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Elisabeth Kjær Jensen,1,* Thomas K Ringsted,1,* Joakim M Bischoff,1 Morten A Petersen,2 Kirsten Møller,3,4 Henrik Kehlet,5 Mads U Werner1,6 1Department of Anaesthesia, Pain and Respiratory Support, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; 2Statistical Research Unit, Department of Palliative Care, Bispebjerg Hospital, Copenhagen, Denmark; 3Department of Neuroanaesthesiology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; 4Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 5Section for Surgical Pathophysiology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; 6Department of Clinical Sciences, Lund University, Lund, Sweden*These authors contributed equally to this workCorrespondence: Elisabeth Kjær Jensen, Multidisciplinary Pain Center 7612, Department of Anesthesia, Pain and Respiratory Support, Neuroscience Center, Rigshospitalet, Ole Maaløes Vej 26, Copenhagen N, 2200, Denmark, Tel +45 3545 7612, Email elisabeth.kjaer@live.dkPurpose: After groin hernia repair (globally more than 20 million/year) 2– 4% will develop persistent severe pain (PSPG). Pain management is challenging and may require multimodal interventions, including re-surgery. Quantitative somatosensory testing (QST) is an investigational psychophysiological tool with the potential to uncover the pathophysiological mechanisms behind the pain, ie, revealing neuropathic or inflammatory components. The primary objective was to examine and describe the underlying pathophysiological changes in the groin areas by QST before and after re-surgery with mesh removal and selective neurectomy.Patients and Methods: Sixty patients with PSPG scheduled for re-surgery and with an inflammatory “component” indicated by blunt pressure algometry were examined in median (95% CI) 7.9 (5.8– 11.5) months before and 4.0 (3.5– 4.6) months after re-surgery. The QST-analyses included standardized assessments of cutaneous mechanical/thermal detection and pain thresholds. Suprathreshold heat stimuli were applied. Deep tissue sensitivity was tested by pressure algometry. Testing sites were the groin areas and the lower arm. Before/after QST data were z-transformed.Results: Re-surgery resulted in median changes in rest, average, and maximal pain intensity scores of − 2.0, − 2.5, and − 2.0 NRS (0/10) units, respectively (P = 0.0001), and proportional increases in various standardized functional scores (P = 0.0001). Compared with the control sites, the cutaneous somatosensory detection thresholds of the painful groin were increased before re-surgery and increased further after re-surgery (median difference: 1.28 z-values; P = 0.001), indicating a successive post-surgical loss of nerve fiber function (“deafferentation”). Pressure algometry thresholds increased after re-surgery (median difference: 0.30 z-values; P = 0.001).Conclusion: In this subset of patients with PSPG who underwent re-surgery, the procedure was associated with improved pain and functional outcomes. While the increase in somatosensory detection thresholds mirrors the surgery-induced cutaneous deafferentation, the increase in pressure algometry thresholds mirrors the removal of the deep “pain generator”. The QST-analyses are useful adjuncts in mechanism-based somatosensory research.Keywords: groin, hernia repair, chronic post-surgical pain, reoperation, sensory thresholds

Inflammatory reactions caused by immunosuppression appear a particular interesting disease due to its very specific and partly unclear etiopathogenesis.

We present two novel approaches to variance estimation of semi-parametric efficient point estimators of the treatment-specific mean: (i) a robust approach that directly targets the variance of the influence function (IF) as a counterfactual mean outcome and (ii) a modified non-parametric bootstrap-based approach. The performance of these approaches to variance estimation is compared to variance estimation based on the sample variance of the empirical IF in simulations across different levels of positivity violations and treatment effect sizes. In this article, we focus on estimation of the nuisance parameters using correctly specified parametric models for the treatment mechanism in order to highlight the challenges posed by violation of positivity assumptions (distinct from the challenges posed by non-parametric estimation of the nuisance parameters). Results demonstrate that (1) variance estimation based on the empirical IF may provide highly anti-conservative confidence interval coverage (as reported previously), (2) the proposed robust approach to variance estimation in this setting provides conservative coverage, and (3) the proposed modified bootstrap maintains close to nominal coverage and improves power. In the appendix, we (a) generalize the robust approach of estimating variance to marginal structural working models and (b) provide a proof of the consistency of the targeted minimum loss-based estimation bootstrap.

Quasi-elastic neutron scattering (QENS) from bulk-water at 300 K, measured on the IRIS backscattering neutron spectrometer (ISIS, UK), is interpreted using the jump diffusion model (JDM), a “minimalistic” multi-timescale relaxation model (MRM) and molecular dynamics simulations (MD). In the case of MRM data analysis is performed in the time domain, where the relaxation of the intermediate scattering function is described by a stretched Mittag-Leffler function, Eα(−(|t|/τ)α). This function displays an asymptotic power law decay and contains the exponential relaxation function as a special case (α = 1). To further compare the two approaches, MD simulations of bulk water were performed using the SPCE force field and the resulting MD trajectories analysed using the nMoldyn software. We show that both JDM and MRM accurately describe the diffusion of bulk water observed by QENS at all length scales, and confirm that MD simulations do not fully describe the quantum effects of jump diffusion.

