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Intrinsic capacity, a crucial concept in healthy ageing, is defined by WHO as “the composite of all the physical and mental capacities that an individual can draw on at any point in time”. Vitality capacity is considered the underlying physiological determinant of intrinsic capacity. To advance the measurement and monitoring of vitality capacity, a working group of WHO staff members and twenty experts representing six WHO regions was convened to discuss and clarify the attributes of vitality capacity and to develop a clear working definition of the concept. Potential biomarkers to measure vitality capacity were identified, and the following consensual working definition was developed: vitality capacity is a physiological state (due to normal or accelerated biological ageing processes) resulting from the interaction between multiple physiological systems, reflected in (the level of) energy and metabolism, neuromuscular function, and immune and stress response functions of the body.

The purpose of this study was to evaluate the effect of chemotherapy and trastuzumab on invasive disease-free survival (iDFS) and overall survival (OS) in patients with human epidermal growth factor receptor 2 (HER2) positive, T1abN0 breast cancer.In the Danish Breast Cancer Group database, patients with HER2-positive, T1abN0 tumors diagnosed between 2007 and 2016 were identified. Cox proportional hazards analysis was performed to analyze the association between adjuvant chemotherapy and trastuzumab and iDFS and OS.Of 605 patients included in the analyses, 465 patients received chemotherapy and trastuzumab and 140 patients did not. Chemotherapy and trastuzumab did not improve iDFS or OS significantly in adjusted analyses. 5-year iDFS was 92.3% vs. 89.9%, Hazard ratio (HR) 1.01 (p = 0.98), and 5-year OS was 97.4% vs. 94.3%, HR 0.60 (p = 0.15), chemotherapy and trastuzumab vs. no chemotherapy/trastuzumab. In unadjusted analyses, significant treatment benefit on OS was found in patients with T1b tumors. The largest absolute treatment benefits were found in patients with T1b tumors and estrogen receptor (ER) negative tumors, respectively, whereas treatment effects in patients with T1a tumors and ER-positive tumors, respectively, were limited.Adjuvant chemotherapy and trastuzumab did not improve OS or iDFS significantly in patients with HER2-positive, T1abN0 breast cancers in adjusted analyses. In unadjusted analyses, significant OS benefit was found in patients with T1b tumors. The largest absolute benefit was observed in patients with T1b tumors and ER-negative tumors, respectively, whereas the effect was limited in patients with T1a tumors and ER-positive tumors, respectively.

Background We have developed a model of stratified exercise therapy that distinguishes three knee osteoarthritis (OA) subgroups (‘high muscle strength subgroup’, ‘low muscle strength subgroup’, ‘obesity subgroup’), which are provided subgroup-specific exercise therapy (supplemented by a dietary intervention for the ‘obesity subgroup’). In a large clinical trial, this intervention was found to be no more effective than usual exercise therapy. The present qualitative study aimed to explore experiences from users of this intervention, in order to identify possible improvements. Methods Qualitative research design embedded within a cluster randomized controlled trial in a primary care setting. A random sample from the experimental arm (i.e., 15 patients, 11 physiotherapists and 5 dieticians) was interviewed on their experiences with receiving or applying the intervention. Qualitative data from these semi-structured interviews were thematically analysed. Results We identified four themes: one theme regarding the positive experiences with the intervention and three themes regarding perceived barriers. Although users from all 3 perspectives (patients, physiotherapists and dieticians) generally perceived the intervention as having added value, we also identified several barriers, especially for the ‘obesity subgroup’. In this ‘obesity subgroup’, physiotherapists perceived obesity as difficult to address, dieticians reported that more consultations are needed to reach sustainable weight loss and both physiotherapists and dieticians reported a lack of interprofessional collaboration. In the ‘high muscle strength subgroup’, the low number of supervised sessions was perceived as a barrier by some patients and physiotherapists, but as a facilitator by others. A final theme addressed barriers to knee OA treatment in general, with lack of motivation as the most prominent of these. Conclusion Our qualitative study revealed a number of barriers to effective application of the stratified exercise therapy, especially for the ‘obesity subgroup’. Based on these barriers, the intervention and its implementation could possibly be improved. Moreover, these barriers are likely to account at least partly for the lack of superiority over usual exercise therapy. Trial registration The Netherlands National Trial Register (NTR): NL7463 (date of registration: 8 January 2019).

Data de publicació electrònica: 04-04-2022 Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harboring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20), delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: defective cell membrane expression (1), impaired LGI1-binding (2), and/or impaired interaction with the postsynaptic density protein PSD-95 (3). We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics. Funding: most families were collected as part of the SYNaPS Study Group collaboration funded by the Wellcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA). This study was also supported by JSPS/MEXT KAKENHI (Grants 19H03331, 19K22439 and 21K19390 to Y.F., Grant 19K16269 to Y.M., and Grants 20H00459 and 20H04915 to M.F.) and Japan Agency for Medical Research and Development (21wm0525022h0001 to Y.F.); intramural funding (fortüne) from the University of Tübingen (Grant 2545-1-0) and the Ministry of Science, Research and Art Baden-Württemberg to B.V. P.S. contributed to this work within the framework of the DINOGMI Department of Excellence of MIUR 2018-2022 (legge 232 del 2016). T.B.H. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – 418081722, 433158657. I.S.P., V.Y.V. are supported by the Government Assignment of the Russian Ministry of Health (#121061500066-2). HL receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). S.H. is funded by TUBITAK (Turkish Scientific and Technological Research Council) Project number 216S771. R.H. is a Wellcome Trust Investigator (109915/Z/15/Z), who received support from the Medical Research Council (UK) (MR/N025431/1 and MR/V009346/1), the European Research Council (309548), the Newton Fund (UK/Turkey, MR/N027302/1), the Addenbrookes Charitable Trust (G100142), the Evelyn Trust, the Stoneygate Trust, the Lily Foundation and an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014)

Background Cognitive behavioral therapy for targeted-therapy related fatigue (CBT-TTF) has demonstrated preliminary efficacy in reducing fatigue in patients treated with tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML). Purpose The aim of the current analyses was to explore whether fatigue perpetuating factors (disturbed sleep/wake cycle, dysregulated activity patterns, maladaptive cognitions about fatigue and cancer, insufficient processing of cancer and treatment, inadequate social support and interactions, heightened fear of cancer progression) changed over time in patients receiving CBT-TTF, and whether the effect of CBT-TTF on fatigue was mediated by these factors. Methods Secondary data analyses were conducted from a pilot randomized controlled trial. Patients with CML treated with a TKI who reported moderate to severe fatigue were randomized 2:1 to CBT-TTF delivered via FaceTime for iPad or a waitlist control condition (WLC). Self-report measures of fatigue and fatigue perpetuating factors were obtained before randomization and post-intervention (i.e., approximately 18 weeks later). Mixed model and mediation analyses using bootstrap methods were used. Results A total of 36 participants (CBT-TTF n = 22, WLC n = 14) who had baseline and 18-week follow-up data and attended >5 sessions for CBT-TTF were included. Participants randomized to CBT-TTF reported improvements in activity (mental, physical, social, p’s ≤ .023) and cognitions (helplessness, catastrophizing, focusing on symptoms, self-efficacy, p’s ≤ .003) compared to WLC. Mental activity, social activity, self-efficacy, helplessness, and focusing on symptoms, as well as sleep and insufficient processing (avoidance) mediated the relationship between treatment group and fatigue. Conclusions CBT-TTF appears to improve TKI-related fatigue in CML patients through changes in behavior (sleep, activity patterns) and cognitions about fatigue and cancer. A larger randomized controlled trial is warranted to confirm these findings.

