 5-dimension (EQ-5D), time trade-off [TTO] and standard gamble [SG] methods) were extracted. In addition, utility estimates were generated by mapping from SF-36 and EORTC QLQ-30 to the EQ-5D-3L UK value set using published mapping algorithms. RESULTS: Searches identified 33 eligible studies. Twenty-six studies reported HRQoL for patients with differentiated thyroid cancer and seven studies for patients with general thyroid cancer. We identified studies which used different methods and tools to quantify the HRQoL in patients with thyroid cancer, such as the EQ-5D-3L, SF-36, EORTC QLQ-30 and SG and TTO techniques to estimate utility values. Utility estimates range from 0.205 (patients with low-risk differentiated thyroid cancer) to utility values approximate to the average UK population (following successful thyroidectomy surgery and radioiodine treatment). Utility estimates for different health states, across thyroid cancer sub-types and interventions are presented. CONCLUSION: A catalogue of utility values is provided for use when carrying out economic modelling of thyroid cancer; by including mapped values, this approach broadens the scope of health states that can be considered within cost-effectiveness modelling.