Aim: The aims of this paper were to validate four items assessing how patients' needs regarding support to and from their relatives are met and to investigate patients' evaluation of this support.Method: Items were validated by patient-observer agreement and cognitive interviews. Adequacy of support was assessed in a cross-sectional study of 1,490 Danish cancer patients; 147 of these also answered an open-ended question.Results: All items performed well in the validation. Only 4 % reported lack of support from their relatives, whereas 9 and 11 % had lacked support from the health care professionals regarding how to tell the relatives about the disease and regarding the relatives in general, respectively. Although the patients' expectations are not unequivocal, a large proportion (35 %) reported that the health care professionals had shown little interest in how the relatives were doing. This was most pronounced for female patients and patients sampled in urban areas. Compared to older patients, younger patients lacked more support with respect to the relatives in general and regarding how to tell them about the disease. Divorced patients were less satisfied than married patients on all measures.Conclusion: While most patients felt well-supported by their relatives, the oldest, the divorced, and those without children may be a vulnerable group. Many patients reported that the health care staff showed insufficient interest in the well-being of the relatives. Thus, it may be beneficial for both the patient and the relatives if health care professionals acknowledge and support the relatives in fulfilling their important role as caregiver and companion. [ABSTRACT FROM AUTHOR]

Purpose: The number of cancer survivors is growing and cancer is now viewed as a chronic disease. This has highlighted the importance of providing adequate rehabilitation to prevent physical, psychological, and social sequelae of cancer. However, it is unclear whether those in need of rehabilitation are offered this.Methods: Using patient-observer agreement and cognitive interviews, we validated a seven-item questionnaire designed to assess cancer patients' perception of the sufficiency of the offered rehabilitation. A cross-sectional study among 2,202 Danish cancer patients affiliated with hospitals was carried out.Results: The questionnaire was well understood, indicating good validity. In the cross-sectional study, 1,490 patients (68%) participated. Up to 39% of cancer patients did not receive the physical rehabilitation they felt they needed. About half of those who had felt a need to talk to a psychologist were offered this. Insufficiency of other rehabilitation offers was reported by 10-24%. Age most consistently predicted insufficient rehabilitation; higher age predicted insufficient information about support from other sources (than hospital staff) and younger age predicted lack of help to manage symptoms, return to everyday life, and deal with financial and especially work-related consequences. We found no consistent signs of traditional social inequality in the perception of rehabilitation, but we observed some signs of social inequality for unemployed or divorced/separated patients.Conclusions: Age predicted sufficiency of the rehabilitation in two directions, possibly reflecting different needs in younger and older patients. When tailoring rehabilitation programs, it should be ensured that the different needs are met. [ABSTRACT FROM AUTHOR]

CONTEXT: To improve palliative care, it is important that questionnaires accurately assess the needs of the patients. No questionnaire existed that combined three different and important approaches to needs assessment. We developed such a questionnaire, called the Three-Levels-of-Needs Questionnaire (3LNQ), based on literature searches. The 3LNQ measures 12 important needs with three different approaches when used as a supplement to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30): problem intensity, problem burden, and felt need. OBJECTIVES: To investigate the initial validity of the 3LNQ. METHODS: We used a relatively new method that investigates whether the questionnaire has the same meaning for the patients as for the researchers. To do this, 74 patients with advanced cancer filled out the questionnaire and participated in an open-ended interview. The patients' responses to the questionnaire before the interview were compared against the researchers' responses based on the interviews. Items showing substantial agreement were accepted as valid without further analysis. For the remaining items, reasons for disagreements were analyzed qualitatively. RESULTS: All items on problem intensity, eight of 12 items on problem burden, and three of 12 items on felt need were accepted as valid because of high agreement. Analysis of the qualitative data concerning the remaining items showed that most disagreements did not indicate problems with the patients' self-assessment. Instead, different causes for disagreements were elucidated, but these did not interfere with validity. CONCLUSION: The 3LNQ appears to measure palliative needs comprehensively, and this initial validation showed satisfactory results. The analysis gave important insights into the patients' perceptions of their own situations, into their expectations of the health care system, and into the complexity of needs assessment. [ABSTRACT FROM AUTHOR]

BACKGROUND: Health-related quality of life (HRQOL) questionnaires should ideally be adapted to the individual patient and at the same time scores should be directly comparable across patients. This is achievable using a computerised adaptive test (CAT). Basing the CAT on an existing instrument enables measurement within an established HRQOL framework and allows backward-compatibility with studies using the original instrument. Because of these advantages the EORTC Quality of Life Group (QLG) has initiated a project to develop a CAT version of the widely used EORTC QLQ-C30. METHODS: We present the EORTC QLG's strategy for developing a CAT. For each dimension of the EORTC QLQ-C30 our approach includes literature search and conceptualisation, formulation of new items, expert and patient evaluations, field-testing, and psychometric analyses of the items. The strategy is illustrated with the initial results of the development of CAT for physical functioning (PF). RESULTS: We identified 975 PF items in the literature. Of these, 407 items were deemed relevant, i.e. measured one of the PF aspects measured by the QLQ-C30. Based on these items we developed 86 new items. Review by the EORTC CAT-project group reduced this to 66 items. Based on expert and patient evaluations several items were revised and the list was further reduced to 51 items. CONCLUSIONS: Based on the findings for PF, we believe that our approach will generate item pools that are relevant and appropriate for cancer patients. These will form the basis for a backward-compatible CAT assessing the HRQOL dimensions of the EORTC QLQ-C30. [ABSTRACT FROM AUTHOR]

The average patient has breast cancer for eight years before it's detectable. Still, education counts. [ABSTRACT FROM AUTHOR]

Failure (or success) in finding a statistically significant effect of a large-scale intervention may be due to choices made in the evaluation. To highlight the potential limitations and pitfalls of some common identification strategies used for estimating causal effects of community-level interventions, we apply a roadmap for causal inference to a pre-post evaluation of a national nutrition program in Madagascar. Selection into the program was non-random and strongly associated with the pre-treatment (lagged) outcome. Using structural causal models (SCM), directed acyclic graphs (DAGs) and simulated data, we illustrate that an estimand with the outcome defined as the post-treatment outcome controls for confounding by the lagged outcome but not by possible unmeasured confounders. Two separate differencing estimands (of the pre- and post-treatment outcome) have the potential to adjust for a certain type of unmeasured confounding, but introduce bias if the additional identification assumptions they rely on are not met. In order to illustrate the practical impact of choice between three common identification strategies and their corresponding estimands, we used observational data from the community nutrition program in Madagascar to estimate each of these three estimands. Specifically, we estimated the average treatment effect of the program on the community mean nutritional status of children 5 years and under and found that the estimate based on the post-treatment estimand was about a quarter of the magnitude of either of the differencing estimands (0.066 SD vs. 0.26–0.27 SD increase in mean weight-for-age z-score). Choice of estimand clearly has important implications for the interpretation of the success of the program to improve nutritional status of young children. A careful appraisal of the assumptions underlying the causal model is imperative before committing to a statistical model and progressing to estimation. However, knowledge about the data-generating process must be sufficient in order to choose the identification strategy that gets us closest to the truth.