Background: Current guidelines in HER2-positive metastatic breast cancer (mBC) recommend the combination of trastuzumab and a chemotherapeutic agent for 3rd line or later treatments. This study aims to describe the treatment of HER2-positive mBC in 3rd line or later after previous treatment with T-DM1 for mBC in a real-world setting.Material and methods: This observational population-based study included all women diagnosed with HER2-positive mBC in Denmark, previously treated with T-DM1 in the metastatic setting. Patients were included on the date of progression leading to initiation of 3rd line treatment if the patient had received T-DM1 in 1st or 2nd line. If the patient received T-DM1 in 3rd line or later the inclusion was based on the date of progression on T-DM1. The primary end points were overall survival (OS) and progression-free survival (PFS).Results: The study included 272 women with a mean age of 59 (27-86) and a median of 3 (2-11) treatment lines prior to inclusion. At index, all patients had received T-DM1 and 167 (62%) patients had received pertuzumab in the metastatic setting. During follow-up 183 patients received chemotherapy. Of these patients, 120 received chemotherapy combined with trastuzumab, 50 received chemotherapy combined with other HER2-targeted therapy, and 13 received chemotherapy as monotherapy. The remaining 89 patients received either HER2-targeted monotherapy (41), endocrine therapy (31), experimental treatment (10), or no treatment (7). Median PFS was 5.5 months (95% CI, 4.8-6.5) and median OS was 18.5 months (95% CI, 16.2-21.3).Conclusion: In this real-world study, we found that patients were treated with a wide variety of anti-cancer agents with modest efficacy. However, patients in this study did not have access to newer therapies like tucatinib and T-DXd. Background: Current guidelines in HER2-positive metastatic breast cancer (mBC) recommend the combination of trastuzumab and a chemotherapeutic agent for 3rd line or later treatments. This study aims to describe the treatment of HER2-positive mBC in 3rd line or later after previous treatment with T-DM1 for mBC in a real-world setting.Material and methods: This observational population-based study included all women diagnosed with HER2-positive mBC in Denmark, previously treated with T-DM1 in the metastatic setting. Patients were included on the date of progression leading to initiation of 3rd line treatment if the patient had received T-DM1 in 1st or 2nd line. If the patient received T-DM1 in 3rd line or later the inclusion was based on the date of progression on T-DM1. The primary end points were overall survival (OS) and progression-free survival (PFS).Results: The study included 272 women with a mean age of 59 (27-86) and a median of 3 (2-11) treatment lines prior to inclusion. At index, all patients had received T-DM1 and 167 (62%) patients had received pertuzumab in the metastatic setting. During follow-up 183 patients received chemotherapy. Of these patients, 120 received chemotherapy combined with trastuzumab, 50 received chemotherapy combined with other HER2-targeted therapy, and 13 received chemotherapy as monotherapy. The remaining 89 patients received either HER2-targeted monotherapy (41), endocrine therapy (31), experimental treatment (10), or no treatment (7). Median PFS was 5.5 months (95% CI, 4.8-6.5) and median OS was 18.5 months (95% CI, 16.2-21.3).Conclusion: In this real-world study, we found that patients were treated with a wide variety of anti-cancer agents with modest efficacy. However, patients in this study did not have access to newer therapies like tucatinib and T-DXd.

Contains fulltext : 248769.pdf (Publisher’s version ) (Open Access) BACKGROUND: Fatigue is often reported by patients with childhood cancer both during and after cancer treatment. Several instruments to measure fatigue exist, although none are specifically validated for use in childhood cancer survivors (CCS). The aim of the current study was to present norm values and psychometric properties of the Checklist Individual Strength (CIS) and Short Fatigue Questionnaire (SFQ) in a nationwide cohort of CCS. METHODS: In total, 2073 participants were included from the Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort. Normative data, construct validity, structural validity, and internal consistency were calculated for the CIS and SFQ. In addition, reliability and a cutoff score to indicate severe fatigue were determined for the SFQ. RESULTS: Correlations between CIS/SFQ and vitality measures asking about fatigue were high (>0.8). Correlations between CIS/SFQ and measures of different constructs (sleep, depressive emotions, and role functioning emotional) were moderate (0.4-0.6). Confirmatory factor analysis resulted in a four-factor solution for the CIS and a one-factor solution for the SFQ with Cronbach's alpha for each (sub)scale showing good to excellent values (>0.8). Test-retest reliability of the SFQ was adequate (Pearson's correlation = 0.88; ICC = 0.946; weighted Cohen's kappa item scores ranged 0.31-0.50) and a cut-off score of 18 showed good sensitivity and specificity scores (92.6% and 91.3%, respectively). CONCLUSION: The current study shows that the SFQ is a good instrument to screen for severe fatigue in CCS. The CIS can be used as a tool to assess the multiple fatigue dimensions in CCS.

OBJECTIVES: Determine whether the Fear of Birth Scale (FOBS) is a useful screening instrument for Fear of Childbirth (FoC) and examine the potential added value of screening by analyzing how often pregnant women discuss their FoC during consultation.METHODS: This cross-sectional survey study included nulliparous pregnant women of all gestational ages, recruited via the internet, hospital and midwifery practices. The online questionnaires included the FOBS and Wijma Delivery Expectations Questionnaire version A (W-DEQ A). The latter was used as golden standard for assessing FoC (cutoff: ≥85).RESULTS: Of the 364 included women, 67 (18.4%) had FoC according to the W-DEQ A. Using the FOBS with a cutoff score of ≥49, the sensitivity was 82.1% and the specificity 81.1%, with 111 (30.5%) women identified as having FoC. Positive predictive value was 49.5% and negative predictive value 95.3%. Of the women with FoC (FOBS ≥49), 68 (61.3%) did not discuss FoC with their caregiver.CONCLUSION: The FOBS is a useful screening instrument for FoC. A positive score must be followed by further assessment, either by discussing it during consultation or additional evaluation with the W-DEQ A. The majority of pregnant women with FoC do not discuss their fears, underscoring the need for screening.

Background Fatigue is the most frequent and burdensome symptom of patients with diffuse glioma. It is closely linked to decreased health-related quality of life and symptoms such as depression and sleep disturbances. Currently, there is no evidence-based treatment that targets severe fatigue in patients with brain tumours. Cognitive behavioural therapy is aimed at fatigue-maintaining beliefs and behaviour. This therapy has been proven effective in reducing severe fatigue in cancer survivors and patients with multiple sclerosis. A blended therapy program combines sessions with a therapist with therapist-guided web-based therapy modules. The aim of this randomized controlled trial is to determine the efficacy of blended cognitive behavioural therapy in treating severe fatigue in patients with diffuse glioma. Methods We will include a maximum of 100 patients with diffuse glioma with clinically and radiologically stable disease and severe fatigue (i.e. Checklist Individual Strength, subscale fatigue severity ≥ 35). Patients will be randomized to blended cognitive behavioural therapy or a waiting list condition. The 12-week intervention GRIP on fatigue consists of five patient-therapist sessions and five to eight individualized web-based therapy modules supported by email contact. The primary outcome measure is fatigue severity. Secondary outcome measures include sleep quality, health-related quality of life, depression, anxiety, functional impairment and subjective and objective cognitive functioning. Primary and secondary outcome measures will be assessed at baseline and after 14 and 24 weeks. Magnetoencephalography and MRI will be used to evaluate potential biomarkers for intervention success. This trial has a Bayesian design: we will conduct multiple interim analyses to test for efficacy or futility of the trial. This is the first trial within the GRIP trial platform: a platform developing four to five different interventions for the most common symptoms in patients with diffuse glioma. Discussion The results of the GRIP on fatigue trial will provide information about the efficacy of this intervention on fatigue in patients with diffuse glioma. Multiple other outcomes and possible predictors of treatment success will also be explored. Trial registration Netherlands Trial Register NL8711. Registered on 14 June 2020.

