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Introduction: Current perioperative education for patients undergoing lumbar surgery is only limited effective in preventing unfavorable outcome. Perioperative pain neuroscience education (PPNE) is a recently introduced intervention that aims to inform such patients about what to expect from their recovery, to improve maladaptive pain cognitions, and to reconceptualize pain. As such, this study aims to evaluate the effectiveness of PPNE on quality of life at 6 weeks post-surgery in at-risk patients undergoing surgery for lumbar radiculopathy. Methods: Following screening, 108 at-risk patients (i.e., having chronic pain = 6 months, and maladaptive degrees of kinesiophobia and pain catastrophizing) undergoing surgery for lumbar radiculopathy will be randomized into an experimental (PPNE) or control (perioperative biomedical education) group. Intervention includes a pre-and postoperative in-person session with a physiotherapist, and access to an educational web application. The primary outcome measure is quality of life which will be assessed at 1 week pre-surgery, and 6 weeks, 6 months and 1 year post-surgery. Results: The central hypothesis describes that due to the effect of PPNE these patients, despite their risk profile for unfavorable outcome, will have good surgical outcome with improvements in quality of life. Discussion: Findings will provide insight in the effectiveness of PPNE as a preventive measure for unfavorable surgical outcome and will be valuable for all clinicians working with such at-risk patients. Process evaluation: Though recruitment for this study has recently started, the process has been slow. As such, updated recruitment strategies are needed to help overcome current barriers. [ABSTRACT FROM AUTHOR]

Introduction: The benefits of perioperative pain neuroscience education (PPNE) for people undergoing surgery for lumbar radiculopathy have recently been established. 1,2 However so far, not much is known about which factors influence PPNE's treatment success. Therefore, this study aims to assess the potential influence of preoperative pain intensity, pain cognitions and sensory function on the PPNE treatment effect for postoperative quality of life 1 year following surgery for lumbar radiculopathy. Methods: This study is a secondary analysis of a randomized controlled trial in which 120 patients were randomized to receive either PPNE or perioperative biomedical education (PBE).3 Quality of life was assessed using the Short Form 36-item Health Survey (SF-36) at baseline (1 week pre-surgery), and 6 weeks, 6 months and 1 year post-surgery. Linear mixed models will be built for the SF-36 Physical component, SF-36 Mental component, and SF-6D utility scores using the following independent variables: treatment (PPNE versus PBE), time, and baseline scores for back pain intensity, leg pain intensity, pain catastrophizing, kinesiophobia, hypervigilance, and measures of quantitative sensory testing (i.e., electrical pain threshold, temporal summation, and conditioned pain modulation). Results: It is hypothesized that patients who report unfavorable scores for these preoperative factors will show a larger treatment effect of PPNE on postoperative quality of life. Discussion: Findings will provide novel insight into the potential moderating effect of preoperative factors on treatment outcome following PPNE in people undergoing surgery for lumbar radiculopathy. Process evaluation: Analysis for this study is underway and results are expected in Spring 2022. [ABSTRACT FROM AUTHOR]

Background: Diagnostic uncertainty is a well-recognized concept in clinical practice, encompassing both technical perspectives and the subjective perceptions of physicians. Post-mortem diagnostics (PMD), which involves all post-mortem investigations to assess diseases and injuries and determine the cause of death, shares this inherent uncertainty due to the complexity and multidisciplinary nature of autopsies., Methods: A comprehensive literature review was conducted to uncover relevant publications focusing on diagnostic uncertainty in PMD. An expert panel evaluated expressions and sources of diagnostic uncertainty to identify factors influencing PMD uncertainty., Results:  Literature specifically addressing PMD uncertainty is sparse, though implicit and explicit references exist. This article illustrates the presence of uncertainty in PMD by drawing upon both literature and pathology practice. We introduce the definition of PMD uncertainty as "the inability to determine the exact cause of death and/or the precise significance of certain autopsy findings". PMD uncertainty can stem from a pathologist's subjective perception, but often results from several objective factors. Six factors inherent to the PMD setting were identified as contributing to this uncertainty. To systematically express the certainty of cause-of-death determinations, we developed a new Post-Mortem Diagnostic Certainty Scale (PMDCS) featuring eight categories, distinguishing between assignable and non-assignable causes of death., Conclusion: Understanding and applying the concept of PMD uncertainty will enhance comprehension of the importance of certain post-mortem findings and improve the accuracy of autopsy result interpretation. While eliminating PMD uncertainty entirely is not feasible, standardizing investigations can reduce uncertainty, and using the PMDCS can improve the clarity of autopsy reports., Competing Interests: Declarations. Ethical approval Ethical approval was not required for this study. Conflict of interest The authors have no competing interests to declare that are relevant to the content of this article. No funds, grants, or other support was received., (© 2024. The Author(s).)

Forensic autopsies remain indispensable for accurately determining the cause and manner of death. However, pathologists face significant challenges inherent to the complex process of postmortem diagnostics (PMD), including the potential for diagnostic errors. The implementation of quality assurance (QA) mechanisms is crucial for minimizing these errors. Nonetheless, the lack of QA programs, specifically tailored for forensic pathology, continues to pose a significant obstacle. This article explores the enhancement of PMD after the adoption of ISO 17020 accreditation at a Belgian forensic institute in 2010. Drawing on over a decade of experience, it details on the development and implementation of label-specific standard operating procedures (SOPs) designed to address the various types of deaths in forensic practice. Additionally, it underscores the necessity of adapting international directives from leading organizations into effective local protocols, aiming to standardize practices and improve efficacy. Through a comparative review of existing international guidelines, this study provides forensic pathologists and institutions worldwide with practical strategies for qualitative standardization and improving their PMD., Competing Interests: Declarations. Conflict of interest: The authors have no competing interests to declare that are relevant to the content of this article. No funds, grants, or other support was received. Ethical approval: Ethical approval was not required for this study., (© 2024. The Author(s).)