This paper describes a targeted maximum likelihood estimator (TMLE) for the parameters of longitudinal static and dynamic marginal structural models. We consider a longitudinal data structure consisting of baseline covariates, time-dependent intervention nodes, intermediate time-dependent covariates, and a possibly time-dependent outcome. The intervention nodes at each time point can include a binary treatment as well as a right-censoring indicator. Given a class of dynamic or static interventions, a marginal structural model is used to model the mean of the intervention-specific counterfactual outcome as a function of the intervention, time point, and possibly a subset of baseline covariates. Because the true shape of this function is rarely known, the marginal structural model is used as a working model. The causal quantity of interest is defined as the projection of the true function onto this working model. Iterated conditional expectation double robust estimators for marginal structural model parameters were previously proposed by Robins (2000, 2002) and Bang and Robins (2005). Here we build on this work and present a pooled TMLE for the parameters of marginal structural working models. We compare this pooled estimator to a stratified TMLE (Schnitzer et al. 2014) that is based on estimating the intervention-specific mean separately for each intervention of interest. The performance of the pooled TMLE is compared to the performance of the stratified TMLE and the performance of inverse probability weighted (IPW) estimators using simulations. Concepts are illustrated using an example in which the aim is to estimate the causal effect of delayed switch following immunological failure of first line antiretroviral therapy among HIV-infected patients. Data from the International Epidemiological Databases to Evaluate AIDS, Southern Africa are analyzed to investigate this question using both TML and IPW estimators. Our results demonstrate practical advantages of the pooled TMLE over an IPW estimator for working marginal structural models for survival, as well as cases in which the pooled TMLE is superior to its stratified counterpart.

Due to the need to evaluate the effectiveness of community-based programs in practice, there is substantial interest in methods to estimate the causal effects of community-level treatments or exposures on individual level outcomes. The challenge one is confronted with is that different communities have different environmental factors affecting the individual outcomes, and all individuals in a community share the same environment and intervention. In practice, data are often available from only a small number of communities, making it difficult if not impossible to adjust for these environmental confounders. In this paper we consider an extreme version of this dilemma, in which two communities each receives a different level of the intervention, and covariates and outcomes are measured on a random sample of independent individuals from each of the two populations; the results presented can be straightforwardly generalized to settings in which more than two communities are sampled. We address the question of what conditions are needed to estimate the causal effect of the intervention, defined in terms of an ideal experiment in which the exposed level of the intervention is assigned to both communities and individual outcomes are measured in the combined population, and then the clock is turned back and a control level of the intervention is assigned to both communities and individual outcomes are measured in the combined population. We refer to the difference in the expectation of these outcomes as the marginal (overall) treatment effect. We also discuss conditions needed for estimation of the treatment effect on the treated community. We apply a nonparametric structural equation model to define these causal effects and to establish conditions under which they are identified. These identifiability conditions provide guidance for the design of studies to investigate community level causal effects and for assessing the validity of causal interpretations when data are only available from a few communities. When the identifiability conditions fail to hold, the proposed statistical parameters still provide nonparametric treatment effect measures (albeit non-causal) whose statistical interpretations do not depend on model specifications. In addition, we study the use of a matched cohort sampling design in which the units of different communities are matched on individual factors. Finally, we provide semiparametric efficient and doubly robust targeted MLE estimators of the community level causal effect based on i.i.d. sampling and matched cohort sampling.

Examines the use of trade credit by small firms whose access to capital markets may be limited. Advantage that suppliers gain from lending to constrained firms; Theories on trade credit; Price discrimination through trade credit; Economic shocks; Robustness checks.

Abstract Background The global spread of the highly pathogenic avian influenza H5N1 virus has stimulated interest in a better understanding of the mechanisms of H5N1 dispersal, including the potential role of migratory birds as carriers. Although wild birds have been found dead during H5N1 outbreaks, evidence suggests that others have survived natural infections, and recent studies have shown several species of ducks capable of surviving experimental inoculations of H5N1 and shedding virus. To investigate the possibility of migratory birds as a means of H5N1 dispersal into North America, we monitored for the virus in a surveillance program based on the risk that wild birds may carry the virus from Asia. Results Of 16,797 birds sampled in Alaska between May 2006 and March 2007, low pathogenic avian influenza viruses were detected in 1.7% by rRT-PCR but no highly pathogenic viruses were found. Our data suggest that prevalence varied among sampling locations, species (highest in waterfowl, lowest in passerines), ages (juveniles higher than adults), sexes (males higher than females), date (highest in autumn), and analytical technique (rRT-PCR prevalence = 1.7%; virus isolation prevalence = 1.5%). Conclusion The prevalence of low pathogenic avian influenza viruses isolated from wild birds depends on biological, temporal, and geographical factors, as well as testing methods. Future studies should control for, or sample across, these sources of variation to allow direct comparison of prevalence rates.