Background Myotonic dystrophy type 1 (DM1) is an incurable multisystem disease caused by a CTG-repeat expansion in the DM1 protein kinase (DMPK) gene. The OPTIMISTIC clinical trial demonstrated positive and heterogenous effects of cognitive behavioral therapy (CBT) on the capacity for activity and social participations in DM1 patients. Through a process of reverse engineering, this study aims to identify druggable molecular biomarkers associated with the clinical improvement in the OPTIMISTIC cohort. Methods Based on full blood samples collected during OPTIMISTIC, we performed paired mRNA sequencing for 27 patients before and after the CBT intervention. Linear mixed effect models were used to identify biomarkers associated with the disease-causing CTG expansion and the mean clinical improvement across all clinical outcome measures. Results We identified 608 genes for which their expression was significantly associated with the CTG-repeat expansion, as well as 1176 genes significantly associated with the average clinical response towards the intervention. Remarkably, all 97 genes associated with both returned to more normal levels in patients who benefited the most from CBT. This main finding has been replicated based on an external dataset of mRNA data of DM1 patients and controls, singling these genes out as candidate biomarkers for therapy response. Among these candidate genes were DNAJB12, HDAC5, and TRIM8, each belonging to a protein family that is being studied in the context of neurological disorders or muscular dystrophies. Across the different gene sets, gene pathway enrichment analysis revealed disease-relevant impaired signaling in, among others, insulin-, metabolism-, and immune-related pathways. Furthermore, evidence for shared dysregulations with another neuromuscular disease, Duchenne muscular dystrophy, was found, suggesting a partial overlap in blood-based gene dysregulation. Conclusions DM1-relevant disease signatures can be identified on a molecular level in peripheral blood, opening new avenues for drug discovery and therapy efficacy assessments.

Contains fulltext : 248803.pdf (Publisher’s version ) (Open Access) BACKGROUND: Cancer-related fatigue is a debilitating late effect after treatment for childhood cancer. The prevalence of fatigue in childhood cancer survivors (CCSs) and associated factors for fatigue has varied widely in previous studies. Two important aspects of cancer-related fatigue, its severity and chronicity, are often not assessed. This study investigated the prevalence of, and risk factors for, severe chronic fatigue (CF) in a national cohort of Dutch CCSs. METHODS: In this study, 2810 CCSs (5-year survivors of all childhood malignancies diagnosed between 1963 and 2001 with a current age of 12-65 years) and 1040 sibling controls were included. CF was assessed with the Short Fatigue Questionnaire and was defined as a score ≥ 18 and persistence of fatigue for ≥6 months. Cancer- and treatment-related characteristics, current health problems, and demographic and lifestyle variables were assessed as potential risk factors for CF via multivariable logistic regression analyses. RESULTS: In adult CCSs and sibling controls (≥18 years old), the prevalence of CF was 26.1% and 14.1%, respectively (P < .001). In adolescent CCSs and sibling controls (2, 2.20; 95% CI, 1.50-3.21), and a central nervous system diagnosis (OR, 1.74; 95% CI, 1.17-2.60) were significantly associated with CF in adult CCSs. CONCLUSIONS: This study shows that CCSs, regardless of their cancer diagnosis, report CF more often than sibling controls. This study provides new evidence for the prevalence of fatigue in CCSs.

Patients with connective tissue disease (CTD) present unique surgical, perioperative, operative, and postoperative challenges related to the often underlying severe pulmonary hypertension and right ventricular dysfunction. The International Society for Heart and Lung Transplantation-supported consensus document on lung transplantation in patients with CTD standardization addresses the surgical challenges and relevant cardiac involvement in the perioperative, operative, and postoperative management in patients with CTD.

Increased gallbladder wall thickness (GBWT) is a common finding. Reported causes include advanced chronic liver disease (ACLD), ascites and hypalbuminemia. GBWT is a marker for the prediction of esophageal varices. It remains unclear which of these factors is the decisive driver of GBWT. We aim to investigate whether there is a predominant factor associated with the GBWT.We enrolled 258 patients with ascites, hypalbuminemia and/or ACLD and 98 healthy volunteers that underwent abdominal ultrasound. Differences of mean GBWT in subgroups of patients with ACLD, ascites, and/or hypalbuminemia were analyzed. Correlation between various parameters and GBWT were calculated using multiple regression analysis.GBWT in patients with ACLD + ascites + hypalbuminemia (n = 59; 5.70 ± 2.05 mm) was pathologically increased compared to patients with hypalbuminemia + ascites without ACLD (n = 36; 2.14 ± 0.66 mm; p .001) and to patients with only hypalbuminemia (n = 76; 2.02 ± 0.80 mm; p .001). GBWT of patients with ACLD + hypalbuminemia (n = 30; 3.42 ± 1.52 mm) and with ACLD and normal albumin level were not different (n = 46; 3.10 ± 1.62 mm; p .999). Significant correlation was seen between GBWT and ACLD (r = .53; p .001) and ascites (r = .51; p .001) but not albumin level (r = .04; p = .510).We demonstrate that ACLD is predominantly associated with GBWT. In contrast to the current literature, serum albumin level appears not to be associated with pathological GBWT.

Diabetes-related distress is common in diabetes and has implications for well-being. Cognitive behavioural therapy (CBT) and third-wave CBT hold promise as treatments for diabetes-related distress, although previous findings are inconclusive. We aimed to conduct a systematic review with meta-analysis to understand the efficacy of these interventions in treating diabetes-related distress, while also assessing the associative benefits of these interventions on depression, anxiety and glycaemic control. We also aimed to conduct a narrative synthesis, and subgroup analyses to identify intervention components most useful in treating diabetes-related distress.We searched seven electronic databases from inception to April 2021. Data extraction was independently performed by two reviewers. Methodological quality was assessed. The protocol was registered with the Prospective Register Of Systematic Reviews (PROSPERO): CRD42021240628.We included 22 randomised controlled trials investigating the efficacy of CBT and third-wave CBT interventions on diabetes-related distress. CBT for diabetes-related distress significantly reduced distress (SMD = -0.278, p = 0.010) and depression (SMD = -0.604, p = 0.016). Third-wave CBT for diabetes-related distress significantly reduced anxiety (SMD = -0.451, p = 0.034). No significant effect of either intervention on glycated haemoglobin was observed. CBT interventions that included a digital component, were delivered by a psychological practitioner, and included behavioural activation bolstered the effects on diabetes-related distress.CBT aiming to target diabetes-related distress is beneficial for distress and depression. Third-wave CBT for diabetes-related distress is beneficial for anxiety. More work is needed to optimise interventions to improve both mental and physical health outcomes in people with diabetes.