Background: The adipose tissue may serve as a source of energy supporting cancer growth and metastasis. Our understanding of the adipocytes which compose the adipose tissue in different anatomical locations of the body as well as potential microscopic tumor infiltration in patients with metastatic breast cancer remains limited. This study therefore investigates regional variations in adipocyte size and adipose tissue tumor infiltration in patients with metastatic breast cancer., Methods: Within the UPTIDER rapid autopsy program, (NCT04531696), 94 adipose tissue samples from subcutaneous, visceral, retroperitoneal, and mammary depots of 22 patients with metastatic breast cancer were collected and analyzed. Distant adipocyte size was quantified using digital pathology, and tumor infiltration was assessed histologically. Linear mixed quantile regression analyzed the associations between adipocyte size, fat depot type and major histological subtypes., Results: Distant adipocyte size did not significantly differ across fat depots. A trend towards smaller adipocytes in mammary fat at autopsy versus diagnosis was observed, suggesting potential age and/or treatment effects. Adipocyte size correlated positively with BMI at death, especially in subcutaneous and visceral fat. Visceral fat exhibited higher tumor infiltration, notably in patients with invasive lobular carcinoma (ILC)., Conclusion: This study highlights the relatively uniform adipocyte size across fat depots in patients with metastatic breast cancer, with potential changes in mammary adipocytes over the disease course. The microscopic tumor cell infiltration observed in the visceral fat, mainly for ILC, underscores the need to undertake additional research to understanding the contribution of the adipose tissue in breast cancer metastasis., Competing Interests: Declaration of competing interest All authors have no competing financial or non-financial interests to declare., (Copyright © 2024. Published by Elsevier Ltd.)

The immune landscape of hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer (HR+/HER2- mBC), the most common subtype of BC, remains understudied. This is mainly because of reduced sample acquisition opportunities from metastases as compared with primary tumors. In this study, we explored stromal tumor-infiltrating lymphocytes (sTIL) in metastatic samples collected through our post-mortem tissue donation program UZ/KU Leuven Post-mortem Tissue Donation program to Enhance Research (NCT04531696). sTIL were scored as a continuous parameter according to the international guidelines on 427 metastases and 38 primary untreated tumors acquired from 20 patients with HR+/HER2- mBC. Estrogen receptor (ER) status was evaluated on 362 metastases with a cutoff value for positivity set at 1% according to the American Society of Clinical Oncology/College of American Pathologists guidelines. Our analyses show that 54% and 15% of metastases had sTIL levels of ≥1% and ≥5%, respectively. sTIL levels tended to be lower in metastases as compared with their respective primary tumors (estimate, -2.83; 95% CI, -5.77 to 0.11; P = .07). sTIL levels were lower in metastases from invasive lobular carcinoma than in metastases from invasive breast carcinoma of no special type (estimate, -1.67; 95% CI, -2.35 to -0.98; P < .001). A loss of ER expression was observed in 14% of all metastases, yet a negative ER status was not significantly associated with increased sTIL levels. Finally, sTIL levels were significantly higher in lung and axillary lymph node metastases compared with all metastases. Although these analyses were conducted on multiple metastases obtained at the end of life after several lines of treatment, the data provide novel and valuable insights into the state of immune infiltration in patients with HR+/HER2- mBC., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Though perioperative pain neuroscience education (PPNE) positively influences patients' surgical outcomes, little is known about the mechanisms behind this treatment's success. Therefore, this study aims to evaluate the potential mediating role of pain cognitions and pain sensitivity in the treatment effect of PPNE on postoperative quality of life in people undergoing surgery for lumbar radiculopathy. This secondary analysis uses data from 120 participants of a randomized controlled trial who were randomized to receive either PPNE or perioperative biomedical education before undergoing surgery for lumbar radiculopathy. Quality of life was assessed 1-year postsurgery using the short form 36-item health survey (SF36) physical and mental component scores. Potential mediators included pain cognitions (ie, kinesiophobia, pain catastrophizing, and hypervigilance) and pain sensitivity (ie, endogenous nociceptive modulation), assessed 6 weeks postsurgery. Mediation models were constructed using structural equation modeling, and 95% confidence intervals (CIs) were calculated using 10,000 bootstrap samples. Analyses show a significant total effect for PPNE (estimate = .464, 95% CI [.105, .825]) and a significant indirect effect via pain catastrophizing on the SF36 physical component (estimate = .124, 95% CI [.001, .293]). No mediating effect was found through the remaining pain cognitions or pain sensitivity measures. Also, no potential mediators were identified for the treatment effect of PPNE on the SF36 mental component. Our findings suggest that pain catastrophizing mediates the treatment effect of PPNE on physical health-related quality of life in people undergoing surgery for lumbar radiculopathy. PERSPECTIVE: This secondary analysis identified pain catastrophizing as a mediator for PPNE in people undergoing surgery for lumbar radiculopathy. More so, its findings indicate that this educational intervention can enhance the postoperative physical health-related quality of life of these patients by addressing their catastrophizing thoughts. TRIAL REGISTRATION: Clinicaltrials.gov (NCT02630732)., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Primary tumors with a mixed invasive breast carcinoma of no-special type (IBC-NST) and invasive lobular cancer (ILC) histology are present in approximately five percent of all patients with breast cancer and are understudied at the metastatic level. Here, we characterized the histology of metastases from two patients with primary mixed IBC-NST/ILC from the postmortem tissue donation program UPTIDER (NCT04531696). The 14 and 43 metastatic lesions collected at autopsy had morphological features and E-cadherin staining patterns consistent with pure ILC. While our findings still require further validation, they may challenge current clinical practice and imaging modalities used in these patients., Competing Interests: Declaration of Competing interest All authors declare to have no conflict of interest, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

