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Purpose Hydralazine, doxazosin, and verapamil are currently recommended by the Endocrine Society as acceptable bridging treatment in those in whom full cessation of antihypertensive medication is infeasible during screening for primary aldosteronism (PA). This is under the assumption that they cause minimal to no effect on the aldosterone-to-renin ratio, the most widely used screening test for PA. However, limited evidence is available regarding the effects of these particular drugs on said ratio. Methods In the present study, we retrospectively assessed the changes in aldosterone, renin, and aldosterone-to-renin values in essential hypertensive participants before and after treatment with either hydralazine (n = 26) or doxazosin (n = 20) or verapamil (n = 15). All samples were taken under highly standardized conditions. Results Hydralazine resulted in a borderline significant rise in active plasma renin concentration (19 vs 25 mIU/L, p = 0.067) and a significant fall in the aldosterone-to-renin ratio (38 vs 24, p = 0.017). Doxazosin caused declines in both plasma aldosterone concentration (470 vs 330 pmol/L, p = 0.028) and the aldosterone-to-renin ratio (30 vs 20, p = 0.020). With respect to verapamil, we found no statistically significant effect on any of these outcome variables. Conclusion We conclude that the assumption that these drugs can be used with little consequence to the aldosterone-to-renin cannot be substantiated. While it is possible that they are indeed the best option when full antihypertensive drug cessation is infeasible, the potential effects of these drugs must still be taken into account when interpreting the aldosterone-to-renin ratio.

Objectives Given the strong association between systemic inflammation and cognitive decline, we aimed to determine whether nonneurologic infections are associated with accelerated cognitive decline and structural changes in the brain using pre- and post-infection neuropsychologic assessments and repeated brain MR images. Design Additional analysis of the prospective observational Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort study. Setting Single-center study at the Radboud university medical center, Nijmegen, The Netherlands, between January 2006 and September 2015. Patients Five-hundred three participants (50-85 yr old) with cerebral small vessel disease were included and followed for 9 years. Measurements and main results Participants underwent repeated cognitive measurements and brain MRI. Infectious events were collected. Sepsis episodes were analyzed, and additionally, patients were stratified in three groups: having had a severe infectious episode (e.g., sepsis or hospitalization for infection), a mild, or no infectious episode. Development of dementia, trajectories of cognition, and structural brain changes on MRI in the subsequent follow-up periods were compared between the groups. Complete infectious data were available from 331 patients (mean age 64 ± 8 yr, 57% males). Twenty-nine participants (9%) suffered from a sepsis episode, 69 (21%) from a severe, 201 (61%) from a mild, and 61 (18%) had no infectious episode during follow-up. After correction for age, baseline cognition, and brain volume, each sepsis episode remained associated with an 82% increased risk to develop dementia within the follow-up period (hazard ratio, 1.82; 95% CI, 1.07-3.10; p = 0.027). Infections had no effect on the trajectory of structural changes to the brain after correction for baseline differences. Conclusions In this 9-year observational follow-up study, sepsis episodes were associated with subsequent development of dementia. Nonneurologic infections had no effect on the trajectory of structural cerebral changes.

Contains fulltext : 243898.pdf (Publisher’s version ) (Open Access) OBJECTIVE: There is generally limited but conflicting literature on the incidence, causes, and outcomes of pediatric out-of-hospital cardiac arrest. This study was performed to determine the incidence and outcome of pediatric out-of-hospital cardiac arrest reported by all helicopter emergency medical services in the Netherlands and to provide a description of causes and treatments and, in particular, a description of the specific interventions that can be performed by a physician-staffed helicopter emergency medical service. METHODS: A retrospective analysis was performed of all documented pediatric (0 < 18 years of age) out-of-hospital cardiac arrests from July 2015 to July 2017, attended by all 4 Dutch helicopter emergency medical service teams. RESULTS: Two hundred two out-of-hospital cardiac arrests were identified. The overall incidence in the Netherlands is 3.5 out-of-hospital cardiac arrests in children per 100,000 pediatric inhabitants. The overall survival rate for out-of-hospital cardiac arrest was 11.4%. Eleven (52%) of the survivors were in the drowning group and between 12 and 96 months of age. CONCLUSION: Helicopter emergency medical services are frequently called to pediatric out-of-hospital cardiac arrests in the Netherlands. The survival rate is normal to high compared with other countries. The 12- to 96-month age group and drowning seem to have a relatively favorable outcome.

Objective In cognitively normal adults, nutritional parameters are related to cognitive decline and incidence of dementia. Studies on the role of nutrition in predementia stages subjective cognitive decline and mild cognitive impairment, and mild stages of Alzheimer's disease (AD) dementia in a clinical setting are lacking. In the absence of a curative treatment, this evidence is important for targeting nutritional factors to potentially prevent or delay further cognitive decline. Our aim is to investigate associations of nutritional parameters with clinical progression in patients ranging from those who are cognitively normal to those who have AD dementia. Design Longitudinal. Setting and Participants Memory clinic, 551 patients (219 with subjective cognitive decline, 135 with mild cognitive impairment, and 197 with AD dementia), mean age 64 ± 8 years. Measurements We assessed body mass index, fat-free mass, Mini-Nutritional Assessment, and dietary intake with the Dutch Healthy Diet food frequency questionnaire and the 238-item healthy life in an urban setting (HELIUS) food frequency questionnaire at baseline. Cox proportional hazard models were used to evaluate associations of nutritional parameters with clinical progression. Additional analyses were restricted to patients who were amyloid positive. Results We observed clinical progression in 170 patients (31%) over 2.2 ± 0.9 years. Poorer Mini-Nutritional Assessment score [hazard ratio (95% confidence interval) 1.39 (1.18–1.64)], lower body mass index [1.15 (0.96–1.38)], lower fat-free mass [1.40 (0.93–2.10)], and a less healthy dietary pattern [1.22 (1.01–1.48)] were associated with a higher risk of clinical progression. Similar effect sizes were found in patients who were amyloid positive. Conclusions and Implications Poorer nutritional status and a less healthy dietary pattern are associated with a higher risk of clinical progression. This study provides support for investigating whether improving nutritional status can alter the clinical trajectory of AD.

ObjectivesIt has been suggested that diffusion tensor imaging (DTI) measures sensitive to white matter (WM) damage may predict future dementia risk not only in cerebral small vessel disease (SVD), but also in mild cognitive impairment. To determine whether DTI measures were associated with cognition cross-sectionally and predicted future dementia risk across the full range of SVD severity, we established the International OPtimising mulTImodal MRI markers for use as surrogate markers in trials of Vascular Cognitive Impairment due to cerebrAl small vesseL disease collaboration which included six cohorts.MethodsAmong the six cohorts, prospective data with dementia incidences were available for three cohorts. The associations between six different DTI measures and cognition or dementia conversion were tested. The additional contribution to prediction of other MRI markers of SVD was also determined.ResultsThe DTI measure mean diffusivity (MD) median correlated with cognition in all cohorts, demonstrating the contribution of WM damage to cognition. Adding MD median significantly improved the model fit compared to the clinical risk model alone and further increased in all single-centre SVD cohorts when adding conventional MRI measures. Baseline MD median predicted dementia conversion. In a study with severe SVD (SCANS) change in MD median also predicted dementia conversion. The area under the curve was best when employing a multimodal MRI model using both DTI measures and other MRI measures.ConclusionsOur results support a central role for WM alterations in dementia pathogenesis in all cohorts. DTI measures such as MD median may be a useful clinical risk predictor. The contribution of other MRI markers varied according to disease severity.

Purpose To investigate the prevalence of adjustment disorder (AD) among cancer patients and the acceptance of psychological treatment, in relation to sociodemographic, clinical, and psychological factors. Methods Breast, prostate, and head and neck cancer patients of all stages and treatment modalities (N = 200) participated in this observational study. Patients completed the Hospital Anxiety and Depression Scale, Checklist Individual Strength, Distress Thermometer and problem list. Patients with increased risk on AD based on these questionnaires were scheduled for a diagnostic interview. Patients diagnosed with AD were invited to participate in a randomized controlled trial on the cost-effectiveness of psychological treatment. Participation in this trial was used as a proxy of acceptance of psychological treatment. Logistic regression analyses were used to investigate associated factors. Results The overall prevalence of AD was estimated at 13.1%. Sensitivity analyses showed prevalence rates of AD of 11.5%, 15.0%, and 23.5%. Acceptance of psychological treatment was estimated at 65%. AD was associated both with being employed (OR = 3.3, CI = 1.3–8.4) and having a shorter time since diagnosis (OR = 0.3, CI = 0.1–0.8). Conclusion Taking sensitivity analysis into account, the prevalence of AD among cancer patients is estimated at 13 to 15%, and is related to being employed and having a shorter time since diagnosis. The majority of cancer patients with AD accept psychological treatment.