Contains fulltext : 283508.pdf (Publisher’s version ) (Open Access) Marfan syndrome (MFS) is a connective tissue disorder affecting the cardiovascular, ocular, and skeletal system, which may be accompanied by psychological features. This study aimed to determine the prevalence of fatigue, anxiety, and symptoms of depression in MFS patients, and to assess the degree to which sociodemographic and clinical variables are associated with fatigue and psychological aspects. The prevalence of fatigue, anxiety, and symptoms of depression were assessed in two cohorts of MFS patients and compared with healthy controls. The checklist individual strength (CIS), and hospital anxiety and depression scale (HADS) questionnaires were utilized. Medical status was assessed (family history of MFS, aortic root dilatation >40 mm, previous aortic surgery, aortic dissection, chronic pain, skeletal involvement, and scoliosis). Severe fatigue was experienced by 37% of the total MFS cohort (n = 155). MFS patients scored significantly higher on the CIS questionnaire, concerning severe fatigue, as compared with the general Dutch population (p

Contains fulltext : 220431.pdf (Publisher’s version ) (Closed access) BACKGROUND: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. METHODS: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1.5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score

Background Previous findings suggest that impulsivity is related to chronic low-grade inflammation. Inflammation is known to trigger the kynurenine pathway to a pathological level in various impulsivity-related disorders. Nonetheless, murine models and recent human studies have shown that physical exercise, in particular High Intensity Interval Training (HIIT), could counterbalance the negative effects of inflammation on the kynurenine pathway. Aim This study evaluates the effects of eight weeks of HIIT versus an active control group on impulsivity levels and accompanying alterations of inflammatory-mediated changes of the kynurenine pathway in a sample of emotionally impulsive humans. Methods Participants were randomly allocated to either HIIT or stretching conditions (three trainings per week for eight weeks). Fitness level was evaluated via VO2peak values at the beginning at end of the intervention. Kynurenine metabolites, pro-inflammatory cytokines, and impulsivity levels were evaluated at T0, T4, and T8 weeks. Statistical analyses were performed using mixed models. Results Fifty-three participants were included in the modified Intention To Treat analysis (45 finished the intervention). The HIIT group (n = 28) largely increased the aerobic fitness of its participants and produced physiological changes while the stretching group (n = 25) did not. HIIT reduced interleukin 6 levels (small to moderate interaction) and reduced the activity of the neurotoxic branch of the kynurenine pathway (small to moderate interaction for KYNA/QA and KYN/QA) after eight weeks of training while the active control did not change. Both interventions were effective to decrease emotion-related impulsivity, however only the HIIT group decreased participants’ emotion-unrelated levels. Changes in emotion-related and -unrelated impulsivity were moderately correlated to changes in KYNA/KYN. Conclusion This study demonstrated that HIIT was able to switch the kynurenine pathway from its neurotoxic branch to its neuroprotective one. This shift was associated with a decrease in impulsivity. Based on these findings, future work may consider investigating more intensively the effect of HIIT on impulsivity-related disorders.

Antibiotic underdosing in prophylactic antibiotic regimes after lung transplantation (LTx) can increase the risk of infection. We aimed to study whether β-lactam concentrations achieved desirable pharmacodynamic targets in the early phase after LTx and the association between drug concentrations and the development of early infections or the acquisition of multidrug-resistant (MDR) strains. We reviewed patients in whom broad-spectrum β-lactam levels were measured after LTx during antibiotic prophylaxis. β-Lactam concentrations were considered "insufficient" if drug levels remained below four times the clinical breakpoint of the minimal inhibitory concentration for Pseudomonas aeruginosa. The primary outcome was the occurrence of an infection and/or acquisition of MDR pathogens in the first 14 days after transplantation. A total of 70 patients were included. "Insufficient" drug concentrations were found in 40% of patients. In 27% of patients, an early MDR pathogen was identified and 49% patients were diagnosed with an early posttransplant infection. Patients with "insufficient" drug concentrations acquired more frequently MDR bacteria and/or developed an infection than others (22/28, 79% vs. 20/42, 48% - p = .01). β-Lactam levels were often found to be below the desired drug targets in the early phase after transplantation and may be associated with the occurrence of early infectious complications.

Sepsis can result from a variety of pathogens, originating from a range of sources. A vast range of presenting symptoms is included in the catch-all term of “bacteremia,” making diagnosis and prognosis particularly troublesome. One underexplored factor contributing to disparate outcomes is the age of the patient. Neonatal sepsis in very-low-birth-weight infants can result in vastly different immunological outcomes unique from sepsis in adults. It is also becoming increasingly clear, both from preclinical experimental models and clinical observations, that the age and history of previous microbial exposures can significantly influence the course of infection from sepsis and cytokine storms to immunopathology. In this study, we will explore key differences between neonatal and adult sepsis, experimental models used to study sepsis, and how responses to the surrounding microbial universe shape development of the immune system and impact, positively or negatively, the course of disease.

RNA editing processes are strikingly different in animals and plants. Up to thousands of specific cytidines are converted into uridines in plant chloroplasts and mitochondria whereas up to millions of adenosines are converted into inosines in animal nucleo-cytosolic RNAs. It is unknown whether these two different RNA editing machineries are mutually incompatible. RNA-binding pentatricopeptide repeat (PPR) proteins are the key factors of plant organelle cytidine-to-uridine RNA editing. The complete absence of PPR mediated editing of cytosolic RNAs might be due to a yet unknown barrier that prevents its activity in the cytosol. Here, we transferred two plant mitochondrial PPR-type editing factors into human cell lines to explore whether they could operate in the nucleo-cytosolic environment. PPR56 and PPR65 not only faithfully edited their native, co-transcribed targets but also different sets of off-targets in the human background transcriptome. More than 900 of such off-targets with editing efficiencies up to 91%, largely explained by known PPR-RNA binding properties, were identified for PPR56. Engineering two crucial amino acid positions in its PPR array led to predictable shifts in target recognition. We conclude that plant PPR editing factors can operate in the entirely different genetic environment of the human nucleo-cytosol and can be intentionally re-engineered towards new targets.

Background The efficacy and safety of complement inhibition in COVID-19 patients is unclear. Methods A multicenter randomized controlled, open-label trial. Hospitalized COVID-19 patients with signs of systemic inflammation and hypoxemia (PaO2/FiO2 below 350 mmHg) were randomized (2:1 ratio) to receive standard of care with or without the C5 inhibitor zilucoplan daily for 14 days, under antibiotic prophylaxis. The primary outcome was improvement in oxygenation at day 6 and 15. Results 81 patients were randomly assigned to zilucoplan (n = 55) or the control group (n = 26). 78 patients were included in the safety and primary analysis. Most were men (87%) and the median age was 63 years. The mean improvement in PaO2/FiO2 from baseline to day 6 was 56.4 mmHg in the zilucoplan group and 20.6 mmHg in the control group (mean difference + 35.8; 95% confidence interval (CI) − 9.4 to 80.9; p = 0.12), an effect also observed at day 15. Day 28 mortality was 9% in the zilucoplan and 21% in the control group (odds ratio 0.4; 95% CI 0.1 to 1.5). At long-term follow up, the distance walked in a 6-min test was 539.7 m in zilucoplan and 490.6 m in the control group (p = 0.18). Zilucoplan lowered serum C5b-9 (p Conclusion Administration of zilucoplan to COVID-19 patients in this proof-of-concept randomized trial was well tolerated under antibiotic prophylaxis. While not reaching statistical significance, indicators of respiratory function (PaO2/FiO2) and clinical outcome (mortality and 6-min walk test) suggest that C5 inhibition might be beneficial, although this requires further research in larger randomized studies.