Abstract Background The purpose of this study was to assess the feasibility of conducting biological tetrachloroethylene (perchloroethylene, PCE) exposure assessments of dry cleaning employees in conjunction with evaluation of possible PCE health effects. Methods Eighteen women from four dry cleaning facilities in southwestern Ohio were monitored in a pilot study of workers with PCE exposure. Personal breathing zone samples were collected from each employee on two consecutive work days. Biological monitoring included a single measurement of PCE in blood and multiple measurements of pre- and post-shift PCE in exhaled breath and trichloroacetic acid (TCA) in urine. Results Post-shift PCE in exhaled breath gradually increased throughout the work week. Statistically significant correlations were observed among the exposure indices. Decreases in PCE in exhaled breath and TCA in urine were observed after two days without exposure to PCE. A mixed-effects model identified statistically significant associations between PCE in exhaled breath and airborne PCE time weighted average (TWA) after adjusting for a random participant effect and fixed effects of time and body mass index. Conclusion Although comprehensive, our sampling strategy was challenging to implement due to fluctuating work schedules and the number (pre- and post-shift on three consecutive days) and multiplicity (air, blood, exhaled breath, and urine) of samples collected. PCE in blood is the preferred biological index to monitor exposures, but may make recruitment difficult. PCE TWA sampling is an appropriate surrogate, although more field intensive. Repeated measures of exposure and mixed-effects modeling may be required for future studies due to high within-subject variability. Workers should be monitored over a long enough period of time to allow the use of a lag term.

Abstract Background It is usually preferable to model and estimate prevalence ratios instead of odds ratios in cross-sectional studies when diseases or injuries are not rare. Problems with existing methods of modeling prevalence ratios include lack of convergence, overestimated standard errors, and extrapolation of simple univariate formulas to multivariable models. We compare two of the newer methods using simulated data and real data from SAS online examples. Methods The Robust Poisson method, which uses the Poisson distribution and a sandwich variance estimator, is compared to the log-binomial method, which uses the binomial distribution to obtain maximum likelihood estimates, using computer simulations and real data. Results For very high prevalences and moderate sample size, the Robust Poisson method yields less biased estimates of the prevalence ratios than the log-binomial method. However, for moderate prevalences and moderate sample size, the log-binomial method yields slightly less biased estimates than the Robust Poisson method. In nearly all cases, the log-binomial method yielded slightly higher power and smaller standard errors than the Robust Poisson method. Conclusion Although the Robust Poisson often gives reasonable estimates of the prevalence ratio and is very easy to use, the log-binomial method results in less bias in most common situations, and because it fits the correct model and obtains maximum likelihood estimates, it generally results in slightly higher power, smaller standard errors, and, unlike the Robust Poisson, it always yields estimated prevalences between zero and one.

Background: Differential item functioning (DIF) methods can be used to determine whether different subgroups respond differently to particular items within a health-related quality of life (HRQoL) subscale, after allowing for overall subgroup differences in that scale. This article reviews issues that arise when testing for DIF in HRQoL instruments. We focus on logistic regression methods, which are often used because of their efficiency, simplicity and ease of application.Methods: A review of logistic regression DIF analyses in HRQoL was undertaken. Methodological articles from other fields and using other DIF methods were also included if considered relevant.Results: There are many competing approaches for the conduct of DIF analyses and many criteria for determining what constitutes significant DIF. DIF in short scales, as commonly found in HRQL instruments, may be more difficult to interpret. Qualitative methods may aid interpretation of such DIF analyses.Conclusions: A number of methodological choices must be made when applying logistic regression for DIF analyses, and many of these affect the results. We provide recommendations based on reviewing the current evidence. Although the focus is on logistic regression, many of our results should be applicable to DIF analyses in general. There is a need for more empirical and theoretical work in this area. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Patients’ perceptions of care including the communication with health care staff is recognized as an important aspect of the quality of cancer care. Using mixed methods, we developed and validated a short instrument assessing this communication. Methods: Based on focus group interviews with 77 informants, an 8-item instrument was developed. This short instrument aimed at assessing overall aspects of the communication between cancer patients and health care staff. The items were validated first through cognitive interviews with patient–observer agreement with 52 cancer patients who completed the questions and then participated in tape-recorded open-ended interviews. Observer ratings of the interviews were compared with the patients’ written responses collected before interviews and kappa values were calculated. The comprehensibility of each item was subsequently elaborated in traditional cognitive interviews with 17 cancer patients. Finally, psychometric analyses took place with data from 1490 cancer patients. Results: The weighted kappas concerning patient–observer agreement ranged 0.31–0.88. Disagreements mainly consisted of the observer choosing the response category indicating the highest level of satisfaction whereas the patients had chosen the second highest level. Cognitive interviews showed that the questions were generally interpreted as intended. One item was excluded due to low validity. A sum scale of the remaining seven items had high reliability (Cronbach''s alpha 0.89). Conclusions: Seven items performed well. They proved to be valid measures of satisfaction with communication with the health care staff and constitute a sum scale with high reliability. The cognitive interviews provided valuable insight into the patients’ perception of communication. [Copyright &y& Elsevier]

Opioids are the major class of analgesics used in the management of moderate to severe cancer pain, and constipation is a common side effect of opioid administration. While monitoring for quality-assurance, nurses found that 95% of patients interviewed on a 28-bed oncology unit of a Midwestern hospital reported constipation as the major side effect of their opioid regimen for pain control. Through the efforts of a nursing research utilization committee, a protocol to prevent opioid-induced constipation in patients with cancer was developed and implemented. [ABSTRACT FROM AUTHOR]