The purpose was to describe the operation technique of an anterior lateral intercostal artery perforator (LICAP) flap and analyse outcomes and complications. An anterior LICAP flap is a good and safe alternative for direct oncoplastic breast reconstruction. It is a reliable flap that provides sufficient volume and good esthetic outcomes.

OBJECTIVES Obstetric anal sphincter injury (OASI) is an important factor in the etiology of anal incontinence. This study aimed to evaluate whether anal sphincter defects, levator avulsion or levator ballooning after OASI are associated with severity of anal incontinence. Furthermore, we evaluated whether factors such as constipation and altered stool consistency are associated with symptoms of incontinence after OASI. METHODS In this multicenter prospective observational cohort study, women with OASI were invited to participate at least 3 months after primary repair. All women completed validated questionnaires, including St Mark's incontinence score, Bristol stool scale (BSS) and Cleveland clinic constipation score (CCCS), and underwent four-dimensional (4D) transperineal ultrasound for assessment of the levator ani muscle and anal sphincter. RESULTS In total, 220 women were included. Median follow-up was 4 months (range, 3-98 months). Univariate linear regression analysis showed an association of St Mark's incontinence score with a residual defect of the external anal sphincter (EAS) (β, 1.55 (95% CI, 0.04-3.07); P = 0.045), higher parity (β, 0.85 (95% CI, 0.02-1.67); P = 0.046), BSS (β, 1.28 (95% CI, 0.67-1.89); P

Background To investigate changes in gait performance over time and how these changes are associated with the decline in structural network efficiency and cognition in older patients with cerebral small vessel disease (SVD). Methods In a prospective, single-center cohort with 217 older participants with SVD, we performed 1.5T MRI scans, cognitive tests, and gait assessments evaluated by Timed UP and Go (TUG) test twice over 4 years. We reconstructed the white matter network for each subject based on diffusion tensor imaging tractography, followed by graph-theoretical analyses to compute the global efficiency. Conventional MRI markers for SVD, that is, white matter hyperintensity (WMH) volume, number of lacunes, and microbleeds, were assessed. Results Baseline global efficiency was not related to changes in gait performance, while decline in global efficiency over time was significantly associated with gait decline (ie, increase in TUG time), independent of conventional MRI markers for SVD. Neither baseline cognitive performance nor cognitive decline was associated with gait decline. Conclusions We found that disruption of the white matter structural network was associated with gait decline over time, while the effect of cognitive decline was not. This suggests that structural network disruption has an important role in explaining the pathophysiology of gait decline in older patients with SVD, independent of cognitive decline.

As the COVID-19 pandemic took hold in 2020, Chief Medical Officers (CMOs) entered the public spotlight like never before. Amidst this increased visibility, the role is deeply contested. Much of the disagreement concerns whether CMOs should act independently of the government: while some argue CMOs should act as independent voices who work to shape government policy to protect public health, others stress that CMOs are civil servants whose job is to support the government. The scope and diversity of debates about the CMO role can be explained by its inherently contradictory nature, which requires incumbents to balance their commitments as physicians with their mandates as civil servants who advise and speak on the government’s behalf. The long-haul COVID-19 pandemic has further tested the CMO role and has shone light on its varying remits and expectations across different jurisdictions, institutions and contexts. It is perhaps unsurprising, then, that calls to amend the CMO role have emerged in some jurisdictions during the pandemic. However, any discussions about changing the CMO role need a stronger understanding of how different institutional and individual approaches impact what incumbents feel able to do, say and achieve. Based on an ongoing comparative analysis of the position across five countries with Westminster-style political systems, we provide an overview of the CMO role, explain its prominence in a pandemic, examine some debates surrounding the role and discuss a few unanswered empirical questions before describing our ongoing study in greater detail.

Introduction It is unclear why cerebral small vessel disease (SVD) leads to lacunar stroke in some and to non–lobar intracerebral hemorrhage (ICH) in others. We investigated differences in MRI markers of SVD in patients with lacunar stroke or non–lobar ICH. Patients and methods We included patients from two prospective cohort studies with either lacunar stroke (RUN DMC) or non–lobar ICH (FETCH). Differences in SVD markers (white matter hyperintensities [WMH], lacunes, cerebral microbleeds [CMB]) between groups were investigated with univariable tests; multivariable logistic regression analysis, adjusted for age, sex, and vascular risk factors; spatial correlation analysis and voxel–wise lesion symptom mapping. Results We included 82 patients with lacunar stroke (median age 63, IQR 57–72) and 54 with non-lobar ICH (66, 59–75). WMH volumes and distribution were not different between groups. Lacunes were more frequent in patients with a lacunar stroke (44% vs. 17%, adjusted odds ratio [aOR] 5.69, 95% CI [1.66–22.75]) compared to patients with a non–lobar ICH. CMB were more frequent in patients with a non–lobar ICH (71% vs. 23%, aOR for lacunar stroke vs non–lobar ICH 0.08 95% CI [0.02–0.26]), and more often located in non–lobar regions compared to CMB in lacunar stroke. Discussion Although we obserd different types of MRI markers of SVD within the same patient, ischemic markers of SVD were more frequent in the ischemic type of lacunar stroke, and hemorrhagic markers were more prevalent in the hemorrhagic phenotype of non-lobar ICH. Conclusion There are differences between MRI markers of SVD between patients with a lacunar stroke and those with a non-lobar ICH.

The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic has proven a challenge to healthcare systems since its first appearance in late 2019. The global spread and devastating effects of coronavirus disease 2019 (COVID-19) on patients have resulted in countless studies on risk factors and disease progression. Overweight and obesity emerged as one of the major risk factors for developing severe COVID-19. Here we review the biology of coronavirus infections in relation to obesity. In particular, we review literature about the impact of adiposity-related systemic inflammation on the COVID-19 disease severity, involving cytokine, chemokine, leptin, and growth hormone signaling, and we discuss the involvement of hyperactivation of the renin-angiotensin-aldosterone system (RAAS). Due to the sheer number of publications on COVID-19, we cannot be completed, and therefore, we apologize for all the publications that we do not cite.

Working memory and episodic memory are two different processes, although the nature of their interrelationship is debated. As these processes are predominantly studied in isolation, it is unclear whether they crucially rely on different neural substrates. To obtain more insight in this, 81 adults with sub-acute ischemic stroke and 29 elderly controls were assessed on a visual working memory task, followed by a surprise subsequent memory test for the same stimuli. Multivariate, atlas- and track-based lesion-symptom mapping (LSM) analyses were performed to identify anatomical correlates of visual memory. Behavioral results gave moderate evidence for independence between discriminability in working memory and subsequent memory, and strong evidence for a correlation in response bias on the two tasks in stroke patients. LSM analyses suggested there might be independent regions associated with working memory and episodic memory. Lesions in the right arcuate fasciculus were more strongly associated with discriminability in working memory than in subsequent memory, while lesions in the frontal operculum in the right hemisphere were more strongly associated with criterion setting in subsequent memory. These findings support the view that some processes involved in working memory and episodic memory rely on separate mechanisms, while acknowledging that there might also be shared processes. Supplementary Information The online version contains supplementary material available at 10.1007/s00429-021-02281-0.

Purpose To measure utilities among cancer patients, a cancer-specific utility instrument called the European Organization for Research and Treatment of Cancer (EORTC) QLU-C10D has been developed based on EORTC quality of life core module (QLQ-C30). This study aimed to provide Dutch utility weights for the QLU-C10D. Methods A cross-sectional valuation study was performed in 1017 participants representative in age and gender of the Dutch general population. The valuation method was a discrete choice experiment containing 960 choice sets, i.e. pairs of QLU-C10D health states, each health state described in terms of the 10 QLU-C10D domains and the duration of that health state. Each participant considered 16 choice sets, choosing their preferred health state from each pair. Utility scores were derived using generalized estimation equation models. Non-monotonic levels were combined. Results Utility decrements were generated for all 10 QLU-C10D domains, with largest decrements for pain (− 0.242), physical functioning (− 0.228), and role functioning (− 0.149). Non-monotonic levels of emotional functioning, pain, fatigue, sleep problems, and appetite loss were combined. No decrement in utility was seen in case of a little or quite a bit impairment in emotional functioning or a little pain. The mean QLU-C10D utility score of the participants was 0.85 (median = 0.91, interquartile range = 0.82 to 0.96). Conclusion Dutch utility decrements were generated for the QLU-C10D. These are important for evaluating the cost-utility of new cancer treatments and supportive care interventions. Further insight is warranted into the added value of the QLU-C10D alongside other utility instruments.