Background Community-acquired pneumonia (CAP) causes a large burden of disease. Due to difficulties in obtaining representative respiratory samples and insensitive standard microbiological methods, the microbiological aetiology of CAP is difficult to ascertain. With a few exceptions, standard-of-care diagnostics are too slow to influence initial decisions on antimicrobial therapy. The management of CAP is therefore largely based on empirical treatment guidelines. Empiric antimicrobial therapy is often initiated in the primary care setting, affecting diagnostic tests based on conventional bacterial culture in hospitalized patients. Implementing rapid molecular testing may improve both the proportion of positive tests and the time it takes to obtain test results. Both measures are important for initiation of pathogen-targeted antibiotics, involving rapid de-escalation or escalation of treatment, which may improve antimicrobial stewardship and potentially patient outcome. Methods Patients presenting to the emergency department of Haukeland University Hospital (HUH) in Bergen, Norway, will be screened for inclusion into a pragmatic randomised controlled trial (RCT). Eligible patients with a suspicion of CAP will be included and randomised to receive either standard-of-care methods (standard microbiological testing) or standard-of-care methods in addition to testing by the rapid and comprehensive real-time multiplex PCR panel, the BioFire® FilmArray® Pneumonia Panel plus (FAP plus) (bioMérieux S.A., Marcy-l’Etoile, France). The results of the FAP plus will be communicated directly to the treating staff within ~2 h of sampling. Discussion We will examine if rapid use of FAP plus panel in hospitalized patients with suspected CAP can improve both the time to and the proportion of patients receiving pathogen-directed treatment, thereby shortening the exposure to unnecessary antibiotics and the length of hospital admission, compared to the standard-of-care arm. The pragmatic design together with broad inclusion criteria and a straightforward intervention could make our results generalizable to other similar centres. Trial registration ClinicalTrials.govNCT04660084. Registered on December 9, 2020

Question: In people with knee osteoarthritis, how much more effective is stratified exercise therapy that distinguishes three subgroups (high muscle strength subgroup, low muscle strength subgroup, obesity subgroup) in reducing knee pain and improving physical function than usual exercise therapy? Design: Pragmatic cluster randomised controlled trial in a primary care setting. Participants: A total of 335 people with knee osteoarthritis: 153 in an experimental arm and 182 in a control arm. Intervention: Physiotherapy practices were randomised into an experimental arm providing stratified ex-ercise therapy (supplemented by a dietary intervention from a dietician for the obesity subgroup) or a control arm providing usual, non-stratified exercise therapy. Outcome measures: Primary outcomes were knee pain severity (numerical rating scale for pain, 0 to 10) and physical function (Knee Injury and Osteoarthritis Outcome Score subscale activities of daily living, 0 to 100). Measurements were performed at baseline, 3 months (primary endpoint) and 6 and 12 months (follow-up). Intention-to-treat, multilevel, regression analysis was performed. Results: Negligible differences were found between the experimental and control groups in knee pain (mean adjusted difference 0.2, 95% CI -0.4 to 0.7) and physical function (-0.8, 95% CI -4.3 to 2.6) at 3 months. Similar effects between groups were also found for each subgroup separately, as well as at other time points and for nearly all secondary outcome measures. Conclusion: This pragmatic trial demonstrated no added value regarding clinical outcomes of the model of stratified exercise therapy compared with usual exercise therapy. This could be attributed to the experimental arm therapists facing difficulty in effectively applying the model (especially in the obesity subgroup) and to elements of stratified exercise therapy possibly being applied in the control arm. Registration: Netherlands National Trial Register NL7463. [Knoop J, Dekker J, van Dongen JM, van der Leeden M, de Rooij M, Peter WFH, de Joode W, van Bodegom-Vos L, Lopuhaa N, Bennell KL, Lems WF, van der Esch M, Vliet Vlieland TPM, Ostelo RWJG (2022) Stratified exercise therapy does not improve outcomes compared with usual exercise therapy in people with knee osteoarthritis (OCTOPuS study): a cluster randomised trial. Journal of Physiotherapy 68:182-190] (c) 2022 Australian Physiotherapy Association. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BackgroundCurrently, there is limited evidence about the long-term impact on physical, social and emotional functioning, i.e. health-related quality of life (HRQL) after mild or moderate COVID-19 not requiring hospitalization. We compared HRQL among persons with initial mild, moderate or severe/critical COVID-19 at 1 and 12 months following illness onset with Dutch population norms and investigated the impact of restrictive public health control measures on HRQL.MethodsRECoVERED, a prospective cohort study in Amsterdam, the Netherlands, enrolled adult participants after confirmed SARS-CoV-2 diagnosis. HRQL was assessed with the Medical Outcomes Study Short Form 36-item health survey (SF-36). SF-36 scores were converted to standard scores based on an age- and sex-matched representative reference sample of the Dutch population. Differences in HRQL over time were compared among persons with initial mild, moderate or severe/critical COVID-19 using mixed linear models adjusted for potential confounders.ResultsBy December 2021, 349 persons were enrolled of whom 269 completed at least one SF-36 form (77%). One month after illness onset, HRQL was significantly below population norms on all SF-36 domains except general health and bodily pain among persons with mild COVID-19. After 12 months, persons with mild COVID-19 had HRQL within population norms, whereas persons with moderate or severe/critical COVID-19 had HRQL below population norms on more than half of the SF-36 domains. Dutch-origin participants had significantly better HRQL than participants with a migration background. Participants with three or more COVID-19 high-risk comorbidities had worse HRQL than part participants with fewer comorbidities. Participants who completed the SF-36 when restrictive public health control measures applied reported less limitations in social and physical functioning and less impaired mental health than participants who completed the SF-36 when no restrictive measures applied.ConclusionsTwelve months after illness onset, persons with initial mild COVID-19 had HRQL within population norms, whereas persons with initial moderate or severe/critical COVID-19 still had impaired HRQL. Having a migration background and a higher number of COVID-19 high-risk comorbidities were associated with worse HRQL. Interestingly, HRQL was less impaired during periods when restrictive public health control measures were in place compared to periods without.

OBJECTIVE: Fatigue is a common symptom among cancer survivors that can be successfully treated with cognitive-behavioral therapy (CBT). Insights into the working mechanisms of CBT are currently limited. The aim of this study was to investigate whether improvements in targeted cognitive-behavioral variables and reduced depressive symptoms mediate the fatigue-reducing effect of CBT.METHODS: We pooled data from three randomized controlled trials that tested the efficacy of CBT to reduce severe fatigue. In all three trials, fatigue severity (checklist individual strength) decreased significantly following CBT. Assessments were conducted pre-treatment and 6 months later. Classical mediation analysis testing a pre-specified model was conducted and its results compared to those of causal discovery, an explorative data-driven approach testing all possible causal associations and retaining the most likely model.RESULTS: Data from 250 cancer survivors (n=129 CBT, n=121 waitlist) were analyzed. Classical mediation analysis suggests that increased self-efficacy and decreased fatigue catastrophizing, focusing on symptoms, perceived problems with activity and depressive symptoms mediate the reduction of fatigue brought by CBT. Conversely, causal discovery and post-hoc analyses indicate that fatigue acts as mediator, not outcome, of changes in cognitions, sleep disturbance and depressive symptoms.CONCLUSIONS: Cognitions, sleep disturbance and depressive symptoms improve during CBT. When assessed pre- and post-treatment, fatigue acts as a mediator, not outcome, of these improvements. It seems likely that the working mechanism of CBT is not a one-way causal effect but a dynamic reciprocal process. Trials integrating intermittent assessments are needed to shed light on these mechanisms and inform optimization of CBT. This article is protected by copyright. All rights reserved.