While there is a great clinical need to understand the biology of metastatic cancer in order to treat it more effectively, research is hampered by limited sample availability. Research autopsy programmes can crucially advance the field through synchronous, extensive, and high-volume sample collection. However, it remains an underused strategy in translational research. Via an extensive questionnaire, we collected information on the study design, enrolment strategy, study conduct, sample and data management, and challenges and opportunities of research autopsy programmes in oncology worldwide. Fourteen programmes participated in this study. Eight programmes operated 24 h/7 days, resulting in a lower median postmortem interval (time between death and start of the autopsy, 4 h) compared with those operating during working hours (9 h). Most programmes (n = 10) succeeded in collecting all samples within a median of 12 h after death. A large number of tumour sites were sampled during each autopsy (median 15.5 per patient). The median number of samples collected per patient was 58, including different processing methods for tumour samples but also non-tumour tissues and liquid biopsies. Unique biological insights derived from these samples included metastatic progression, treatment resistance, disease heterogeneity, tumour dormancy, interactions with the tumour micro-environment, and tumour representation in liquid biopsies. Tumour patient-derived xenograft (PDX) or organoid (PDO) models were additionally established, allowing for drug discovery and treatment sensitivity assays. Apart from the opportunities and achievements, we also present the challenges related with postmortem sample collections and strategies to overcome them, based on the shared experience of these 14 programmes. Through this work, we hope to increase the transparency of postmortem tissue donation, to encourage and aid the creation of new programmes, and to foster collaborations on these unique sample collections. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Research on metastatic cancer has been hampered by limited sample availability. Here we present the breast cancer post-mortem tissue donation program UPTIDER and show how it enabled sampling of a median of 31 (range: 5-90) metastases and 5-8 liquids per patient from its first 20 patients. In a dedicated experiment, we show the mild impact of increasing time after death on RNA quality, transcriptional profiles and immunohistochemical staining in tumor tissue samples. We show that this impact can be counteracted by organ cooling. We successfully generated ex vivo models from tissue and liquid biopsies from distinct histological subtypes of breast cancer. We anticipate these and future findings of UPTIDER to elucidate mechanisms of disease progression and treatment resistance and to provide tools for the exploration of precision medicine strategies in the metastatic setting., (© 2024. The Author(s).)

OBJECTIVE: To explore whether preoperative pain intensity, pain cognitions, and quantitative sensory measures influence the established effectiveness of perioperative pain neuroscience education (PPNE) on health-related quality of life at 1 year after surgery for lumbar radiculopathy. DESIGN: Secondary analysis of a triple-blinded randomized controlled trial. METHODS: Participants (n = 90) were Dutch-speaking adults (18-65 years) who were scheduled for surgery for lumbar radiculopathy in 3 Belgian hospitals. They were randomized (1:1) to receive PPNE (n = 41) or perioperative biomedical education (n = 49). Linear mixed models were built for health-related quality of life (ie, SF-6D utility values, Physical and Mental Component of the 36-item Short Form Health Survey) using the following independent variables: therapy, time, and preoperative scores for back and leg pain intensity, pain catastrophizing, kinesiophobia, hypervigilance, and quantitative sensory measures. RESULTS: The impact of PPNE on SF-6D utility values over time was influenced by kinesiophobia (F = 3.30, P = .02) and leg pain intensity (F = 3.48, P = .02). Regardless of the intervention, back pain intensity negatively influenced SF-6D values over time (F = 3.99, P = .009). The Physical Component scores were negatively impacted by back pain intensity (F = 9.08, P = .003) and were influenced over time by leg pain intensity (F = 2.87, P = .04). The Mental Component scores were negatively impacted by back pain intensity (F = 6.64, P = .01) and pain catastrophizing (F = 5.42, P = .02), as well as hypervigilance (F = 3.16, P = .03) and leg pain intensity (F = 3.12, P = .03) over time. CONCLUSION: PPNE may be more effective than perioperative biomedical education in improving postoperative health utility values in patients who reported higher kinesiophobia and leg pain intensity before surgery for lumbar radiculopathy. J Orthop Sports Phys Ther 2024;54(4):1-10. Epub 8 January 2024. doi:10.2519/jospt.2024.12051 .

We present a protocol for the rapid postmortem bedside procurement of selected tissue samples using an endoscopic endonasal surgical technique that we adapted from skull base surgery. We describe steps for the postmortem collection of blood, cerebrospinal fluid, a nasopharyngeal swab, and tissue samples; the clean-up procedure; and the initial processing and storage of the samples. This protocol was validated with tissue samples procured postmortem from COVID-19 patients and can be applied in another emerging infectious disease. For complete details on the use and execution of this protocol, please refer to Khan et al. (2021) 1 and Khan et al. (2022). 2 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

In people with nonspecific chronic spinal pain (nCSP), disability and quality of life are associated with clinical, cognitive, psychophysical, and demographic variables. However, evidence regarding the interactions between these variables is only limited to this population. Therefore, this study aims to explore path models explaining the multivariate contributions of such variables to disability and quality of life in people with nCSP. This secondary analysis uses baseline data from a randomized controlled trial including 120 participants with nCSP. Structural equation modeling was used to explore path models for the Pain Disability Index (PDI), the Short Form 36-item physical (SF-36 PC), and mental (SF-36 MC) component scores. All models included sex, pain catastrophizing, kinesiophobia, hypervigilance, and pain intensity. Additionally, the PDI and SF-36 PC models included pressure pain thresholds (PPTs) at the dominant pain site (ie, neck or low back). Significant associations were found between sex, pain cognitions, pain intensity, and PPTs. Only pain catastrophizing significantly directly influenced the PDI (P ≤ .001) and SF-36 MC (P = .014), while the direct effects on the SF-36 PC from kinesiophobia (P = .008) and pain intensity (P = .006) were also significant. However, only the combined effect of all pain cognitions on the SF-36 PC was mediated by pain intensity (P = .019). Our findings indicate that patients' pain-related cognitions have an adverse effect on their physical health-related quality of life via a negative influence on their pain intensity in people with nCSP. PERSPECTIVE: This secondary analysis details a network analysis confirming significant interactions between sex, pain cognitions, pain intensity, and PPTs in relation to disability and health-related quality of life in people with chronic spinal pain. Moreover, its findings establish the importance of pain cognitions and pain intensity for these outcomes. TRIALS REGISTRATION: Clinicaltrials.gov (NCT02098005)., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Chronic pain is the most prevalent disease worldwide, leading to substantial disability and socioeconomic burden. Therefore, it can be regarded as a public health disease and major challenge to scientists, clinicians and affected individuals. Behavioral lifestyle factors, such as, physical (in)activity, stress, poor sleep and an unhealthy diet are increasingly recognized as perpetuating factors for chronic pain. Yet, current management options for patients with chronic pain often do not address lifestyle factors in a personalized multimodal fashion. This state-of-the-art clinical perspective aims to address this gap by discussing how clinicians can simultaneously incorporate various lifestyle factors into a personalized multimodal lifestyle intervention for individuals with chronic pain. To do so the available evidence on (multimodal) lifestyle interventions targeting physical (in)activity, stress, sleep and nutritional factors, specifically, was reviewed and synthetized from a clinical point of view. First, advise is provided on how to design a personalized multimodal lifestyle approach for a specific patient. Subsequently, best-evidence recommendations on how to integrate physical (in)activity, stress, sleep and nutritional factors as treatment targets into a personalized multimodal lifestyle approach are outlined. Evidence supporting such a personalized multimodal lifestyle approach is growing, but further studies are needed.