Summary Autoimmune disease is a risk factor for first incident venous thromboembolism (VTE). However, data on the risk of recurrent VTE in people with autoimmune disease is sparse. We explored the risk of recurrent VTE using the RIETE registry, comparing people with autoimmune disease (n = 1305) to those without (n = 50608). Overall rates were 6.5 and 5.1 recurrent VTE/100 years for patients with autoimmune disease vs controls, respectively. After adjustment for sex and unprovoked/provoked VTE yielded an adjusted hazard ratio of 1.29 (95%CI 1.03‐1.62). The analysis was limited by short median follow up time (161 days overall), precluding definitive conclusions on recurrent VTE risks.

Damage to the pelvic floor during pregnancy and vaginal delivery is an inevitable consequence of the natural birthing process. As this damage is associated with functional and anatomical problems in later life, minimizing pelvic floor damage during pregnancy and vaginal delivery may serve as an important factor in the prevention of these unwanted sequelae. Operative vaginal delivery using forceps or vacuum extractor is common practice to achieve or expedite vaginal birth for maternal or fetal indications such as maternal exhaustion or fetal distress. However, operative vaginal delivery is associated with more extensive damage to the pelvic floor and perineal structures with forceps carrying a stronger risk compared to vacuum. The evidence on this subject is discussed with possible suggestions to minimize pelvic floor damage as much as possible.

Objective.Hydroxychloroquine (HCQ) is commonly used as first-line treatment for systemic lupus erythematosus (SLE). Interferon (IFN)-inducible gene expression, IFN-γ–induced protein 10 (IP-10) and B cell activating factor (BAFF) are early mediators in SLE. The purpose of this study was to analyze the effects of HCQ on these factors.Methods.Patients with incomplete SLE (iSLE; antinuclear antibody titer ≥ 1:80, symptoms < 5 years, ≥ 1 objectified clinical American College of Rheumatology or SLE International Collaborating Clinics criteria), or new-onset, mild SLE were included when HCQ treatment was started for clinical reasons. Blood samples were taken at start and after 16 weeks. Three SLE-related IFN-inducible genes were measured in whole blood by real-time PCR, and an IFN score was calculated. Serum levels of IP-10 and BAFF were measured using ELISA.Results.In total, 9 patients were included: 7 with iSLE and 2 with new-onset SLE. The median SLE Disease Activity Index (SLEDAI) was 4. After 16 weeks of treatment with HCQ, the expression of IFN-inducible genes decreased in 8 of 9 patients, and the IFN-3 score decreased significantly (P = 0.012). There was a trend towards lower IP-10 levels (P = 0.055), and a significant decrease in BAFF levels (P = 0.023).Conclusion.HCQ suppresses IFN score and BAFF levels in patients with iSLE or new-onset SLE, and there is a trend towards lowering IP-10 levels. As these biomarkers are early mediators in SLE, this might support the hypothesis that HCQ could influence disease progression. However, prospective research with a larger sample size and longer follow-up is needed.

Purpose The aim of the present study is to investigate the prevalence of body image distress among head and neck cancer (HNC) patients after treatment and to examine its association with sociodemographic and clinical factors, health-related quality of life (HRQOL), HNC symptoms, sexuality, self-compassion, and psychological distress. Second, we aim to explore daily life experiences of HNC patients regarding body image. Methods A cross-sectional survey among HNC patients investigated the prevalence of body image distress based on the Body Image Scale. Multivariable logistic regression analysis was applied to study associations with sociodemographic and clinical factors, HRQOL (EORTC QLQ-C30), HNC symptoms (QLQ-HN43), sexuality (FSFI-6; IIEF-5), self-compassion (SCS-SF), and psychological distress (HADS). Qualitative data from a body image writing intervention was used to explore experiences in daily life related to body image. Results Body image distress was prevalent in 13–20% (depending on cut-off scores) of 233 HNC patients. Symptoms of depression (p p p = 0.001), problems with wound healing (p = 0.013), and larger extent of surgery (p = 0.014) were associated with having body image distress. This model explained 67% of variance. Writing interventions of 40 HNC patients showed that negative body image experiences were related to appearance and function, with social functioning problems described most often. Conclusion Prevalence of body image distress in HNC patients, using different cut-off scores, is 13–20%. Younger patients, patients after extensive surgery, and patients who had wound healing problems are most at risk. There is a significant association between body image distress and depressive symptoms and social functioning.

Purpose We aimed to examine whether pre-treatment, post-treatment and change in health-related quality of Life (HRQoL) is associated with survival, in patients with head and neck cancer (HNC). Methods We included 948 newly diagnosed HNC patients treated with primary or adjuvant (chemo)radiotherapy with curative intent. The EORTC QLQ-C30 questionnaire was assessed pre-treatment and at 6 weeks, 6 months and 12 months post-treatment. Multivariable Cox regression analyses were performed to examine whether HRQoL at all time points and changes in HRQoL over time were associated with survival, after adjusting for demographic, clinical and lifestyle-related variables. Results Higher HRQoL scores were significantly associated with improved 5-year overall survival at all time points, except for the subscale global QoL at 6 weeks. Changes in HRQoL at 6 weeks post-treatment compared to pre-treatment were not significantly associated with survival. Changes in physical (HR: 0.88 95% CI: 0.82–0.96) and emotional functioning (HR: 0.90 95% CI: 0.85–0.96) from pre-treatment to 6 months post-treatment and changes in global QOL, and physical, emotional, and social functioning from pre-treatment to 12 months post-treatment were significantly associated with survival. Conclusion Higher HRQoL reported pre-treatment and post-treatment (6 weeks, 6 months and 12 months) are significantly associated with improved survival, as well as changes in HRQoL at 6 and 12 months compared to pre-treatment. Our results highlight the value of monitoring HRQoL and to identify those patients that report decreased or deteriorated HRQOL. This may help to further improve cancer care in a timely and efficient manner.

Contains fulltext : 235277.pdf (Publisher’s version ) (Closed access) BACKGROUND: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. METHODS: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. FINDINGS: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models. INTERPRETATION: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted. FUNDING: British Heart Foundation and Stroke Association.

Purpose Investigate whether Life Review Therapy and Memory Specificity Training (LRT-MST) targeting incurably ill cancer patients may also have a beneficial effect on caregiving burden, symptoms of anxiety and depression, and posttraumatic growth of the informal caregivers. Methods Data was collected in the context of a randomized controlled trial (RCT) (secondary analyses) on the effect of LRT-MST among incurably cancer patients. Informal caregivers of participating patients were asked to complete outcome measures at baseline (T0), post-intervention (T1), and 1-month follow-up (T2): caregiver burden (caregivers reaction assessment scale (CRA)), symptoms of anxiety and depression (hospital anxiety and depression scale), and posttraumatic growth (posttraumatic growth inventory). Linear mixed models (intention to treat) were used to assess group differences in changes over time. Effect size and independent samples t tests were used to assess group differences at T1 and T2. Results In total, 64 caregivers participated. At baseline, 56% of the caregivers experienced anxiety and 30% depression. No significant effect was found on these symptoms nor on posttraumatic growth or most aspects of caregiver burden. There was a significant effect of LRT-MST on the course of self-esteem (subscale CRA) (p = 0.013). Effect size was moderate post-intervention (ES = − 0.38, p = 0.23) and at 3-month follow-up (ES = 0.53, p = 0.083). Conclusions Many caregivers of incurably ill cancer patients experience symptoms of anxiety and depression. LRT-MST does not improve symptoms of depression and anxiety, negative aspects of caregiver burden, or posttraumatic growth. LRT-MST may have a protective effect on self-esteem of informal caregivers (positive aspect of caregiver burden). Trial registration number Netherlands Trial Register (NTR 2256), registered on 23-3-2010.