Objectives: To analyze prefrailty’s relationship with limitations in activities of daily living (ADLs) and restrictions in social participation. Method: Robust (Fried 0/4; n = 214; Mage = 82.3 years [ SD ±2.1]) and prefrail (Fried 1–2/4; n = 191; Mage = 83.8 years [ SD ±3.2]) community-dwelling older individuals were included. Frailty scores were obtained from weight loss, exhaustion, gait speed, and grip strength. A total disability index (DI) expressed dependency for basic (b-), instrumental (i-), and advanced (a-)ADLs. Total participation score, being a member, total number of memberships, being a board member, level of participation, membership over time, volunteering, and formal participation represented social participation. Results: Logistic regression retained age (OR = 1.224; 95% CI = [1.122, 1.335]), sex (OR = 3.818; 95% CI = [2.437, 5.982]), and a-ADL-DI (OR = 1.230; 95% CI = [1.018, 1.486]) as variables significantly related to prefrailty (68.3%; χ2 = 68.25; df = 3; p < .001). Discussion: Subtle limitations in a-ADLs, higher age, and being a man were associated with prefrailty, revealing the possible role of personal and culturally related a-ADLs as red flags for (pre)frailty.

Background. Bronchoalveolar lavage (BAL) is currently not recommended in noncritically ill patients for the diagnosis of SARS-CoV-2 infection. Indeed, the diagnosis is based on the RT-PCR test on a nasopharyngeal swab (NPS) and abnormal findings on the chest CT scan. However, the sensitivity of the NPS and the specificity of the chest CT scan are low. Results of BAL in case of negative NPS testing are underreported, especially in the subgroup of immunocompromised patients. Objectives. The added value of BAL in the management of unstable, but noncritically ill patients, suspected of having SARS-CoV-2 infection despite one previous negative NPS and the side effects of the procedure for the patients and the health-care providers, were assessed during the epidemic peak of the COVID-19 outbreak in Belgium. Methods. This multicentric study included all consecutive noncritically ill patients hospitalized with a clinical and radiological suspicion of SARS-CoV-2 infection but with a negative NPS. BAL was performed according to a predefined decisional algorithm based on their state of immunocompetence, the chest CT scan features, and their respiratory status. Results. Among the 55 patients included in the study, 14 patients were diagnosed with a SARS-CoV-2 infection. Interestingly, there was a relationship between the cycle threshold of the RT-PCR and the interval of time between the symptom onset and the BAL procedure (Pearson's correlation coefficient=0.8, p=0.0004). Therapeutic management was changed in 33 patients because another infectious agent was identified in 23 patients or because an alternative diagnosis was made in 10 patients. In immunocompromised patients, the impact of BAL was even more marked (change in therapy for 13/17 patients). No significant adverse event was noted for patients or health-care staff. All health-care workers remained negative for SARS-CoV-2 NPS and serology at the end of the study. Conclusions. In this real-life study, BAL can be performed safely in selected noncritically ill patients suspected of SARS-CoV-2 infection, providing significant clinical benefits that outweigh the risks., SCOPUS: ar.j, info:eu-repo/semantics/published

Postural Orthostatic Tachycardia Syndrome (POTS) is a chronic health condition affecting mostly women of childbearing age, and significantly impacting their health and quality of life. It is currently poorly understood with no approved licensed treatments. The aim of this systematic review was to contextualize the symptom burden of POTS, and review factors associated with this burden that may guide future treatments. The specific questions were (1) How does symptom burden in POTS compare to the burden in other long term conditions (LTCs), (2) Which factors are associated with POTS symptom burden, and (3) Which interventions show promise in reducing symptom burden in POTS.Electronic databases (CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, Web of Science, APA PsycArticles, OpenGrey) were searched from inception to January 2022 for observational studies reporting on the association between any biological, psychological or social factors and symptom burden, and randomized controlled trials reporting on interventions for symptom burden in adults with POTS. Two reviewers independently conducted eligibility screening, data extraction and quality assessment. A narrative synthesis was undertaken.5159 entries were screened for eligibility. Twenty-nine studies were included (1372 participants with POTS of a total sample size of 2314, 17 High-, 12 Medium-quality), seventeen were observational and twelve were randomized controlled experimental and intervention trials. Overall methodological quality of the evidence was medium-high but heterogeneity was high and sample sizes modest, allowing moderately robust conclusions. Orthostatic symptom burden was higher in POTS than other LTCs. Serum activity against adrenergic α1 receptors, physical functioning, depression, catastrophizing, prolonged cognitive stress testing and anxiety were significantly associated with symptom burden in medium-high quality studies. Preliminary medium-high quality evidence from predominantly proof-of-concept (n = 11) studies and one 3-month 2 × 2 factorial design trial suggest that compression garments, propranolol, pyridostigmine, desmopressin, and bisoprolol may hold promise in reducing symptom burden. Directions for future research include investigating associated factors over time, the development of complex interventions which address both biological and psychosocial factors associated with symptom burden, and effectiveness trials of these interventions.POTS symptom burden is high, particularly in relation to orthostatic intolerance when compared to other long-term conditions (LTCs). Despite this burden, there are no effectiveness randomized controlled trials of treatment to reduce symptoms in POTS. This review provides a starting point to understanding researched biological and psychosocial factors associated with this burden. There was however inconsistency in the measurement of symptom burden, lowering the confidence of cross-study inferences. A coherent definition of POTS symptom range, severity and impact along with a validated and reliable POTS-specific instrument is currently lacking. A standardized questionnaire to assess POTS symptom burden as a core outcome measure will help clarify future research and clinical practice.

Objectives Existing research on the perspectives of patients with cancer and health care professionals indicates that patient decision making on cancer clinical trial participation is a complex process and may be poorly understood, possibly compromising their decision to participate. This systematic review investigates interventions that support patients in their decision-making processes regarding whether to participate or not and assesses the qualities of the interventions, measures used and related outcomes. Methods Six databases were systematically searched and only studies evaluating interventions that support the decision making of adult patients offered to enter a cancer clinical trial were included. Ten articles met the criteria and were analysed using a narrative synthesis approach. Results The research focus of the included studies reflected the multifactorial nature of what constitutes support for patient decision making in terms of entering a cancer clinical trial. However, most interventions were based on the hypothesis that more information leads to support in decision making, and did not take other factors, such as the relationship to the clinical staff or relatives, the patients’ strong hope for therapeutic benefit or other existential needs into account. The interventions were primarily based on a specific tool, executed once, which seems to imply that decisions need only to be supported once and not at several time points throughout the decision process, and did not assess the importance of a patient’s family- or social relations. Moreover, few interventions focused on the patients’ counselling experience or assessed patient preferences in relation to decision making. Conclusions The findings demonstrate a lack of research on interventions to support patients’ decision making that takes other factors, apart from improving knowledge of trials, into account. Limited evidence exists on the effectiveness of decision support interventions to improve the experience of support in adult patients with cancer. Interventions that take patient preferences in relation to decision making and the social context of decision processes into account need to be developed and assessed.