(1) Background: Surgical phases form the basic building blocks for surgical skill assessment, feedback, and teaching. The phase duration itself and its correlation with clinical parameters at diagnosis have not yet been investigated. Novel commercial platforms provide phase indications but have not been assessed for accuracy yet. (2) Methods: We assessed 100 robot-assisted partial nephrectomy videos for phase durations based on previously defined proficiency metrics. We developed an annotation framework and subsequently compared our annotations to an existing commercial solution (Touch Surgery, Medtronic™). We subsequently explored clinical correlations between phase durations and parameters derived from diagnosis and treatment. (3) Results: An objective and uniform phase assessment requires precise definitions derived from an iterative revision process. A comparison to a commercial solution shows large differences in definitions across phases. BMI and the duration of renal tumor identification are positively correlated, as are tumor complexity and both tumor excision and renorrhaphy duration. (4) Conclusions: The surgical phase duration can be correlated with certain clinical outcomes. Further research should investigate whether the retrieved correlations are also clinically meaningful. This requires an increase in dataset sizes and facilitation through intelligent computer vision algorithms. Commercial platforms can facilitate this dataset expansion and help unlock the full potential, provided that the phase annotation details are disclosed.

Background: Perioperative education should be improved to decrease unfavourable outcomes after lumbar surgery. This trial aimed to compare effectiveness in terms of pain, quality of life, pain cognition, surgical experience, healthcare use, work resumption, and cost-effectiveness of perioperative pain neuroscience education (PPNE) vs traditional biomedical education (perioperative biomedical education [PBE]) in people undergoing surgery for lumbar radiculopathy., Methods: In this multicentre RCT (ClinicalTrials.gov: NCT02630732), patients undergoing surgery for lumbar radiculopathy in three Belgian hospitals were randomised to receive PPNE or PBE. Both groups received one preoperative and one postoperative one-to-one education session and a booklet (balanced interventions), with an essentially different content (PPNE: biopsychosocial; PBE: biomedical). Pain was the primary outcome (Visual Analogue Scales+quantitative sensory testing). Assessments were at 3 days, 6 weeks, and 6 and 12 months after surgery., Results: Between March 2016 and April 2020, participants were randomly assigned to PPNE (n=58) or PBE (n=62). At 12 months, PPNE did not lead to significantly better pain outcomes, but it did result in more favourable 36-item Short Form Health Survey physical component (additional increase: 46.94; 95% confidence interval [CI]: 14.16-79.73; medium effect), Tampa Scale of Kinesiophobia (additional decrease: 3.15; 95% CI: 0.25-6.04; small effect), and Pain Catastrophising Scale (additional decrease: 6.18; 95% CI: 1.97-10.39; medium effect) scores. Females of the PPNE group showed higher probability for work resumption (95% vs 60% in the PBE group). PPNE was cost-effective compared with PBE (incremental costs: €-2732; incremental quality-adjusted life years: 0.012)., Conclusions: Perioperative pain neuroscience education showed superior clinical and cost-effectiveness than perioperative biomedical education in people undergoing surgery for lumbar radiculopathy., Clinical Trial Registration: NCT02630732., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Anti-HER2 antibody-drug conjugates (ADCs) have shown important efficacy in HER2-low metastatic breast cancer (mBC). Criteria for receiving ADCs are based on a single assay on the primary tumour or a small metastatic biopsy. We assessed the intra-patient inter-metastasis heterogeneity of HER2-low status in HER2-negative mBC., Patients and Methods: We included samples of 10 patients (7 ER-positive and 3 ER-negative) donated in the context of our post-mortem tissue donation program UPTIDER. Excisional post-mortem biopsies of 257 metastases and 8 breast tumours underwent central HER2 immunohistochemistry (IHC), alongside 41 pre-mortem primary or metastatic samples. They were classified as HER2-zero, HER2-low (HER2-1+ or HER2-2+, in situ hybridisation [ISH] negative) or HER2-positive (HER2-3+ or HER2-2+, ISH-positive) following ASCO/CAP guidelines 2018. HER2-zero was further subdivided into HER2-undetected (no staining) and HER2-ultralow (faint staining in ≤10% of tumour cells)., Results: Median post-mortem interval was 2.5 h. In 8/10 patients, HER2-low and HER2-zero metastases co-existed, with the proportion of HER2-low lesions ranging from 5% to 89%. A total of 32% of metastases currently classified as HER2-zero were HER2-ultralow. Intra-organ inter-metastasis heterogeneity of HER2-scores was observed in the liver in 3/6 patients. Patients with primary ER-positive disease had a higher proportion of HER2-low metastases as compared to ER-negative disease (46% versus 8%, respectively). At the metastasis level, higher percentages of ER-expressing cells were observed in HER2-low or -ultralow as compared to HER2-undetected metastases., Conclusions: Important intra-patient inter-metastasis heterogeneity of HER2-low status exists. This questions the validity of HER2-low in its current form as a theranostic marker., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TG, MDS, FR, KVB, MM, AM, H-LN, EI, SL, AP, GZ, FM, SVB, AS, IN, PN, WVDB, GF, CD: no conflicts to declare. KP: research grants paid to institution: MSD and Sanofi, speaker fees and honoraria for consultancy and advisory board functions: Astra Zeneca, Eli Lilly, Exact Sciences, Focus Patient, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, speaker fees and honoraria for consultancy and advisory board functions paid to institution: Astra Zeneca, Eli Lilly, Exact Sciences, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, stock options: Need Inc, travel grants: Astra Zeneca, Novartis, Pfizer, PharmaMar, Roche. HW: his institution received financial compensation on his behalf for advisory boards, lecture fees and/or consultancy fees from Immutep Pty, MSD, Astrazenca, Daiichi, AbbVie, Lilly, Roche, EISAI, Pfizer, Sirtex, Gilead. He received travel support from Pfizer and Roche., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Pain is an individualized experience for the person suffering from chronic pain. Significant strides have been made in the last few decades in understanding various biological changes that coincide with chronic pain. This state-of-the-art overview looks at the current evidence related to the biology of chronic pain and the implications these findings have on the delivery of pain neuroscience education (PNE). The paper summarizes the various (epi)genetic, neural, endocrine, and immune factors discovered and explored in the scientific literature concerning chronic pain. Each of these biological factors has various implications for the content and delivery of PNE. We discuss the future directions these biological factors have for the clinical implementation of PNE by linking the importance of behavior change, optimizing the learning environment, and using an individualized multimodal treatment approach with PNE. In addition, future directions for research of PNE based on these biological factors are provided with importance placed on individualized patient-centered care and how PNE can be used with traditional modes of care and growing trends with other care methods. PNE was originally and continues to be rooted in understanding chronic pain biology and how that understanding can improve patient care and outcomes.