Summary Background Due to the time-sensitive effect of endovascular treatment, rapid prehospital identification of large-vessel occlusion in individuals with suspected stroke is essential to optimise outcome. Interhospital transfers are an important cause of delay of endovascular treatment. Prehospital stroke scales have been proposed to select patients with large-vessel occlusion for direct transport to an endovascular-capable intervention centre. We aimed to prospectively validate eight prehospital stroke scales in the field. Methods We did a multicentre, prospective, observational cohort study of adults with suspected stroke (aged ≥18 years) who were transported by ambulance to one of eight hospitals in southwest Netherlands. Suspected stroke was defined by a positive Face-Arm-Speech-Time (FAST) test. We included individuals with blood glucose of at least 2·5 mmol/L. People who presented more than 6 h after symptom onset were excluded from the analysis. After structured training, paramedics used a mobile app to assess items from eight prehospital stroke scales: Rapid Arterial oCclusion Evaluation (RACE), Los Angeles Motor Scale (LAMS), Cincinnati Stroke Triage Assessment Tool (C-STAT), Gaze-Face-Arm-Speech-Time (G-FAST), Prehospital Acute Stroke Severity (PASS), Cincinnati Prehospital Stroke Scale (CPSS), Conveniently-Grasped Field Assessment Stroke Triage (CG-FAST), and the FAST-PLUS (Face-Arm-Speech-Time plus severe arm or leg motor deficit) test. The primary outcome was the clinical diagnosis of ischaemic stroke with a proximal intracranial large-vessel occlusion in the anterior circulation (aLVO) on CT angiography. Baseline neuroimaging was centrally assessed by neuroradiologists to validate the true occlusion status. Prehospital stroke scale performance was expressed as the area under the receiver operating characteristic curve (AUC) and was compared with National Institutes of Health Stroke Scale (NIHSS) scores assessed by clinicians at the emergency department. This study was registered at the Netherlands Trial Register, NL7387. Findings Between Aug 13, 2018, and Sept 2, 2019, 1039 people (median age 72 years [IQR 61–81]) with suspected stroke were identified by paramedics, of whom 120 (12%) were diagnosed with aLVO. Of all prehospital stroke scales, the AUC for RACE was highest (0·83, 95% CI 0·79–0·86), followed by the AUC for G-FAST (0·80, 0·76–0·84), CG-FAST (0·80, 0·76–0·84), LAMS (0·79, 0·75–0·83), CPSS (0·79, 0·75–0·83), PASS (0·76, 0·72–0·80), C-STAT (0·75, 0·71–0·80), and FAST-PLUS (0·72, 0·67–0·76). The NIHSS as assessed by a clinician in the emergency department did somewhat better than the prehospital stroke scales with an AUC of 0·86 (95% CI 0·83–0·89). Interpretation Prehospital stroke scales detect aLVO with acceptable-to-good accuracy. RACE, G-FAST, and CG-FAST are the best performing prehospital stroke scales out of the eight scales tested and approach the performance of the clinician-assessed NIHSS. Further studies are needed to investigate whether use of these scales in regional transportation strategies can optimise outcomes of patients with ischaemic stroke. Funding BeterKeten Collaboration and Theia Foundation (Zilveren Kruis).

The aldosterone‐to‐renin ratio (ARR) is a common screening test for primary aldosteronism in hypertensives. However, patients often use medications that could confound the ARR and, thereby, reduce the interpretability of the test. Since it is not always feasible to stop such medication, several drugs that are supposedly neutral with respect to the ARR have been recommended as alternative treatment. The objective of the present review is to explore whether sufficient evidence exists to justify the recommendations. To this end, we performed a systematic PubMed and Cochrane literature search regarding medications that may influence the ARR. Our review revealed that many commonly prescribed antihypertensives seem to have significant effects on renin, aldosterone, and resulting ARR values. However, the magnitude of these effects is poorly quantifiable with the present level of research. We conclude that several medications can affect the ARR. Not taking this into account could lead to misinterpretation of the ARR. Therefore, standardization of the medications used during ARR measurement is advisable for a reliable and accurate interpretation. Further research is needed to ascertain how to best optimize these medications.

Objective To evaluate the rate of preterm birth (PTB) in a subsequent pregnancy in women who had undergone term induction using a Foley catheter compared with prostaglandins. Methods This was a follow‐up study of two large randomized controlled trials (PROBAAT‐1 and PROBAAT‐2). In the original trials, women with a term singleton pregnancy with the fetus in cephalic presentation and with an indication for labor induction were randomized to receive either a 30‐mL Foley catheter or prostaglandins (vaginal prostaglandin E2 in PROBAAT‐1 and oral misoprostol in PROBAAT‐2). Data on subsequent ongoing pregnancies > 16 weeks’ gestation were collected from hospital charts from clinics participating in this follow‐up study. The main outcome measure was preterm birth 16 weeks' gestation in the Foley catheter and prostaglandin groups, respectively. There were no differences in baseline characteristics between the groups. The overall rate of PTB in a subsequent pregnancy was 9/251 (3.6%) in the Foley catheter group vs 10/258 (3.9%) in the prostaglandin group (relative risk (RR), 0.93; 95% CI, 0.38–2.24), and the rate of spontaneous PTB was 5/251 (2.0%) vs 5/258 (1.9%) (RR, 1.03; 95% CI, 0.30–3.51). Conclusion In women with term singleton pregnancy, induction of labor using a 30‐mL Foley catheter is not associated with an increased risk of PTB in a subsequent pregnancy, as compared to induction of labor using prostaglandins. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Current literature suggests a higher risk of pregnancy-related complications in patients with renal fibromuscular dysplasia (FMD). The aim of our study was to assess the nature and prevalence of pregnancy-related complications in patients subsequently diagnosed with FMD. A call for participation was sent to centers contributing to the European/International FMD Registry. Patients with at least 1 pregnancy were included. Data on pregnancy were collected through medical files and FMD characteristics through the European/International FMD Registry. Data from 534 pregnancies were obtained in 237 patients. Despite the fact that, in 96% of cases, FMD was not diagnosed before pregnancy, 40% of women (n=93) experienced pregnancy-related complications, mostly gestational hypertension (25%) and preterm birth (20%), while preeclampsia was reported in only 7.5%. Only 1 patient experienced arterial dissection and another patient an aneurysm rupture. When compared with patients without pregnancy-related complications, patients with complicated pregnancies were younger at FMD diagnosis (43 versus 51 years old; P P =0.003) but underwent more often renal revascularization (63% versus 40%, P

Intersectorality has become an unchallenged article of faith in health thinking.1 The term ‘intersectoral action’ first formally entered the literature in the 1970s.2 3 It came about when a technical advisory group at WHO contemplated the challenges in sanitation. The technical advisors acknowledged that traditional infectious disease and public health personnel needed to connect with engineering and water management specialists, and that each of these came from a particular disciplinary and government background. Joint work through intersectoral action was deemed critical for the success of sanitation. The term soon entered more policy focused and political realms. Following the Declaration of Alma Ata4 ‘intersectoral action’ was not merely a technical approach, but became a statement of principle. Primary health would only reach its full effectiveness potential, ‘Alma Ata’ declared, when many sectors were engaged in it.2 5 Variations on the terminology started to proliferate. Working across sectors was variously deemed intersectoral action, policy, collaboration and cooperation. The term multisectoral also entered the health vernacular—the suggestion here is that a group of sectors pursues a similar goal, rather than necessarily working together to achieve a particular goal. However, recent discourse proposes that the term ‘multisectoral action for health’ includes all actor and sector configurations that include non-health sectors to—deliberately or as a collateral—potentially improve health.6 The proliferation of intersectoral terminology coincided with similar developments in policy development and administrative and political science scholarship. Partly sponsored by global think tanks such as the World Bank and the international aid industry there was a call for, variously, ‘Whole of Government’ (WoG), ‘Joined-up Government’ (JUG) and horizontal, integrated or coordinated7 policy making. In recent years, these streams of consciousness seem to have coalesced in calls for Health in All Policies (HiAP). Several reviews8 and glossaries9 10 have …

Objectives: Low body weight is an easily assessable cause of Raynaud’s phenomenon (RP), and is frequently overlooked by clinicians. We aim to investigate the association of low body weight (body mass index 2), involuntary weight loss, and nutritional restrictions with the presence of RP. Method: Participants from the Lifelines Cohort completed a validated self-administered connective tissue disease questionnaire. Subjects who reported cold-sensitive fingers and biphasic or triphasic colour changes were considered to suffer from RP. Patient characteristics, anthropometric measurements, and nutritional habits were collected. Statistical analyses was stratified for gender. Results: Altogether, 93 935 participants completed the questionnaire. The prevalence of RP was 4.2% [95% confidence interval (CI) 4.1–4.4%], and was three-fold higher in women than in men (5.7% vs 2.1%, p