The brain-vascular-immune interface has emerged as a dynamic player in brain physiology and disease. We propose integrating vascular risk factors with genetic susceptibility as the nexus for the discovery of mechanisms and therapies for neuroinflammation, neurodegeneration, and neurorepair across polygenic neurologic diseases., Competing Interests: Declaration of interests K.A. is the scientific founder and scientific advisor of Therini Bio and has served as a consultant for F. Hoffman-La Roche and Sanofi. K.A., J.K.R., and M.A.P. are inventors on issued and pending patents related to fibrin. Their interests are managed in accordance with Gladstone Institute’s conflict of interest policies., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Patients with non-cancer disease are less likely to receive specialized palliative care than cancer patients. To be able to provide the best specialized palliative care, it is important to understand palliative care needs of non-cancer patients and whether the type and level of needs differ from those of cancer patients. Large studies including both cancer and non-cancer patients, using validated needs-assessment-tools, are needed to understand differences in palliative care needs at admittance to specialized palliative care., Aims: To compare palliative care needs at the start of palliative care for cancer and non-cancer disease., Design: Six-year nationwide register-based study., Setting/participants: This study included patients from all Danish specialized palliative care services (hospice care, hospital-based palliative care, home-based palliative care, or consultation) who completed a need-assessment-questionnaire. Ordinal logistic regression was performed to study the association between diagnosis and needs., Results: Cancer patients had a higher probability of receiving specialized palliative care. Of the 44,315 palliative care admissions included in this study, 93.3% were on cancer patients. Independent of diagnosis patients experienced on average six needs and high levels of fatigue and impaired physical functioning. Non-cancer patients had significantly higher odds of insomnia, fatigue and impaired emotional functioning, physical functioning, and quality of life whereas cancer patients had higher odds of pain (except for patients with neurological disease)., Conclusions: The higher levels of several symptoms/problems among non-cancer patients compared to cancer patients suggests that referral to specialized palliative care should be improved for non-cancer patients perhaps by improving identification of palliative needs., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Sentinel lymph node mapping is a minimally invasive surgical staging procedure that allows identification of macro- and micrometastases. The implementation of sentinel lymph node mapping to women with low-grade endometrial cancer allows detection of lymph node metastases and avoids the morbidity of radical pelvic lymphadenectomy. The extent of myometrial invasion is highly predictive of lymph node metastases but is hard to determine precisely preoperatively. The exact rate of lymph node metastases in the large group of women with <50% myometrial invasion is low but unknown. The benefit of detecting metastases in this group should balance the risk of lymphedema. There is limited knowledge of early and late lymphedema and its impact on the quality of life in women with low-grade endometrial cancer following sentinel lymph node mapping., Objective: The primary objective was to investigate the risk of patient-reported lymphedema after sentinel lymph node mapping in women with low-grade endometrial cancer. In addition, we aimed to evaluate risk factors for lymphedema and the condition-specific quality of life (QoL) among women who reported lymphedema 12 months after surgery., Study Design: Women with presumed stage I low-grade endometrial cancer were included in a national prospective cohort study on sentinel lymph node mapping from March 2017 to February 2022. Women completed a package of validated patient-reported outcome measures before surgery, 3 and 12 months after surgery. The primary outcome was the leg lymphedema domain score from the European Organisation for Research and Treatment of Cancer-Endometrial Cancer Module (EORTC QLQ-EN24). The lymphedema assessment was further supplemented by 7 validated single items from the European Organisation for Research and Treatment of Cancer item library addressing lymphedema of legs, genitals, and groin. The disease-specific quality of life was assessed using the validated Lymphedema Quality of Life Tool. Scores were linearly transformed to 0 to 100. A change from baseline of 8 points in leg lymphedema sum-score was considered clinically important. Mean difference scores over time with 95% confidence interval were estimated. Multiple linear regression models evaluated baseline predictors associated with the 12 months postoperative lymphedema score, and if early lymphedema predicted lymphedema at 12 months after surgery. Lymphedema condition-specific quality of life was evaluated for women with lymphedema., Results: Seventy-nine % (486/617) completed patient-reported outcome measures at baseline and 12 months. The mean difference score of leg lymphedema from baseline to 12 months was 5.0, confidence interval [3.3, 6.8], that is, below the threshold for clinical importance. Baseline leg lymphedema score and body mass index were positively associated with the leg lymphedema score at 12 months. The leg lymphedema score at 3 months was associated with a higher 12-month score. High scores of lymphedema at 12 months were negatively associated with the women's daily activities, appearance, emotional functioning, and global quality of life and increased their subjective symptom burden., Conclusion: Women with low-grade endometrial cancer have a low risk of lymphedema after sentinel lymph node mapping. Leg swelling at baseline and body mass index predicted more lymphedema at 12 months after surgery. Early lymphedema at 3 months predicted persistent lymphedema. A high leg lymphedema score at 12 months is associated with impairment in several aspects of quality of life., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Life-threatening thrombotic events and neurological symptoms are prevalent in COVID-19 and are persistent in patients with long COVID experiencing post-acute sequelae of SARS-CoV-2 infection 1-4 . Despite the clinical evidence 1,5-7 , the underlying mechanisms of coagulopathy in COVID-19 and its consequences in inflammation and neuropathology remain poorly understood and treatment options are insufficient. Fibrinogen, the central structural component of blood clots, is abundantly deposited in the lungs and brains of patients with COVID-19, correlates with disease severity and is a predictive biomarker for post-COVID-19 cognitive deficits 1,5,8-10 . Here we show that fibrin binds to the SARS-CoV-2 spike protein, forming proinflammatory blood clots that drive systemic thromboinflammation and neuropathology in COVID-19. Fibrin, acting through its inflammatory domain, is required for oxidative stress and macrophage activation in the lungs, whereas it suppresses natural killer cells, after SARS-CoV-2 infection. Fibrin promotes neuroinflammation and neuronal loss after infection, as well as innate immune activation in the brain and lungs independently of active infection. A monoclonal antibody targeting the inflammatory fibrin domain provides protection from microglial activation and neuronal injury, as well as from thromboinflammation in the lung after infection. Thus, fibrin drives inflammation and neuropathology in SARS-CoV-2 infection, and fibrin-targeting immunotherapy may represent a therapeutic intervention for patients with acute COVID-19 and long COVID., (© 2024. The Author(s).)