(1) Background: Dysregulation in serotonergic and noradrenergic systems may be implicated in the neurobiophysiological mechanisms underlying pain-related cognitive impairment in chronic whiplash-associated disorders (CWAD). This study aimed to unravel the role of serotonergic and noradrenergic descending pathways in cognitive functioning at rest and in response to exercise in people with CWAD. (2) Methods: 25 people with CWAD were included in this double-blind, randomized, controlled crossover study. Endogenous descending serotonergic and noradrenergic inhibitory mechanisms were modulated by using a single dose of a selective serotonin reuptake inhibitor (Citalopram) or a selective norepinephrine reuptake inhibitor (Atomoxetine). Cognitive performance was studied at rest and in response to exercise (1) without medication intake; (2) after intake of Citalopram; and (3) after intake of Atomoxetine. (3) Results: After Atomoxetine intake, selective attention improved compared with the no medication day ( p < 0.05). In contrast, a single dose of Citalopram had no significant effect on cognitive functioning at rest. When performing pairwise comparisons, improvements in selective attention were found after exercise for the no medication condition ( p < 0.05). In contrast, after intake of Citalopram or Atomoxetine, selective and sustained attention worsened after exercise. (4) Conclusions: A single dose of Atomoxetine improved selective attention only in one Stroop condition, and a single dose of Citalopram had no effect on cognitive functioning at rest in people with CWAD. Only without medication intake did selective attention improve in response to exercise, whereas both centrally acting medications worsened cognitive performance in response to a submaximal aerobic exercise bout in people with CWAD.

Objective: The present cross-sectional study aims to unravel associations of pain intensity and cognitions with quantitative sensory testing in people scheduled for surgery for lumbar radiculopathy. Additionally, insight will be provided into the presence of dysfunctional nociceptive processing and maladaptive pain cognitions in this population., Design: Cross-sectional study., Setting: Data from three hospitals in Belgium., Subjects: The final sample comprised 120 participants with lumbar radiculopathy scheduled for surgery, included between March 2016 and April 2019., Methods: Self-reported pain intensity was assessed on a visual analog scale, and pain cognitions were assessed with self-reported questionnaires (Pain Catastrophizing Scale, Tampa Scale for Kinesiophobia, and Pain Vigilance and Awareness Questionnaire). Quantitative sensory testing (detection thresholds, pain thresholds, temporal summation, and conditioned pain modulation) was evaluated, as well., Results: Evidence was found for the presence of an impaired inhibitory response to nociceptive stimuli and maladaptive pain cognitions in this population. Kinesiophobia was found to be present to a maladaptive degree in the majority of the patients (n = 106 [88%]). Significant, but weak, associations between electrical pain thresholds at the sural nerves and leg pain intensity (sural nerve symptomatic side: r = -0.23; P = 0.01; non-symptomatic side: r = -0.22; P = 0.02) and kinesiophobia levels (sural nerve non-symptomatic side: r = -0.26; P = 0.006) were identified., Conclusions: Electrical detection thresholds and correlates for endogenous nociceptive facilitation and inhibition were not found to be related to any of the pain cognitions or to pain intensity in people scheduled to undergo surgery for lumbar radiculopathy., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This cross-sectional study explored associations between demographics, pain intensity and cognitions on the one hand and healthcare use (HCU) on the other hand in people undergoing surgery for lumbar radiculopathy. HCU during the 2 months preceding surgery was evaluated using a retrospective questionnaire. Demographics included sex, age and level of education and equivalent income. Back and leg pain intensity were evaluated using a visual analogue scale. Pain cognitions were assessed with the Tampa scale of kinesiophobia, the pain catastrophizing scale and the pain vigilance and awareness questionnaire. The sample comprised 120 participants (52% males; 49 years (Quartile (Q)1-Q3: 37.3-57.43)). The number of visits to the general practitioner was associated with sex (incidence rate ratio (IRR) for males = 0.811; p = 0.050), pain catastrophizing (IRR = 1.010; p = 0.041), pain magnification (IRR = 1.058; p = 0.004) and leg pain intensity (IRR = 1.004; p = 0.038). The number of neurosurgeon visits was associated with level of education (IRR moderate education = 1.518; p = 0.016 (reference: low education)). Receiving zero physiotherapy visits was associated with higher back pain intensity (Beta = 0.018; p = 0.028). Highest level of analgesics used was associated with sex (IRR for males = 0.502; p = 0.047) and leg pain (IRR = 1.014; p = 0.034). Only the association between general practitioner visits and pain magnification remained significant in multivariable analyses (IRR = 1.061; p = 0.033). The results suggest a rather indirect relationship between HCU and demographics, pain intensity and cognitions, involving a potential interplay between several patient- and healthcare system-related factors.