Purpose To investigate the course of health-related quality of life (HRQOL) from diagnosis to 2 years follow-up among patients with oropharyngeal cancer (OPSCC), in relation to human papilloma virus (HPV) status. Methods This study included 270 OPSCC patients. Age, sex, tumor sublocation, tumor stage, HPV status, treatment modality, comorbidity, smoking, and alcohol use were retrieved from medical records. HPV status was positive when p16 and HPV DNA tests were both positive. HRQOL was assessed using the EORTC QLQ-C30/QLQ-H&N35 pretreatment and at 6 weeks, 6, 12, 18, and 24 months after treatment. To compare the course of HRQOL between patients with an HPV-positive versus HPV-negative tumor, linear and logistic mixed models were used. Results Patients with an HPV-positive tumor (29%) were more often male, diagnosed with a tumor of the tonsil or base of the tongue, treated with single treatment, had fewer comorbidities, were less often current smokers and had lower alcohol consumption. Adjusted for confounders, the course of global quality of life, physical, role, and social functioning, fatigue, pain, insomnia, and appetite loss was significantly different: patients with an HPV-positive tumor scored better before treatment, worsened during treatment, and recovered better and faster at follow-up, compared to patients with an HPV-negative tumor. The course of emotional functioning and oral pain was also significantly different between the two groups, but with other trajectories. Conclusion The course of HRQOL is different in patients with an HPV-positive tumor versus an HPV-negative tumor, adjusted for sociodemographic, clinical, and lifestyle confounders.

AbstractThis review investigates the severity and nature of post-stroke working memory deficits with reference to the multi-component model of working memory. We conducted a systematic search in PubMed up to March 2019 with search terms for stroke and memory. Studies on adult stroke patients, that included a control group, and assessed working memory function, were selected. Effect sizes (Hedges’ g) were extracted from 50 studies (in total 3,084 stroke patients) based on the sample size, mean and standard deviation of patients and controls. Performance of stroke patients was compared to healthy controls on low-load (i.e. capacity) and high-load (executively demanding) working memory tasks, grouped by modality (verbal, non-verbal). A separate analysis compared patients in the sub-acute and the chronic stage. Longitudinal studies and effects of lesion location were systematically reviewed. Stroke patients demonstrated significant deficits in working memory with a moderate effect size for both low-load (Hedges’ g = -.58 [-.82 to -.43]) and high-load (Hedges’ g = -.59 [-.73 to -.45]) tasks. The effect sizes were comparable for verbal and non-verbal material. Systematically reviewing the literature showed that working memory deficits remain prominent in the chronic stage of stroke. Lesions in a widespread fronto-parietal network are associated with working memory deficits. Stroke patients show decrements of moderate magnitude in all subsystems of working memory. This review clearly demonstrates the global nature of the impairment in working memory post-stroke.

In 2008, the GEC ESTRO Gyn network launched the first multiinstitutional, observational, and prospective international study on MRI-guided brachytherapy in locally advanced cervical cancer patients (EMBRACE-I). EMBRACE-I was followed by EMBRACE-II from 2016 and ongoing. Among the aims of the EMBRACE studies are to benchmark morbidity outcomes and develop dose-volume effects and predictive models for morbidity. The EMBRACE studies collect both physician (CTCAE v.3) and patient (EORTC QLQ-C30/CX24) reported outcomes, including baseline information, in a regular follow-up schedule. The EMBRACE studies feature high numbers of patients (EMBRACE-I N = 1416, EMBRACE-II N = 1500 expected) enrolled from many institutions worldwide (EMBRACE-I n = 23, EMBRACE-II n = 45). This large-scale multiinstitutional approach offers a unique opportunity to investigate and develop new strategies for improving the quality of assessment and reporting of morbidity. This report presents an overview of the challenges and pitfalls regarding the assessment and reporting of morbidity encountered during more than a decade of development and research activities within the EMBRACE consortium. This includes the recognition and evaluation of inconsistencies in the morbidity assessment, and consequently, the provision of assistance and training in the scoring procedure to reduce systematic assessment bias. In parallel, a variety of methodological approaches were tested to comprehensively summarize morbidity outcomes, and a novel approach was developed to refine dose-effect models and risk factor analyses. The purpose of this report is to present an overview of these findings, describe the learning process, and the strategies that have consequently been implemented regarding educational activities, training, and dissemination.

ObjectivePsychosocial interventions can reduce cancer-related fatigue effectively. However, it is still unclear if intervention effects differ across subgroups of patients. These meta-analyses aimed at evaluating moderator effects of (a) sociodemographic characteristics, (b) clinical characteristics, (c) baseline levels of fatigue and other symptoms, and (d) intervention-related characteristics on the effect of psychosocial interventions on cancer-related fatigue in patients with non-metastatic breast and prostate cancer.MethodsData were retrieved from the Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS) consortium. Potential moderators were studied with meta-analyses of pooled individual patient data from 14 randomized controlled trials through linear mixed-effects models with interaction tests. The analyses were conducted separately in patients with breast (n = 1091) and prostate cancer (n = 1008).ResultsStatistically significant, small overall effects of psychosocial interventions on fatigue were found (breast cancer: β = -0.19 [95% confidence interval (95%CI) = -0.30; -0.08]; prostate cancer: β = -0.11 [95%CI = -0.21; -0.00]). In both patient groups, intervention effects did not differ significantly by sociodemographic or clinical characteristics, nor by baseline levels of fatigue or pain. For intervention-related moderators (only tested among women with breast cancer), statistically significant larger effects were found for cognitive behavioral therapy as intervention strategy (β = -0.27 [95%CI = -0.40; -0.15]), fatigue-specific interventions (β = -0.48 [95%CI = -0.79; -0.18]), and interventions that only targeted patients with clinically relevant fatigue (β = -0.85 [95%CI = -1.40; -0.30]).ConclusionsOur findings did not provide evidence that any selected demographic or clinical characteristic, or baseline levels of fatigue or pain, moderated effects of psychosocial interventions on fatigue. A specific focus on decreasing fatigue seems beneficial for patients with breast cancer with clinically relevant fatigue.

The last 2 decades have witnessed the development and broad adoption of image-guided adaptive brachytherapy (IGABT) combined with radiochemotherapy in patients with locally advanced cervical cancer. A variety of brachytherapy techniques and dose/fractionation schedules have been applied, and until recently, there was no strong evidence available for preferring one approach to another. However, large volumes of data have now provided high level clinical evidence for dose-effect relations for both disease and morbidity endpoints. It is therefore now possible to apply evidence based dose planning aims and dose prescription protocols in IGABT for locally advanced cervical cancer. This review gives an overview of targets/organs-at-risk and disease/morbidity endpoints which are relevant in the context of treatment planning and dose prescription in IGABT. The dosimetric and clinical evidence is summarized to support the implementation of dose prescription protocols which include hard and soft constraints for targets and organs at risk.

Background Malnutrition is common in patients with Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI) and is associated with institutionalization and increased mortality. Malnutrition is the result of a negative energy balance, which could be due to reduced dietary intake and/or higher energy expenditure. To study underlying mechanisms for malnutrition, we investigated dietary intake and resting energy expenditure (REE) of patients with AD dementia, MCI, and controls. In addition, we studied associations of global cognition (Mini-Mental State Examination (MMSE)) and AD biomarkers with dietary intake and REE. Methods We included 219 participants from the NUDAD project, 71 patients with AD dementia (age 68 ± 8 years, 58% female, MMSE 24 ± 3), 52 with MCI (67 ± 8 years, 42% female, MMSE 26 ± 2), and 96 controls (62 ± 7 years, 52% female, MMSE 28 ± 2). We used a 238-item food frequency questionnaire to assess dietary intake (energy, protein, carbohydrate, and fat). In a subgroup of 92 participants (30 patients with AD dementia, 22 with MCI, and 40 controls) we measured REE with indirect calorimetry. Between-group differences in dietary intake and REE were tested with ANOVAs. In the total sample, linear regression analyses were used to explore potential associations of MMSE score and AD biomarkers with dietary intake and REE. All analyses were adjusted for age, sex, education, and body mass index or fat-free mass. Results Patients with AD dementia and MCI did not differ from controls in total energy intake (1991 ± 71 and 2172 ± 80 vs 2022 ± 61 kcal/day, p > 0.05) nor in protein, carbohydrate, or fat intake. Patients with AD dementia and MCI had a higher REE than controls (1704 ± 41 and 1754 ± 47 vs 1569 ± 34 kcal/day, p Conclusions We found a higher REE, despite similar energy intake in patients with AD and MCI compared to controls. These findings suggest that elevated metabolism rather than reduced energy intake explains malnutrition in AD. These results could be useful to optimize dietary advice for patients with AD dementia and MCI.