Bronchiolitis obliterans; Clinical research; Lung transplantation Bronquiolitis obliterante; Investigación clínica; Trasplante de pulmón Bronquiolitis obliterant; Recerca clínica; Trasplantament de pulmó Long-term survival after lung transplantation is limited by chronic allograft dysfunction. The aim of this study was to investigate the effect of locally augmented immunosuppression with liposomal cyclosporine A for inhalation (L-CsA-i) for the prevention of bronchiolitis obliterans syndrome (BOS). In a randomized, double-blind, placebo-controlled, multi-center Phase 3 study, 180 LT recipients in BOS grade 0 were planned to receive L-CsA-i or placebo in addition to triple-drug immunosuppression. L-CsA-i was administered twice daily via an Investigational eFlow nebulizer to recipients of single (SLT) and bilateral lung transplants (BLT) within 6–32 weeks posttransplant, and continued for 2 years. The primary endpoint was BOS-free survival. 130 patients were enrolled before the study was prematurely terminated for business reasons. Despite a 2-year actuarial difference in BOS-free survival of 14.1% in favor of L-CsA-i in the overall study population, the primary endpoint was not met (p = .243). The pre-defined per protocol analysis of SLT recipients (n = 24) resulted in a treatment difference of 58.2% (p = .053). No difference was observed in the BLT (n = 48) subpopulation (p = .973). L-CsA-i inhalation was well tolerated. Although this study failed to meet its primary endpoint, the results warrant additional investigation of L-CsA-i in lung transplant recipients. The study was funded by PARI Pharma GmbH. Open access funding enabled and organized by ProjektDEAL.

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.

Background and Study Aims Recurrent laryngeal nerve palsy (RLNP) is a potential complication of anterior discectomy and fusion (ACDF). There still is substantial disagreement on the actual prevalence of RLNP after ACDF as well as on risk factors for postoperative RLNP. The aim of this study was to describe the prevalence of postoperative RLNP in a cohort of consecutive cases of ACDF and to examine potential risk factors. Materials and Methods This retrospective study included patients who underwent ACDF between 2005 and 2019 at a single neurosurgical center. As part of clinical routine, RLNP was examined prior to and after surgery by independent otorhinolaryngologists using endoscopic laryngoscopy. As potential risk factors for postoperative RLNP, we examined patient's age, sex, body mass index, multilevel surgery, and the duration of surgery. Results 214 consecutive cases were included. The prevalence of preoperative RLNP was 1.4% (3/214) and the prevalence of postoperative RLNP was 9% (19/211). The number of operated levels was 1 in 73.5% (155/211), 2 in 24.2% (51/211), and 3 or more in 2.4% (5/211) of cases. Of all cases, 4.7% (10/211) were repeat surgeries. There was no difference in the prevalence of RLNP between the primary surgery group (9.0%, 18/183) versus the repeat surgery group (10.0%, 1/10; p = 0.91). Also, there was no difference in any characteristics between subjects with postoperative RLNP compared with those without postoperative RLNP. We found no association between postoperative RLNP and patient’s age, sex, body mass index, duration of surgery, or number of levels (odds ratios between 0.24 and 1.05; p values between 0.20 and 0.97). Conclusions In our cohort, the prevalence of postoperative RLNP after ACDF was 9.0%. The fact that none of the examined variables was associated with the occurrence of RLNP supports the view that postoperative RLNP may depend more on direct mechanical manipulation during surgery than on specific patient or surgical characteristics.

Estrogen receptor positive (ER+) breast cancer constitutes almost 85% of all breast cancer patients and are a genetically highly heterogenic group. Data on the association of somatic alterations to outcome and prognosis are however sparse. In this neoadjuvant endocrine phase II trial including postmenopausal breast cancer patients with ER+, HER2 normal breast cancer, we investigated the rate of pathogenic mutations before and after treatment as well as the association with treatment response and survival. Pretreatment and posttreatment tumour samples from 109 patients treated with neoadjuvant letrozole were collected and analysed with Next Generation Sequencing utilizing a panel of 12 genes (ALK, BRAF, EGFR, ERBB2, ERBB3, ESR1, KIT, KRAS, NRAS, PDGFRA, PIK3CA, and RAF1). Residual disease was assessed by a modified Miller Payne scale and the Residual Cancer Burden index. Survival data were collected prospectively. Among the 109 patients, 52 had at least one pathogenic mutation in the pretreatment sample and 60 in the posttreatment sample. The most frequently mutated gene was PIK3CA, followed by EGFR and KRAS. Twelve different pathogenic PIK3CA mutations were identified, primarily in exon 20 and exon 9. An altered PIK3CA mutation profile from the pre- to the posttreatment specimen was significantly associated to improved pathological outcome. Overall and Disease-Free Survival benefits in PIK3CA mutated patients was observed. Considerable heterogeneity was identified both among patients and between pre- and posttreatment samples. PIK3CA has the potential to be a predictive biomarker. To further assess the implications of a treatment related altered PIK3CA mutation profile, more data are needed.

The aim of the present study was to describe histopathologic characteristics of synchronous bilateral breast cancer (SBBC), and by comparing SBBC to unilateral breast cancer (UBC), identify possible etiological mechanisms of SBBC. Patients with primary SBBC (diagnosed within 4 months) and UBC diagnosed in Denmark between 1999 and 2015 were included. Detailed data on histopathology were retrieved from the Danish Breast Cancer Group database and the Danish Pathology Register. Associations between bilateral disease and the different histopathologic characteristics were evaluated by odds ratios and estimated by multinomial regression models. 1214 patients with SBBC and 59,221 with UBC were included. Patients with SBBC more often had invasive lobular carcinomas (OR 1.29; 95% CI 1.13–1.47), a clinically distinct subtype of breast cancer, than UBC patients. Further, they were older than UBC patients, more often had multifocal cancer (OR 1.13; 95% CI 1.01–1.26), and a less aggressive subtype than UBC patients. Invasive lobular carcinoma was associated with having multiple tumors in breast tissue—both in the form of bilateral disease and multifocal disease, and this association was independent of laterality. No similar pattern was observed for other tumor characteristics. We identified two etiological mechanisms that could explain some of the occurrence of SBBC. The high proportion of less aggressive carcinomas and higher age of SBBC compared to UBC patients suggests that many are diagnosed at a subclinical stage as slow-growing tumors have a higher probability of simultaneous diagnosis. The high proportion of invasive lobular carcinoma observed in bilateral and multifocal disease, being independent of laterality, suggests that these patients have an increased propensity to malignant tumor formation in breast tissue.

The aim of this study was to investigate whether there is an impact of donation rates on the quality of lungs used for transplantation and whether donor lung quality affects post-transplant outcome in the current Lung Allocation Score era. All consecutive adult LTx performed in Eurotransplant (ET) between January 2012 and December 2016 were included (N = 3053). Donors used for LTx in countries with high donation rate were younger (42% vs. 33% ≤45 years, P, SCOPUS: ar.j, info:eu-repo/semantics/published

Patient-generated health data (PGHD), or health-related data gathered from patients to help address a health concern, are used increasingly in oncology to make regulatory decisions and evaluate quality of care. PGHD include self-reported health and treatment histories, patient-reported outcomes (PROs), and biometric sensor data. Advances in wireless technology, smartphones, and the Internet of Things have facilitated new ways to collect PGHD during clinic visits and in daily life. The goal of the current review was to provide an overview of the current clinical, regulatory, technological, and analytic landscape as it relates to PGHD in oncology research and care. The review begins with a rationale for PGHD as described by the US Food and Drug Administration, the Institute of Medicine, and other regulatory and scientific organizations. The evidence base for clinic-based and remote symptom monitoring using PGHD is described, with an emphasis on PROs. An overview is presented of current approaches to digital phenotyping or device-based, real-time assessment of biometric, behavioral, self-report, and performance data. Analytic opportunities regarding PGHD are envisioned in the context of big data and artificial intelligence in medicine. Finally, challenges and solutions for the integration of PGHD into clinical care are presented. The challenges include electronic medical record integration of PROs and biometric data, analysis of large and complex biometric data sets, and potential clinic workflow redesign. In addition, there is currently more limited evidence for the use of biometric data relative to PROs. Despite these challenges, the potential benefits of PGHD make them increasingly likely to be integrated into oncology research and clinical care.