Cerebellar injury in preterm infants with central nervous system (CNS) hemorrhage results in lasting neurological deficits and an increased risk of autism. The impact of blood-induced pathways on cerebellar development remains largely unknown, so no specific treatments have been developed to counteract the harmful effects of blood after neurovascular damage in preterm infants. Here, we show that fibrinogen, a blood-clotting protein, plays a central role in impairing neonatal cerebellar development. Longitudinal MRI of preterm infants revealed that cerebellar bleeds were the most critical factor associated with poor cerebellar growth. Using inflammatory and hemorrhagic mouse models of neonatal cerebellar injury, we found that fibrinogen increased innate immune activation and impeded neurogenesis in the developing cerebellum. Fibrinogen inhibited sonic hedgehog (SHH) signaling, the main mitogenic pathway in cerebellar granule neuron progenitors (CGNPs), and was sufficient to disrupt cerebellar growth. Genetic fibrinogen depletion attenuated neuroinflammation, promoted CGNP proliferation, and preserved normal cerebellar development after neurovascular damage. Our findings suggest that fibrinogen alters the balance of SHH signaling in the neurovascular niche and may serve as a therapeutic target to mitigate developmental brain injury after CNS hemorrhage., Competing Interests: Competing interests statement:K.A. is the scientific founder, advisor, and shareholder of Therini Bio, Inc. and has served as a consultant for F. Hoffmann-La Roche. Her interests are managed by Gladstone Institutes according to its conflict of interest policy. The other authors declare that they have no competing interests.

Aims: Computerised adaptive test (CAT) provides individualised patient reported outcome measurement while retaining direct comparability of scores across patients and studies. Optimal CAT measurement requires an appropriate CAT-setting, the set of criteria defining the CAT including start item, item selection criterion, and stop criterion. The European Organisation for Research and Treatment of Cancer (EORTC) CAT Core allows for assessing the 14 functional and symptom domains covered by the EORTC QLQ-C30 questionnaire. The aim was to present a general approach for selecting CAT-settings and to use this to develop a portfolio of standard settings for the EORTC CAT Core optimised for different purposes and populations., Methods: Using simulations, the measurement properties of CATs of different length and precision were evaluated and compared allowing for identifying the most suitable settings. All CATs were initiated with the most informative QLQ-C30 item. For each domain two fixed-length and two fixed-precision standard CATs were selected focusing on efficiency (brief version) and precision (long), respectively., Results: The brief fixed-length CATs included 3-5 items each while the long versions included 5-8 items. The fixed-precision CATs aimed for reliability of 0.65-0.95 (brief versions) and 0.85-0.98 (long versions), respectively. Median sample size savings using the CATs compared to the QLQ-C30 scales ranged 20%-31%, although savings varied considerably across the domains., Conclusion: The EORTC CAT Core standard settings simplify selection of relevant and appropriate CATs. The CATs prioritise either brevity and efficiency or precision, but all provide increased measurement precision and hence, reduced sample size requirements compared to the QLQ-C30 scales. The CATs may be used as they are or modified to accommodate specific requirements., (© 2024. The Author(s).)

Forest loss and degradation due to land cover changes imperil biodiversity worldwide. Subtropical and tropical ecosystems experience high deforestation rates, negatively affecting species like primates. Madagascar's endemic lemurs face exceptionally high risks of population declines and extirpation. We examined how short-term land cover changes within a fragmented landscape in southeastern Madagascar impacted the density of lemur species. Using line transects, we assessed density changes in nine lemur species across five forest fragments. Diurnal surveys were conducted monthly from 2015 to 2019 on 35 transects (total effort = 1268 km). Additionally, 21 transects were surveyed nocturnally in 2015 and 2016 (total effort = 107.5 km). To quantify forest cover changes, we generated land use/land cover (LULC) maps from Sentinel-2 imagery using supervised classification for each year. For the LULC maps, we overlayed species-specific buffers around all transects and calculated the proportion of land cover classes within them. We observed declines in the annual densities of four diurnal and cathemeral lemur species between 2015 and 2019, with species-specific declines of up to 80% (Varecia variegata). While the density of two nocturnal species decreased, one increased fivefold (Cheirogaleus major) between 2015 and 2016. By 2019, Grassland was the dominant land type (50%), while Paddy Fields had the smallest coverage (1.03%). Mature Agricultural Land increased the most (63.37%), while New Agricultural Land decreased the most (-66.36%). Unexpectedly, we did not find evidence that higher forest cover supported a higher lemur population density within sampled areas, but we found support for the negative impact of degraded land cover types on three lemur species. Our study underscores the urgent need to address land-use changes and their repercussions for primate populations in tropical ecosystems. The diverse responses of lemur species to modified habitats highlight the complexity of these impacts and emphasize the importance of targeted conservation efforts., (© 2024 The Authors. American Journal of Primatology published by Wiley Periodicals LLC.)

Purpose: In this study, we developed Danish utility weights for the European Organisation for Research and Treatment of Cancer (EORTC) QLU-C10D, a cancer-specific utility instrument based on the EORTC QLQ-C30., Methods: Following a standardized methodology, 1001 adult participants from the Danish general population were quota-sampled and completed a cross-sectional web-based survey and discrete choice experiment (DCE). In the DCE, participants considered 16 choice sets constructed from the key 10 dimensions of the QLU-C10D and chose their preferred health state for each one. Utility weights were calculated using conditional logistic regression with correction for non-monotonicity., Results: The sample (n = 1001) was representative of the Danish general population with regard to age and gender. The domains with the largest utility decrements, i.e., the domains with the biggest impact on health utility, were physical functioning (- 0.224), pain (- 0.160), and role functioning (- 0.136). The smallest utility decrements were observed for the domains lack of appetite (- 0.024), sleep disorders (- 0.057), and fatigue (- 0.064). Non-monotonicity of severity levels was observed for the domains sleep disturbances, lack of appetite, and bowel problems. Deviations from monotonicity were not statistically significant., Conclusion: The EORTC QLU-C10D is a relatively new multi-attribute utility instrument and is a promising cancer-specific health technology assessment candidate measure. The country-specific Danish utility weights from this study can be used for cost-utility analyses in Danish patients and for comparison with other country-specific utility data., (© 2024. The Author(s).)