Background: Higher vitamin E intake has been widely related to lower risks of cognitive decline and dementia. Animal models suggest that this relationship might be (partially) explained by the protection of vitamin E against presynaptic protein oxidation. Objective: In this cross-sectional study, we aimed to examine the associations between brain tocopherols and presynaptic protein levels in elderly humans. Methods: We examined associations of α- and γ-tocopherol brain levels with presynaptic protein levels in 113 deceased participants (age 88.5±6.0 years, 45 (40%) female) from the prospective Memory and Aging project. Three distinct presynaptic proteins, a SNARE protein composite, a synaptotagmin synaptophysin composite and the protein-protein interaction between synaptosomal-associated protein 25 (SNAP-25), and syntaxin were measured in two cortical brain regions. Linear regression models assessed associations of brain tocopherols with presynaptic protein levels. Results: Higher brain γ-tocopherol levels were associated with higher levels of the SNARE protein composite, complexin-I, complexin-II, the synaptotagmin synaptophysin composite, and septin-5 in the midfrontal cortex (B(SE) = 0.272 to 0.412 (0.084 to 0.091), p

Introduction Unambiguous data on sexual dysfunction after Hodgkin lymphoma (HL) treatment are scarce. Aims To form a baseline in this area, we compared patient-reported sexual function in sexually active male HL survivors in complete remission with a sexually active, age-matched, male Dutch sample population. Furthermore, we explored whether sociodemographic and clinical factors were associated with sexual dysfunction in HL survivors and investigated whether reporting to perceive sexual problems was indicative for sexual dysfunction. Methods This cross-sectional study included male patients with HL who were treated with chemotherapy and age-matched sexually active males. Main outcome measures Outcome measures included the internationally validated International Index of Erectile Function (IIEF) and self-reported sexual problems by adding 3 items to the study-specific questionnaire. Results Erectile dysfunction (ED) occurred in 23.3% of the HL survivors vs in 23.0% of controls: respectively 13.3% and 12.3% had moderate to severe ED. However, more HL survivors positively answered the question whether they did perceive sexual problems than controls (20.0% vs 7.0%; P = .087). More patients treated with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procabazine, and prednisone (BEACOPP) had sexual problems 33.3% vs 8.3% who were treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (P = .057). Importantly, we found that the mean IIEF score for erectile function was 15.7 in HL survivors who reported to perceive sexual problems (moderate ED) vs 28.3 (normal) in those without perceiving sexual problems. Conclusion In general, sexual function of male HL survivors is comparable to that of matched normal controls. Perceiving sexual problems was associated with lower sexual function measured by the IIEF. None of the HL survivors who were treated with doxorubicin, bleomycin, vinblastine, and dacarbazine perceived sexual problems. However, one-third of HL survivors who were treated with BEACOPP did, including ED in one-third of the cases. This is an important consideration for daily clinical practice as BEACOPP is increasingly used as standard therapy in advanced-stage HL.

Objective The assessment of risk factors, including mediolateral episiotomy (MLE), for the recurrence of obstetric anal sphincter injury (rOASI). Design Population-based cohort study. Setting Data from the nationwide database of the Dutch Perinatal Registry (Perined). Population A cohort of 391 026 women at term, of whom 9943 had an OASI in their first delivery and had a second vaginal delivery of a liveborn infant in cephalic position. Methods Possible risk factors were tested for statistical significance using univariate and multivariate logistic regression analysis. Main outcome measures Rate of rOASI. Results The rate of rOASI was 5.8%. Multivariate analysis identified a birthweight of ≥4000 g (adjusted OR, aOR, 2.1, 95% CI 1.6-2.6) and a duration of second stage of ≥30 minutes (aOR 1.8, 95% CI 1.4-2.3) as statistically significant risk factors for rOASI. Mediolateral episiotomy was associated with a statistically significant lower rate of rOASI in spontaneous vaginal delivery (SVD) (aOR 0.4, 95% CI 0.3-0.5) and in operative vaginal delivery (OVD) (aOR 0.2, 95% CI 0.1-0.5). Conclusions Women with a history of OASI have a higher rate of OASI in their next delivery. Duration of the second stage of ≥30 minutes and a birthweight of ≥4000 g are significantly associated with an increased rate of rOASI. Mediolateral episiotomy is associated with a significantly lower rate of rOASI in both SVD and OVD. Tweetable abstract Mediolateral episiotomy is associated with a significant lower recurrence rate of OASI in women with an OASI in their first delivery.

Incomplete systemic lupus (iSLE) is an acknowledged condition of patients with clinical signs of lupus who do not fulfill classification criteria for SLE. Some patients with iSLE have persistent mild disease, but others have serious organ involvement, and up to 55% progress to established SLE. Research on this subject could reveal predictive or diagnostic biomarkers for SLE. Ideally, it would become possible to discern those patients with critical organ involvement or a high risk for progression to SLE. This high-risk group might benefit from early treatment, which would preferably be confirmed in randomized controlled trials. This process would, however, require agreement on a definition of iSLE. The Systemic Lupus International Collaborating Clinics (SLICC) classification criteria was composed in order to diagnose SLE earlier. The present review outlines the clinical characteristics of iSLE after introduction of SLICC criteria and furthermore proposes a definition of iSLE with the aim of discriminating the high-risk group from those with a lower risk.

Background Gliomas are associated with significant healthcare burden, yet reports of costs are scarce. While many costs are unavoidable there may be treatable symptoms contributing to higher costs. We describe healthcare and societal costs in glioma patients at high risk for depression and their family caregivers, and explore relationships between costs and treatable symptoms. Methods Data from a multicenter randomized trial on effects of internet-based therapy for depressive symptoms were used (NTR3223). Costs of self-reported healthcare utilization, medication use, and productivity loss were calculated for patients and caregivers separately. We used generalized linear regression models to predict costs with depressive symptoms, fatigue, cognitive complaints, tumor grade (low-/high-grade), disease status (stable or active/progression), and intervention (use/non-use) as predictors. Results Multiple assessments from baseline through 12 months from 91 glioma patients and 46 caregivers were used. Mean overall costs per year were M = €20,587.53 (sd = €30,910.53) for patients and M = €5,581.49 (sd = €13,102.82) for caregivers. In patients, higher healthcare utilization costs were associated with more depressive symptoms; higher medication costs were associated with active/progressive disease. In caregivers, higher overall costs were linked with increased caregiver fatigue, cognitive complaints, and lower patient tumor grade. Higher healthcare utilization costs were related to more cognitive complaints and lower tumor grade. More productivity loss costs were associated with increased fatigue (all P Conclusions There are substantial healthcare and societal costs for glioma patients and caregivers. Associations between costs and treatable psychological symptoms indicate that possibly, adequate support could decrease costs. Trial registration Netherlands Trial Register NTR3223.

BACKGROUND AND OBJECTIVES In head and neck surgery, intraoperative and postoperative evaluation of tumor margins is achieved by histopathological assessment, which is a multistep process. Intraoperative analysis of tumor margins to obtain a preliminary diagnosis is usually carried out on frozen sections. Analysis of frozen sections is challenging due to technical difficulties in processing. Full-field optical coherence tomography (FFOCT) provides ex vivo images of fresh tissue samples at a microscopic scale without tissue processing. The objectives of our study were to define the diagnostic criteria required to interpret head and neck FFOCT images and to evaluate the reliability of a histological diagnosis made on an "optical biopsy" produced by head and neck FFOCT imaging compared with conventional histology. STUDY DESIGN/MATERIALS AND METHODS First, we established an atlas of comparative images (FFOCT/standard histology) and defined the diagnostic criteria based on FFOCT images. Two pathologists subsequently performed a blinded review on 57 FFOCT images (32 patients). Specificity and sensitivity were measured by comparison with the standard histological diagnosis. The primary endpoint was major concordance, defined as two classifications leading to the same therapeutic decision (treatment/no treatment). RESULTS Pathologists identified four main criteria for tissue diagnosis on FFOCT images: heterogeneous cell distribution, stromal reaction, coiling, and keratinization abnormalities. The correlation study showed good results, with sensitivity from 88% to 90% and specificity from 81% to 87%, regardless of whether the FFOCT image review was performed by a pathologist with or without previous experience in optical imaging. CONCLUSIONS Our results demonstrate that FFOCT images can be used by pathologists for differential diagnosis, and that high-resolution FFOCT imaging can provide an assessment of microscopic architecture in head and neck tissues without tissue processing requirements. Lasers Surg. Med. © 2020 Wiley Periodicals, Inc.