Background: Currently, evidence regarding fear avoidance beliefs as potential predictors for lumbar surgery outcomes seems insufficient and strong conclusions are not yet available., Objective: This systematic review aimed to evaluate the predictive value of preoperative fear avoidance beliefs for postoperative pain intensity, functional status, and health-related quality of life following surgery for lumbar degenerative disease., Study Design: Systematic review and best evidence synthesis., Methods: An extensive search was performed in PubMed/Medline, EMBASE, PsycINFO, CINAHL and the Cochrane library for articles published up until October 2021. Two independent reviewers performed the screening, data extraction, and quality assessment, with a third independent reviewer consulting to resolve any disagreement. Observational studies that included patients undergoing surgery for lumbar degenerative disease, as well as evaluated fear avoidance beliefs (i.e., pain-related fear, pain catastrophizing, pain anxiety) in relation to a surgical outcome measure (i.e., pain intensity, functional status and health-related quality of life) were included in the review. The CHARMS- and QUIPS-tools were used for data extraction and quality assessment, respectively. A best evidence synthesis was performed resulting in conclusions regarding strong, moderate, conflicting, and limited levels of evidence., Results: A total of 24 studies (n = 17,881) were included in this review. Following best evidence synthesis, 3 included studies reported no significant predictive value of preoperative pain-related fear for postoperative pain intensity resulting in moderate evidence for this relationship. Moderate evidence was also found indicating no significant predictive value of preoperative pain-related fear for postoperative functional status, as 6 out of 8 relevant studies reported this result. Only one study reported on the predictive value of preoperative pain catastrophizing for postoperative health-related quality of life, resulting in limited evidence for the absence of this predictive relationship. All other relationships were found to have conflicting evidence., Limitations: To evaluate surgical outcome, only patient-reported outcome measures as used by spine registries were included. Thus, our findings cannot be extrapolated to all surgery outcomes following lumbar degenerative disease and should only be interpreted in relation to postoperative pain intensity, functional status, or health-related quality of life., Conclusion: Best evidence synthesis showed moderate evidence indicating that preoperative pain-related fear is not a significant predictor for postoperative pain and function following surgery for lumbar degenerative disease. Additionally, limited evidence was found for a lack of predictive value of preoperative pain catastrophizing for postoperative health-related quality of life. As current evidence regarding the predictive value of preoperative fear avoidance beliefs following such a surgery is mixed, further research is required before more definitive conclusions can be made.

Every year, thousands of suspicious deaths are accounted for by an overdose of opioids. Occasionally all traditional matrices are unavailable due to decomposition. Skeletal tissue may pose a valid alternative. However, reference data on postmortem concentrations in bone tissue and bone marrow (BM) is sparse. Therefore, a liquid chromatography--tandem mass spectrometry method was developed and fully validated for the analysis of four opioids and two metabolites (tramadol, O-desmethyltramadol, morphine, fentanyl, norfentanyl, codeine) in bone tissue and BM. Sample preparation was performed using solid phase extraction (BM), methanolic extraction (bone) and a protein precipitation (whole blood). All validation parameters were successfully fulfilled. This method was applied to analyze 22 forensic cases involving opioids. All six opioids were proven to be detectable and quantifiable in all specimens sampled. When tramadol blood concentrations were correlated with bone concentrations, a linear trend could be detected. The same was seen between tramadol blood and BM concentration. A similar linear trend was seen when correlating codeine blood concentration with bone and BM concentration. Although some variability was detected, the same linear trend was seen for morphine. For fentanyl and norfentanyl, the sample size was too small to draw conclusions, regarding correlation. As far as the authors know this is the first-time fentanyl and norfentanyl are quantified in skeletal tissue. In conclusion, due to the absence of reference data for drugs in skeletal tissue, these findings are a step forward toward a more thorough understanding of drug concentration found in postmortem skeletal tissue., (© The Author(s) 2021. Published by Oxford University Press.)

Purpose: The primary goal of this study was to compare the health-related quality of life (HRQoL) of people with lumbar radiculopathy to age- and sex-adjusted population norms. Additionally, it aimed to explore the associations between the HRQoL difference scores and measures related to pain cognitions, pain intensity, and endogenous nociceptive modulation., Methods: Using answers from the Short Form 36-item Health Survey and UK population norms, SF-6D difference scores were calculated. A one-sample t test was used to assess the SF-6D difference scores. Univariate and multivariate regression analyses were used to assess the associations between SF-6D difference scores and pain intensity [Visual Analogue Scale (VAS) for back and leg pain], pain cognitions [Pain Catastrophizing Scale (PCS), Tampa Scale for Kinesiophobia (TSK), Pain Vigilance and Awareness Questionnaire (PVAQ)], and correlates for endogenous nociceptive modulation using quantitative sensory testing., Results: One hundred and twenty people with lumbar radiculopathy scheduled for surgery were included in this study. The mean SF-6D difference score of - 0.26 [SD = 0.09] was found to be significantly less than 0 [95%CI: - 0.27 to - 0.24]. Univariate analyses showed a significant influence from PCS, TSK, and PVAQ on the SF-6D difference scores. The final multivariate regression model included PCS and PVAQ, with only PCS maintaining a statistically significant regression coefficient [b = - 0.002; 95% CI: - 0.004 to - 0.001]., Conclusion: People diagnosed with lumbar radiculopathy report significantly lower HRQoL scores when compared with age- and sex-adjusted UK norm values. Even though all examined pain cognitions were found to have a significant association, pain catastrophizing showed the most significant relation to the SF-6D difference scores., Clinical Trial Registration: ClinicalTrials.gov Identifier No. NCT02630732. Date of registration: November 25, 2015., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Alcohol-associated liver disease (ALD) represents a spectrum of histopathological changes, including alcoholic steatosis, steatohepatitis, and cirrhosis. One of the early responses to excessive alcohol consumption is lipid accumulation in the hepatocytes. Lipid ω-hydroxylation of medium- and long-chain fatty acid metabolized by the cytochrome P450 4A (CYP4A) family is an alternative pathway for fatty acid metabolism. The molecular mechanisms of CYP4A in ALD pathogenesis have not been elucidated. In this study, WT and Shp-/- mice were fed with a modified ethanol-binge, National Institute on Alcohol Abuse and Alcoholism model (10 days of ethanol feeding plus single binge). Liver tissues were collected every 6 hours for 24 hours and analyzed using RNA-Seq. The effects of REV-ERBα agonist (SR9009, 100 mg/kg/d) or CYP4A antagonist (HET0016, 5 mg/kg/d) in ethanol-fed mice were also evaluated. We found that hepatic Cyp4a10 and Cyp4a14 expression were significantly upregulated in WT mice, but not in Shp-/- mice, fed with ethanol. ChIP quantitative PCR and promoter assay revealed that REV-ERBα is the transcriptional repressor of Cyp4a10 and Cyp4a14. Rev-Erbα-/- hepatocytes had a marked induction of both Cyp4a genes and lipid accumulation. REV-ERBα agonist SR9009 or CYP4A antagonist HET0016 attenuated Cyp4a induction by ethanol and prevented alcohol-induced steatosis. Here, we have identified a role for the SHP/REV-ERBα/CYP4A axis in the pathogenesis of ALD. Our data also suggest REV-ERBα or CYP4A as the potential therapeutic targets for ALD.