This study investigates early onset of treatment response as predictor of symptomatic and functional outcome 3 years after initiation of methylphenidate (MPH) administration in a naturalistic, clinical cohort of children and adolescents with ADHD. Children were followed across an initial 12-week MPH treatment trial and after 3 years, with ratings of symptoms and impairment. Associations between a clinically significant MPH treatment response in week 3 (defined as ≥ 20% reduction in clinician-rated symptoms) and in week 12 (defined as ≥ 40% reduction), and 3-year outcome were tested in multivariate linear regression models, adjusting for sex, age, comorbidity, IQ, maternal education, parental psychiatric disorder, and baseline symptoms and function. We did not have information on treatment adherence or the nature of treatments beyond 12 weeks. 148 children, mean age 12.4 years (range 10-16 years), 77% males, participated in the follow-up. We found a significant decrease in symptom score from baseline [M = 41.9 (SD = 13.2)] to 3-year follow-up [M = 27.5 (SD = 12.7), p < 0.001, and in impairment score from baseline (M = 41.6 (SD = 19.4)] to 3-year follow-up [M = 35.6 (SD = 20.2), p = 0.005]. Treatment responses in week 3 and week 12 were significant predictors of the long-term outcome of symptoms, but not of impairment at 3-year follow-up, when adjusting for other well-known predictors. Early treatment response predicts long-term outcome over and above other well-known predictors. Clinicians should follow-up patients carefully, during the first months of treatment, and detect non-responders, since there might be a window of opportunity to alter the outcome, by changing the treatment strategy.Clinical trial registration: ClinicalTrials.gov, registration number NCT04366609, April 28, 2020 retrospectively registered., (© 2023. The Author(s).)

Objective: To provide equipercentile equating of physical function (PF) scores from frequently used patient-reported outcome measures (PROMs) in cancer patients to facilitate data pooling and comparisons., Study Design and Setting: Adult cancer patients from five European countries completed the European Organization for Research and Treatment of Cancer (EORTC) computer adaptive test (CAT) Core, EORTC Quality of Life Questionnaire Version 3.0 (QLQ-C30), Functional Assessment of Cancer Therapy - General (FACT-G), 36-item Short Form Health Survey (SF-36), and the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function 20a short form. The R package "equate" was used to establish conversion tables of PF scores on those measures with a bivariate rank correlation of at least 0.75., Results: In total, 953 patients with cancer (mean age 58.9 years, 54.7% men) participated. Bivariate rank correlations between PF scores from the EORTC CAT Core, EORTC QLQ-C30, SF-36, and PROMIS were all above 0.85, but below 0.69 for the FACT-G. Conversion tables were established for all measures but the FACT-G. These tables indicate which score from one PROM best matches the score from another PROM and provide standard errors of converted scores., Conclusion: Our analysis indicates that linking of PF scores from both EORTC measures (CAT and QLQ-C30) with PROMIS and SF-36 is possible, whereas the physical domain of the FACT-G seems to be different. The established conversion tables may be used for comparing results or pooling data from clinical studies using different PROMs., Competing Interests: Declaration of competing interest David Cella reports to hold a compensated position as President of FACIT.org and an uncompensated position as President of the PROMIS Health Organization and member of its Board of Directors. Bernhard Holzner reports holding intellectual property rights on the software tool CHES. All other coauthors declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to examine the symptomatology of patients with advanced cancer at admittance to palliative care services and to investigate how the symptomatology changed during the first month, and whether these changes were associated with various patient characteristics., Methods: In a longitudinal study in Chile, outpatients with advanced cancer completed the questionnaires European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 Palliative Care and the Hospital Anxiety and Depression Scale. Prevalence and severity of symptoms and problems (S/Ps) at baseline were calculated. Differences in S/P scores from baseline to follow-up were calculated overall and according to patient characteristics. Multiple linear regression was used to study the associations between patient characteristics and changes in S/P scores., Results: At baseline, 201 patients answered the questionnaires and 177 completed the follow-up. Fatigue, pain and sleeping difficulties were the most prevalent S/Ps reported, and also had the highest mean scores at baseline. S/P scores at baseline varied significantly according to sex, age, civil status, residence, children, prior and current antineoplastic treatment. Emotional functioning, pain, sleeping difficulties, constipation and anxiety improved significantly during the first month of palliative care. Residence, cohabitation status, diagnosis and current antineoplastic treatment were associated with changes in S/P scores., Conclusions: Patients reported moderate-to-severe levels of S/Ps at admittance to palliative care. Several S/Ps improved the first month. Certain patient characteristics were associated with changes in S/P scores. This information may guide clinicians to more effective interventions that can improve the quality of life of patients receiving palliative care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: In line with the World Health Organizations' health definition, patient-reported outcome (PRO) measures frequently cover aspects of social health. Our study aimed to evaluate the role functioning (RF) and social functioning (SF) contents assessed by PRO measures commonly used in cancer patients., Methods: We analysed the item content of the SF and RF domains of the EORTC CAT Core, the EORTC QLQ-C30, the SF-36, and the FACT-G as well as the PROMIS item bank covering the Ability to Participate in Social Roles and Activities. Following an established methodology we linked item content to the International Classification of Functioning, Disability and Health (ICF) framework., Results: The content of 85 items was assigned to three ICF components ('Activities and Participation', 'Body Functions', and 'Environmental Factors'). The EORTC CAT Core RF items were mostly related to the first-level ICF categories 'Domestic life' and 'Community, social and civic life', while its SF item bank focused on 'Interpersonal interactions and relationships'. These three categories were also covered by the PROMIS social participation item bank. The FACT-G Social/Family scale focused on environmental factors ('Support and Relationships' and 'Attitudes') while the SF-36 Role-physical/emotional scales had a stronger focus on 'General tasks and demands' and 'Major life areas'., Conclusions: Our results highlight conceptual overlap and differences among PRO measures for the assessment of social health in cancer. This information may help to select the most appropriate measure for a specific setting or study purpose and to better understand the possibilities of linking scores across different PRO measures., (© 2023 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd.)