Publisher's version, Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development., The study was supported by the German Federal Ministry of Education and Research (BMBF), through the Integrated Network IntegraMent, under the auspices of the e:Med programme (grants 01ZX1314A to MMN and SC; 01ZX1314G to MR; 01ZX1614J to BMM) through grants 01EE1406C to MR and 01EE1409C to MR and SHW, and through ERA-NET NEURON, “SynSchiz—Linking synaptic dysfunction to disease mechanisms in schizophrenia—a multilevel investigation” (01EW1810 to MR) and BMBF grants 01EE1409C and 01EE1406C to MR and SHW; by the German Research Foundation (DFG grants FOR2107; RI908/11-2 to MR; NO246/10-2 to MMN; MU1315/8-2 to BMM; WI 3439/3-2 to SHW), by the Andalusian regional Health and Innovation Government (grants PI-0060-2017, RC-0006-2015 the Nicolas Monarde Programme for YDO and CTS-546) and by the Swiss National Science Foundation (SNSF grant 156791 to SC). MMN is a member of the DFG-funded cluster of excellence ImmunoSensation. The PGC has received major funding from the US National Institute of Mental Health and the US National Institute of Drug Abuse (U01 MH109528 and U01 MH1095320). We thank the research participants and employees of 23andMe, Inc. for their contribution to the MDD meta-analysis published in [14]. We thank the International Genomics of Alzheimer's Project (IGAP) for providing summary results data for the present analyses. See the Supplementary Data for extended Acknowledgements.

AIMS: Since December 2015, the European/International Fibromuscular Dysplasia (FMD) Registry enrolled 1022 patients from 22 countries. We present their characteristics according to disease subtype, age and gender, as well as predictors of widespread disease, aneurysms and dissections. METHODS AND RESULTS: All patients diagnosed with FMD (string-of-beads or focal stenosis in at least one vascular bed) based on CTA, MRA and/or catheter-based angiography were eligible.Patients were predominantly women (82%) and Caucasians (88%). Age at diagnosis was 46±16 years (12% ≥65yo), 86% were hypertensive, 72% had multifocal and 57% multivessel FMD. Compared to patients with multifocal FMD, patients with focal FMD were younger, more often men, had less often multivessel FMD but more revascularizations. Compared to women with FMD, men were younger, had more often focal FMD and arterial dissections. Compared to younger patients with FMD, patients ≥65yo had more often multifocal FMD, lower eGFR and more atherosclerotic lesions. Independent predictors of multivessel FMD were age at FMD diagnosis, stroke, multifocal subtype, presence of aneurysm or dissection and family history of FMD. Predictors of aneurysms were multivessel and multifocal FMD. Predictors of dissections were age at FMD diagnosis, male gender, stroke and multivessel FMD. CONCLUSIONS: The European/International FMD Registry allowed large-scale characterization of distinct profiles of patients with FMD and, more importantly, identification of a unique set of independent predictors of widespread disease, aneurysms and dissections, paving the way for targeted screening, management and follow-up of FMD. TRANSLATIONAL PERSPECTIVE: Fibromuscular dysplasia (FMD) is nowadays considered as a systemic arterial disease, warranting brain-to-pelvis vascular imaging in all patients. However, most current evidence is derived from a limited number of expert centres. Furthermore, one size may not fit all. Based on analysis of the first thousand patients enrolled in the European/International FMD registry (46 centres; 22 countries) we characterized distinct patient profiles according to FMD subtype, age and gender and identified predictors of widespread disease, aneurysms and dissections, paving the way for individualized management and follow-up. Further studies will allow refining patient characterization according to ethnicity, genetic profile and imaging biomarkers.

OBJECTIVES: To evaluate whether the Morphological Uterus Sonographic Assessment (MUSA) features of adenomyosis need to be better defined and, if deemed necessary, to reach consensus on the updated definitions. METHODS: A modified Delphi procedure was performed among European gynecologists with expertise in ultrasound diagnosis of adenomyosis. To identify MUSA features that might need revision, 15 two-dimensional (2D) video recordings (four recordings also included three-dimensional (3D) still images) of transvaginal ultrasound (TVS) examinations of the uterus were presented in the first Delphi round (online questionnaire). Experts were asked to confirm or refute the presence of each of the nine MUSA features of adenomyosis (described in the original MUSA consensus statement) in each of the 15 videoclips and to provide comments. In the second Delphi round (online questionnaire), the results of the first round and suggestions for revision of MUSA features were shared with the experts before they were asked to assess a new set of 2D and 3D still images of TVS examinations and to provide feedback on the proposed revisions. A third Delphi round (virtual group meeting) was conducted to discuss and reach final consensus on revised definitions of MUSA features. Consensus was predefined as at least 66.7% agreement between experts. RESULTS: Of 18 invited experts, 16 agreed to participate in the Delphi procedure. Eleven experts completed and four experts partly finished the first round. The experts identified a need for more detailed definitions of some MUSA features. They recommended use of 3D ultrasound to optimize visualization of the junctional zone. Fifteen experts participated in the second round and reached consensus on the presence or absence of ultrasound features of adenomyosis in most of the still images. Consensus was reached for all revised definitions except those for subendometrial lines and buds and interrupted junctional zone. Thirteen experts joined the online meeting, in which they discussed and agreed on final revisions of the MUSA definitions. There was consensus on the need to distinguish between direct features of adenomyosis, i.e. features indicating presence of ectopic endometrial tissue in the myometrium, and indirect features, i.e. features reflecting changes in the myometrium secondary to presence of endometrial tissue in the myometrium. Myometrial cysts, hyperechogenic islands and echogenic subendometrial lines and buds were classified unanimously as direct features of adenomyosis. Globular uterus, asymmetrical myometrial thickening, fan-shaped shadowing, translesional vascularity, irregular junctional zone and interrupted junctional zone were classified as indirect features of adenomyosis. CONCLUSION: Consensus between gynecologists with expertise in ultrasound diagnosis of adenomyosis was achieved regarding revised definitions of the MUSA features of adenomyosis and on the classification of MUSA features as direct or indirect signs of adenomyosis. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. ispartof: ULTRASOUND IN OBSTETRICS & GYNECOLOGY vol:60 issue:1 pages:118-131 ispartof: location:England status: published

Contains fulltext : 240301.pdf (Publisher’s version ) (Open Access) Background: Neurocognition and speech, relevant domains in head and neck cancer (HNC), may be affected pretreatment. However, the prevalence of pretreatment deficits and their possible concurrent predictors are poorly understood. Methods: Using an HNC prospective cohort (Netherlands Quality of Life and Biomedical Cohort Study, N >= 444) with a cross-sectional design, we investigated the estimated prevalence of pretreatment deficits and their relationship with selected demographic, behavioral, and disease-related factors. Results: Using objective assessments, rates of moderate-to-severe neurocognitive deficit ranged between 4% and 8%. From patient-reported outcomes, 6.5% of patients reported high levels of cognitive failures and 46.1% reported speech deficits. Patient-reported speech functioning was worse in larynx compared to other subsites. Other nonspeech outcomes were unrelated to any variable. Patient-reported neurocognitive and speech functioning were modestly correlated, especially in the larynx group. Conclusions: These findings indicate that a subgroup of patients with HNC shows pretreatment deficits, possibly accentuated in the case of larynx tumors. 13 p.