RNA analysis of post-mortem tissues, or thanatotranscriptomics, has become a topic of interest in forensic science due to the essential information it can provide in forensic investigations. Several studies have previously investigated the effect of death on gene transcription, but it has never been conducted with samples of the same individual. For the first time, a longitudinal mRNA expression analysis study was performed with post-mortem human blood samples from individuals with a known time of death. The results reveal that, after death, two clearly differentiated groups of up- and down-regulated genes can be detected. Pathway analysis suggests active processes that promote cell survival and DNA damage repair, rather than passive degradation, are the source of early post-mortem changes of gene expression in blood. In addition, a generalized linear model with an elastic net restriction predicted post-mortem interval with a root mean square error of 4.75 h. In conclusion, we demonstrate that post-mortem gene expression data can be used as biomarkers to estimate the post-mortem interval though further validation using independent sample sets is required before use in forensic casework., (© 2021. The Author(s).)

Background: Pain neuroscience education (PNE) combined with cognition-targeted exercises is an effective treatment for people with chronic spinal pain (CSP). However, it is unclear why some patients benefit more from this treatment. We expect that patients with more pronounced maladaptive pain cognitions, such as kinesiophobia, might show poorer treatment responses., Objective: The objective of this study was to assess the influence of baseline kinesiophobia levels on the treatment outcomes of PNE combined with cognition-targeted exercises in people with CSP. This study was a secondary analysis of a multicenter, double-blind, randomized controlled trial., Methods: Outcome measures included a numeric rating scale for pain (NRS), the Pain Disability Index (PDI), quality of life (Medical Outcomes Study 36-Item Health Survey [SF-36]), Pain Catastrophizing Scale (PCS), and Pain Vigilance and Awareness Questionnaire (PVAQ). Regression models were built using treatment (PNE plus cognition-targeted exercises or neck/back school plus general exercises), baseline scores on the Tampa Scale for Kinesiophobia (TSK), and time (in months) as independent variables., Results: A significant 3-way interaction effect was found for the models of PDI, PCS, PVAQ, and the SF-36 mental domain, with estimates of -0.01, -0.01, -0.01, and 0.07, respectively. A significant effect of baseline TSK scores was found for the physical domain of the SF-36 (estimate = -3.16). For the NRS, no significant effect of baseline TSK scores was found., Conclusion: Our findings indicate that PNE plus cognition-targeted exercises can successfully decrease the unfavorable influence of pretreatment kinesiophobia on disability, mental health, pain catastrophizing, and hypervigilance over time in people with CSP. Nevertheless, higher scores in pretreatment kinesiophobia might still be a key factor for the lack of improvement in pain catastrophizing and hypervigilance following treatment. Regardless of the followed treatment program, pretreatment kinesiophobia was also shown to significantly influence physical health in people with CSP., Impact: This study provides novel insight into the unfavorable influence of kinesiophobia on treatment outcomes in people with CSP, and how PNE plus cognition-targeted exercises can limit this impact. Because this is one of the first studies to research possible predictors of this experimental treatment, its findings motivate further exploration of other possible influencing factors for treatment success of PNE plus cognition-targeted exercises., Lay Summary: People with chronic spinal pain and high levels of fear of movement were found to have worse treatment outcomes compared to people with low levels of fear of movement. However, our experimental treatment, which includes pain neuroscience education combined with exercise therapy that reintroduces specific movements patients might fear, can decrease this negative influence of fear of movement in these patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Pain neuroscience education (PNE) and motivational interviewing (MI) have been widely implemented and tested in the field of chronic pain management, and both strategies have been shown to be effective in the short term (small effect sizes) for the management of chronic pain. PNE uses contemporary pain science to educate patients about the biopsychosocial nature of the chronicity of their pain experience. The goal of PNE is to optimize patients' pain beliefs/perceptions to facilitate the acquisition of adaptive pain-coping strategies. MI, on the other hand, is a patient-centered communication style for eliciting and enhancing motivation for behavior change by shifting the patient away from a state of indecision or uncertainty. Conceptually, PNE and MI appear to be complementary interventions, with complementary rather than overlapping effects; MI primarily improves cognitive and behavioral awareness and, potentially, adherence to treatment principles, whereas PNE potentially increases pain knowledge/beliefs, awareness, and willingness to explore psychological factors that are potentially associated with pain. Therefore, combining PNE with MI might lead to improved outcomes with larger and longer-lasting effect sizes. The combined use of PNE and MI in patients having chronic pain is introduced here, along with a description of how clinicians might be able to integrate PNE and MI in the treatment of patients experiencing chronic pain. Clinical trials are needed to examine whether combining PNE with MI is superior to PNE or MI alone for improving pain and quality of life in patients having chronic pain., (© 2020 American Physical Therapy Association.)