Purpose: The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group has developed item banks covering the 14 domains of the EORTC QLQ-C30 quality of life questionnaire. These allow for dynamic assessment and for forming population/study specific static short forms. To simplify selection of relevant short forms, we here present a portfolio of standard short forms with measurement properties optimized for different populations., Methods: For each domain, a brief and a long version were constructed for each of three populations having mild, moderate, and severe symptoms, respectively. The most informative items were prioritised while also taking content into consideration. All short forms included at least one QLQ-C30 item. The measurement precision/power of the short forms was compared to the corresponding QLQ-C30 scales using simulations., Results: In total, 84 short forms were constructed. The brief versions included 3-5 items each, the long versions 5-9 items. Estimated sample size savings using the suggested short forms while maintaining the same power as with the QLQ-C30 ranged 3-50% across domains with median savings of 19% (brief versions) and 28% (long versions), respectively., Conclusion: The suggested short forms allow for simple selection of items particularly relevant for patients with mild, moderate, or severe symptoms, respectively. They facilitate the use of smaller samples without loss of power compared to the QLQ-C30 scales. The suggested short forms may be used as they are or adapted to the specific aims of individual studies/settings., (© 2023. The Author(s).)

The market of non-alcoholic and low-alcohol beer has grown continuously thanks to the advocacy for healthy and responsible drinking. Non-alcoholic and low-alcohol products usually possess less higher alcohols and acetates and more aldehyde off-flavors due to the manufacturing processes. The employment of non-conventional yeasts partially mitigates this problem. In this study, we used proteases to optimize the wort amino acid profile for better aroma production during yeast fermentation. The design of experiments was applied to increase the leucine molar fraction, aiming to boost 3-methylbutan-1-ol and 3-methylbutyl acetate (banana-like aromas). This led to an increase from 7% to 11% leucine in wort after protease treatment. The aroma output in the subsequent fermentation, however, was yeast-dependent. An 87% increase of 3-methylbutan-1-ol and a 64% increase of 3-methylbutyl acetate were observed when Saccharomycodes ludwigii was used. When Pichia kluyveri was employed, higher alcohols and esters from valine and isoleucine were increased: 58% more of 2-methylpropyl acetate, 67% more of 2-methylbutan-1-ol, and 24% more of 2-methylbutyl acetate were observed. Conversely, 3-methylbutan-1-ol decreased by 58% and 3-methylbutyl acetate largely remained the same. Apart from these, the amounts of aldehyde intermediates were increased to a varying extent. The impact of such increases in aromas and off-flavors on the perception of low-alcohol beer remains to be evaluated by sensory analysis in future studies.

Background: Knowledge about the process and the results of the implementation of clinical guidelines to improve palliative care is limited. A national project aimed at improving the quality of life of advanced cancer patients admitted to specialized palliative care services in Denmark by implementing clinical guidelines for the treatment of pain, dyspnea, constipation, and depression., Aim: To investigate the degree of clinical guideline implementation by evaluating the proportion of patients treated according to guidelines among those who qualified (i.e. reported severe symptom level) before and after the 44 palliative care services implemented the guidelines, and how often different types of interventions were provided., Design: This is a national register-based study., Setting/participants: Data from the improvement project were stored in and later obtained from the Danish Palliative Care Database. Adult patients with advanced cancer admitted to palliative care between September 2017 and June 2019 who answered the EORTC QLQ-C15-PAL questionnaire were included., Results: In total 11,330 patients answered the EORTC QLQ-C15-PAL. The proportions of services that implemented the four guidelines ranged 73%-93%. Among services that had implemented guidelines, the proportion of patients receiving interventions was roughly constant over time reaching between 54% and 86% (lowest for depression). Pain and constipation were frequently treated pharmacologically (66%-72%), whereas dyspnea and depression were frequently treated non-pharmacologically (61% each)., Conclusions: Implementing clinical guidelines was more successful for physical symptoms than for depression. The project generated national data on interventions provided when guidelines were followed, which may be used to understand differences in care and outcomes.

Objectives: Few studies have examined whether access to, and quality of, specialised palliative care changed during the COVID-19 pandemic. This study investigated changes in access to and quality of specialised palliative care during the pandemic in Denmark compared to previously., Methods: An observational study using data from the Danish Palliative Care Database combined with other nationwide registries was conducted, including 69 696 patients referred to palliative care services in Denmark from 2018 to 2022. Study outcomes included number of referrals and admissions to palliative care, and the proportions of patients fulfilling four palliative care quality indicators. The indicators assessed admissions among referred, waiting time from referral to admission, symptom screening using the European Organisation for Research and Treatment of Cancer Quality of Life Questionaire-Core-15-Palliative Care (EORTC QLQ-C15-PAL) questionnaire at admission, and discussion at multidisciplinary conference. Logistic regression analysed whether the probability of fulfilling each indicator differed between the pandemic period and pre-pandemic, while adjusting for possible confounders., Result: Number of referrals and admissions to specialised palliative care were lower during the pandemic. The odds for being admitted within 10 days of referral was higher during the pandemic (OR: 1.38; 95% CI: 1.32 to 1.45) whereas the odds for answering the EORTC questionnaire (0.88; 95% CI: 0.85 to 0.92) and for being discussed at multidisciplinary conference (0.93; 95% CI: 0.89 to 0.97) were lower compared with pre-pandemic., Conclusions: Fewer patients were referred to specialised palliative care during the pandemic, and fewer were screened for palliative care needs. In future pandemics or similar scenarios, it is important to pay special attention to referral rates and to maintain the same high level of specialised palliative care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)