Contains fulltext : 244201.pdf (Publisher’s version ) (Open Access) Recent studies suggest that a subset of cortical microinfarcts may be identifiable on T2* but invisible on T1 and T2 follow-up images. We aimed to investigate whether cortical microinfarcts are associated with iron accumulation after the acute stage. The RUN DMC - InTENse study is a serial MRI study including individuals with cerebral small vessel disease (SVD). 54 Participants underwent 10 monthly 3 T MRIs, including diffusion-weighted imaging, quantitative R1 (=1/T1), R2 (=1/T2), and R2* (=1/T2*) mapping, from which MRI parameters within areas corresponding to microinfarcts and control region of interests (ROIs) were retrieved within 16 participants. Finally, we compared pre- and post-lesional values with repeated measures ANOVA and post-hoc paired t-tests using the mean difference between lesion and control ROI values. We observed 21 acute cortical microinfarcts in 7 of the 54 participants (median age 69 years [IQR 66-74], 63% male). R2* maps demonstrated an increase in R2* values at the moment of the last available follow-up MRI (median [IQR], 5 [5-14] weeks after infarction) relative to prelesional values (p = .08), indicative of iron accumulation. Our data suggest that cortical microinfarcts are associated with increased R2* values, indicative of iron accumulation, possibly due to microhemorrhages, neuroinflammation or neurodegeneration, awaiting histopathological verification.

ObjectiveTo determine the contribution of common genetic variants to risk of early onset ischemic stroke (IS).MethodsWe performed a meta-analysis of genome-wide association studies of early onset IS, ages 18-59, using individual level data or summary statistics in 16,927 cases and 576,353 non-stroke controls from 48 different studies across North America, Europe, and Asia. We further compared effect sizes at our most genome-wide significant loci between early and late onset IS and compared polygenic risk scores for venous thromboembolism between early versus later onset IS.ResultsWe observed an association between early onset IS and ABO, a known stroke locus. The effect size of the peak ABO SNP, rs8176685, was significantly larger in early compared to late onset IS (OR 1.17 (95% C.I.: 1.11-1.22) vs 1.05 (0.99-1.12); p for interaction = 0.008). Analysis of genetically determined ABO blood groups revealed that early onset IS cases were more likely to have blood group A and less likely to have blood group O compared to both non-stroke controls and to late onset IS cases. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with early, compared to late, onset IS (p=0.008).ConclusionThe ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with early onset IS, compared with late onset IS, supporting a stronger role of prothrombotic factors in early onset IS.

OBJECTIVE: To develop a standardized sonographic evaluation and reporting system for Cesarean scar pregnancy (CSP) in the first trimester, for use by both general gynecology and expert clinics. METHODS: A modified Delphi procedure was carried out, in which 28 international experts in obstetric and gynecological ultrasonography were invited to participate. Extensive experience in the use of ultrasound to evaluate Cesarean section (CS) scars in early pregnancy and/or publications concerning CSP or niche evaluation was required to participate. Relevant items for the detection and evaluation of CSP were determined based on the results of a literature search. Consensus was predefined as a level of agreement of at least 70% for each item, and a minimum of three Delphi rounds were planned (two online questionnaires and one group meeting). RESULTS: Sixteen experts participated in the Delphi study and four Delphi rounds were performed. In total, 58 items were determined to be relevant. We differentiated between basic measurements to be performed in general practice and advanced measurements for expert centers or for research purposes. The panel also formulated advice on indications for referral to an expert clinic. Consensus was reached for all 58 items on the definition, terminology, relevant items for evaluation and reporting of CSP. It was recommended that the first CS scar evaluation to determine the location of the pregnancy should be performed at 6-7 weeks' gestation using transvaginal ultrasound. The use of magnetic resonance imaging was not considered to add value in the diagnosis of CSP. A CSP was defined as a pregnancy with implantation in, or in close contact with, the niche. The experts agreed that a CSP can occur only when a niche is present and not in relation to a healed CS scar. Relevant sonographic items to record included gestational sac (GS) size, vascularity, location in relation to the uterine vessels, thickness of the residual myometrium and location of the pregnancy in relation to the uterine cavity and serosa. According to its location, a CSP can be classified as: (1) CSP in which the largest part of the GS protrudes towards the uterine cavity; (2) CSP in which the largest part of the GS is embedded in the myometrium but does not cross the serosal contour; and (3) CSP in which the GS is partially located beyond the outer contour of the cervix or uterus. The type of CSP may change with advancing gestation. Future studies are needed to validate this reporting system and the value of the different CSP types. CONCLUSION: Consensus was achieved among experts regarding the sonographic evaluation and reporting of CSP in the first trimester. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. ispartof: ULTRASOUND IN OBSTETRICS & GYNECOLOGY vol:59 issue:4 pages:437-449 ispartof: location:England status: published

Introduction: Open-label placebos have been proposed as way of using long recognized analgesic placebo effects in an ethical manner. Recent evidence shows efficacy of open-label placebos for clinical conditions, but there is need for more research on open-label placebos in acute pain. In the treatment of acute postoperative pain, minimization of opioid related side effects remains one of the key challenges. Therefore, this study aims at investigating the potential of adding unconditioned open-label placebos to treatment as usual as a means of reducing opioid consumption and its related side effects in patients with acute postoperative pain.Methods and Analysis: This is the protocol of an ongoing single site randomized controlled trial. The first patient was enrolled in May 2020. In total, 70 patients suffering from acute postoperative pain following dorsal lumbar interbody fusion are randomized to either a treatment as usual group or an experimental intervention group. The treatment as usual group consists of participants receiving a patient-controlled morphine pump. On day 1 and 2 post-surgery, patients in the intervention group receive, in addition to treatment as usual, two open-label placebo injections per day along with an evidence-based treatment rationale explaining the mechanisms of placebos. The primary outcome is measured by means of self-administered morphine during day 1 and 2 post-surgery. Several other outcome measures including pain intensity and adverse events as well as potential predictors of placebo response are assessed. Analysis of covariance will be used to answer the primary research question and additional statistical techniques such as generalized linear mixed models will be applied to model the temporal course of morphine consumption.Discussion: This study will provide valuable insights into the efficacy of open-label placebos in acute pain and will potentially constitute an important step toward the implementation of open-label placebos in the clinical management of acute postoperative pain. In addition, it will shed light on a cost-efficient and patient-centered strategy to reduce opioid consumption and its related side effects, without any loss in pain management efficacy.Ethics and Dissemination: The “Ethikkommission Nordwest- und Zentralschweiz” (BASEC2020-00099) approved the study protocol. Results of the analysis will be submitted for publication in a peer-reviewed journal.Clinical Trial Registration: The study is registered at ClinicalTrials.gov (NCT04339023) and is listed in the Swiss national registry at kofam.ch (SNCTP000003720).

Background Anxiety disorders are highly prevalent and cause substantial economic burden. Blended cognitive-behavioural therapy (bCBT), which integrates Internet-based CBT and face-to-face CBT (ftfCBT), is an attractive and potentially cost-saving treatment alternative to conventional CBT for patients with anxiety disorders in specialised mental health care. However, little is known about the effectiveness of bCBT in routine care. We examined the acceptability, effectiveness and cost-effectiveness of bCBT versus ftfCBT in outpatient specialised care to patients with panic disorder, social anxiety disorder and generalised anxiety disorder. Methods and findings Patients with anxiety disorders were randomised to bCBT (n = 52) or ftfCBT (n = 62). Acceptability of bCBT and ftfCBT were evaluated by assessing treatment preference, adherence, satisfaction and therapeutic alliance. Costs and effects were assessed at post-treatment and one-year follow-up. Primary outcome measure was the Beck Anxiety Inventory (BAI). Secondary outcomes were depressive symptoms, general psychopathology, work and social adjustment, quality of life and mastery. Incremental cost-effectiveness ratios (ICERs) were computed from societal and healthcare perspectives by calculating the incremental costs per incremental quality-adjusted life year (QALY). No significant differences between bCBT and ftfCBT were found on acceptability or effectiveness measures at post-treatment (Cohen’s d between-group effect size on BAI = 0.15, 95% CI −0.30 to 0.60) or at one-year follow-up (d = −0.38, 95% CI −0.84 to 0.09). The modelled point estimates of societal costs (bCBT €10945, ftfCBT €10937) were higher and modelled point estimates of direct medical costs (bCBT €3748, ftfCBT €3841) were lower in bCBT. The acceptability curves showed that bCBT was expected to be a cost-effective intervention. Results should be carefully interpreted due to the small sample size. Conclusions bCBT appears an acceptable, clinically effective and potentially cost-saving alternative option for treating patients with anxiety disorders. Trials with larger samples are needed to further investigate cost-effectiveness. Trial registration Netherlands Trial Register: NTR4912.