Blood analysis is the golden standard in the field of forensic toxicology. However, when extended decomposition of the remains has occurred, alternative matrices are required. Skeletal tissue may provide an appropriate sample of choice since it is very resistant to putrefaction. However, today, the absence of reference data of drug concentrations in skeletal tissue poses a problem to meaningfully and reliably conduct toxicological testing on human skeletal material. The present study investigates the viability of skeletal tissue as an alternative matrix to evaluate xenobiotic consumption in legal cases. Blood, bone tissue and bone marrow of different forensic cases were screened for 415 compounds of forensic interest. Afterwards, methadone, clomipramine, citalopram and their respectively metabolites positive samples were quantified using fully validated methods. Sample preparation was carried out by SPE (whole blood and bone marrow), methanol extraction (bone sections) or protein precipitation (whole blood). All samples were analyzed using liquid chromatography coupled to a triple quad mass spectrometer. Multiple drugs were successfully identified in all sampled matrices. In bone (marrow) not as many substances were detected as in blood but it poses a valid alternative when blood is not available. Especially bone marrow showed big potential with a concordance of 80.5% with blood. Clomipramine, citalopram and their metabolites were proven to be detectable and quantifiable in all specimens sampled. Bone marrow showed the highest concentrations followed by blood and bone tissue. When citalopram blood concentrations were correlated with the bone concentrations, a linear trend could be detected. The same was seen between blood and bone marrow for citalopram concentrations. Methadone was also proven to be detectable in all specimens sampled. However, its metabolites EMDP and EDPP were absent or below the LOD in some samples. Overall, methadone concentrations were higher in bone marrow than in bone. With exception of one case, blood concentrations were higher than bone concentrations. For methadone, a linear trend could be found between blood and bone concentration. Comparing methadone concentrations in blood and bone marrow an exponential trend could be seen. In conclusion, these findings show the potential forensic value of bone and bone marrow as an alternative matrix. Aside to that, a standard protocol for the sample collection and processing is proposed., Competing Interests: Declaration of Competing Interest The authors state that there is no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Context: Alloplastic temporomandibular joint replacement., Aims: To search for evidence for the use of periprosthetic autologous fat transplantation., Setting and Design: Systematic review., Materials and Methods: We searched in PubMed Central, Elsevier ScienceDirect Complete, Wiley Online Library Journals, Ovid Lippincott Williams and Wilkins, and Cochrane Library plus Results. Six studies reported improved results with the use of autologous fat graft (AFG) in patients treated with a total joint replacement, mainly about increased mobility. Three studies involved patients from the same surgeon with increased inclusions and increased follow-up period. A 1997 study by Wolford showed a significant difference in heterotopic bone formation between patients treated with AFG, compared to those who were not, indicating the potential and usefulness of AFG., Conclusion: A prospective multicenter randomized controlled trial of this promising concept is warranted before justifying common application because of the added morbidity and the questionable advantage., Competing Interests: There are no conflicts of interest.

In recent years, the increasing number of asphyxiation cases due to helium inhalation is remarkable. All described cases in the literature where diagnosed as suicide. In this article, however, we describe a triple infant homicide in which helium, as balloon gas, was administered to three young children after sedation causing asphyxiation and death through the medical findings and toxicological analysis. During autopsy, in addition to standard toxicological samples, gas samples from lungs as well as lung tissue itself were directly collected into headspace vials. Besides routine toxicological analysis, which revealed toxic levels of doxylamine, qualitative analysis on gas and lung samples was performed using headspace gas chromatography-mass spectrometry. As carrier gas, the commonly used helium was replaced by nitrogen. In gas samples from lungs of all three children, no helium was found. Nevertheless, lung tissue samples were found positive on helium. Therefore, sedation followed by asphyxia due to helium inhalation can strongly be assumed as the cause of death of all three children., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The effect of internal mammary and medial supraclavicular lymph-node irradiation (regional nodal irradiation) added to whole-breast or thoracic-wall irradiation after surgery on survival among women with early-stage breast cancer is unknown., Methods: We randomly assigned women who had a centrally or medially located primary tumor, irrespective of axillary involvement, or an externally located tumor with axillary involvement to undergo either whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation (nodal-irradiation group) or whole-breast or thoracic-wall irradiation alone (control group). The primary end point was overall survival. Secondary end points were the rates of disease-free survival, survival free from distant disease, and death from breast cancer., Results: Between 1996 and 2004, a total of 4004 patients underwent randomization. The majority of patients (76.1%) underwent breast-conserving surgery. After mastectomy, 73.4% of the patients in both groups underwent chest-wall irradiation. Nearly all patients with node-positive disease (99.0%) and 66.3% of patients with node-negative disease received adjuvant systemic treatment. At a median follow-up of 10.9 years, 811 patients had died. At 10 years, overall survival was 82.3% in the nodal-irradiation group and 80.7% in the control group (hazard ratio for death with nodal irradiation, 0.87; 95% confidence interval [CI], 0.76 to 1.00; P=0.06). The rate of disease-free survival was 72.1% in the nodal-irradiation group and 69.1% in the control group (hazard ratio for disease progression or death, 0.89; 95% CI, 0.80 to 1.00; P=0.04), the rate of distant disease-free survival was 78.0% versus 75.0% (hazard ratio, 0.86; 95% CI, 0.76 to 0.98; P=0.02), and breast-cancer mortality was 12.5% versus 14.4% (hazard ratio, 0.82; 95% CI, 0.70 to 0.97; P=0.02). Acute side effects of regional nodal irradiation were modest., Conclusions: In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival. Disease-free survival and distant disease-free survival were improved, and breast-cancer mortality was reduced. (Funded by Fonds Cancer; ClinicalTrials.gov number, NCT00002851.).