Purpose Due to distinct immuno- and neuro-modulatory properties, growing research interest focuses on exercise-induced alterations of the kynurenine (KYN) pathway in healthy and clinical populations. To date, knowledge about the impact of different acute strength exercise modalities on the KYN pathway is scarce. Therefore, we investigated the acute effects of hypertrophic (HYP) compared to maximal (MAX) strength loadings on the KYN pathway regulation. Methods Blood samples of twelve healthy males (mean age and weight: 23.5 ± 3.2 years; 77.5 ± 7.5 kg) were collected before (T0), immediately after (T1), and 1 h after completion (T2) of HYP (5 sets with 10 repetitions at 80% of 1RM) and MAX (15 sets with 1RM) loadings performed in a randomized cross-over design. Serum concentrations of tryptophan (TRP), KYN, kynurenic acid (KA), and quinolinic acid (QA) were assessed using high-performance liquid chromatography. Results The KA/KYN ratio increased from T0 to T1 (p = 0.01) and decreased from T1 to T2 (p = 0.011) in HYP, while it was maintained within MAX. Compared to MAX, serum concentrations of KA were greater in HYP at T1 (p = 0.014). Moreover, the QA/KA ratio was significantly lower in HYP than in MAX at T1 (p = 0.002). Conclusion Acute HYP loading led to increases in the metabolic flux yielding KA, thereby possibly promoting immunosuppression and neuroprotection. Our findings emphasize the potential of acute HYP exercise as short-term modulator of KYN pathway downstream to KA in healthy males and need to be proven in other samples., Eur J Appl Physiol;120

The urgent need for, but limited availability of, SARS-CoV-2 vaccines worldwide has led to widespread consideration of dose sparing strategies. Here, we evaluate the SARS-CoV-2 specific antibody responses following BNT162b2 vaccination in 150 previously SARS-CoV-2-infected individuals from a population-based cohort. One week after first vaccine dose, spike protein antibody levels are 27-fold higher and neutralizing antibody titers 12-fold higher, exceeding titers of fully vaccinated SARS-CoV-2-naive controls, with minimal additional boosting after the second dose. Neutralizing antibody titers against four variants of concern increase after vaccination, however overall neutralization breadth does not improve. Pre-vaccination neutralizing antibody titers and time since infection have the largest positive effect on titers following vaccination. COVID-19 severity and the presence of comorbidities have no discernible impact on vaccine response. In conclusion, a single dose of BNT162b2 vaccine up to 15 months after SARS-CoV-2 infection offers higher neutralizing antibody titers than two vaccine doses in SARS-CoV-2-naive individuals., Graphical Abstract, In a prospective cohort study, van Gils et al find that a single dose of BNT162b2 mRNA vaccine up to 15 months after SARS-CoV-2 infection provides neutralizing titers exceeding two vaccine doses in SARS-CoV-2-naive individuals. This supports wide implementation of a single-dose mRNA vaccine strategy after prior SARS-CoV-2 infection.

In contrast to guideline recommendations, endoscopic testing forThe trial was conducted in a large patient collective in a university hospital. Every elective esophagogastroduodenoscopy from in- and outpatients was included. Prior to endoscopy, suppressive conditions were collected via standardized questionnaire. If1,216 patients were included (median 59 years, 72.0% inpatients, 28.0% outpatients). Overall, 60.6% (737) were underMany patients undergoing esophagogastroduodenoscopy in everyday clinical practice are tested for

IntroductionA substantial proportion of individuals infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), report persisting symptoms weeks and months following acute infection. Estimates on prevalence vary due to differences in study designs, populations, heterogeneity of symptoms and the way symptoms are measured. Common symptoms include fatigue, cognitive impairment and dyspnoea. However, knowledge regarding the nature and risk factors for developing persisting symptoms is still limited. Hence, in this study, we aim to determine the prevalence, severity, risk factors and impact on quality of life of persisting symptoms in the first year following acute SARS-CoV-2 infection.Methods and analysisThe LongCOVID-study is both a prospective and retrospective cohort study being conducted in the Netherlands, with a one year follow-up. Participants aged 5 years and above, with self-reported positive or negative tests for SARS-CoV-2 will be included in the study. The primary outcome is the prevalence and severity of persistent symptoms in participants that tested positive for SARS-CoV-2 compared with controls. Symptom severity will be assessed for fatigue (Checklist Individual Strength (CIS subscale fatigue severity)), pain (Rand-36/SF-36 subscale bodily pain), dyspnoea (Medical Research Council (mMRC)) and cognitive impairment (Cognitive Failure Questionnaire (CFQ)). Secondary outcomes include effect of vaccination prior to infection on persistent symptoms, loss of health-related quality of life (HRQoL) and risk factors for persisting symptoms following infection with SARS-CoV-2.Ethics and disseminationThe Utrecht Medical Ethics Committee (METC) declared in February 2021 that the Medical Research Involving Human Subjects Act (WMO) does not apply to this study (METC protocol number 21-124/C). Informed consent is required prior to participation in the study. Results of this study will be submitted for publication in a peer-reviewed journal.

Lack of rapid and comprehensive microbiological diagnosis in patients with community acquired pneumonia (CAP) hampers appropriate antimicrobial therapy. This study evaluates the real-world performance of the BioFire FilmArray Pneumonia panel plus (FAP plus) and explores the feasibility of evaluation in a randomised controlled trial. Patients presenting to hospital with suspected CAP were recruited in a prospective feasibility study. An induced sputum or an endotracheal aspirate was obtained from all participants. The FAP plus turnaround time (TAT) and microbiological yield were compared with standard diagnostic methods (SDs). 96/104 (92%) enrolled patients had a respiratory tract infection (RTI); 72 CAP and 24 other RTIs. Median TAT was shorter for the FAP plus, compared with in-house PCR (2.6 vs 24.1 h, p plus was higher compared to SDs (91% (162/179) vs 55% (99/179), p Haemophilus influenzae, Streptococcus pneumoniae and influenza A virus were the most frequent pathogens. In conclusion, molecular panel testing in adults with CAP was associated with a significant reduction in time to actionable results and increased microbiological yield. The impact on antibiotic use and patient outcome should be assessed in randomised controlled trials.

Tumor infiltrating lymphocytes (TILs) have predictive and prognostic potential in HER2-positive breast cancer (HER2 + BC). Due to tumor heterogeneity, guidelines recommend evaluation on full tumor-sections over biopsies, but aren't clear regarding tissue microarrays (TMAs). Herein, we investigate the inter-observer agreement of TILs assessment in HER2 + BC on full-sections and TMAs using a standardized method. Two pathologists assessed TILs using HE full-sections and TMAs from 244 patients with HER2 + BC. TILs were assessed in 10% intervals; values

Background: Respiratory tract infections (RTIs) caused by contagious viruses are common among patients presenting to the emergency department (ED). Early detection of these viruses can help prevent nosocomial transmission.Aim: To investigate the efficacy of three rapid molecular methods, namely FilmArray® Pneumonia Panel plus (FAP plus), ID NOW™ Influenza A and B 2 (ID NOW2) point-of-care test, and an in-house real-time polymerase chain reaction (RT-PCR) test, to identify patients with viral RTIs requiring isolation in an emergency setting.Methods: We included a FilmArray® Pneumonia Panel plus in the initial workup of patients with suspected RTIs during a flu season. The RT-PCR and the influenza point-of-care test were performed as part of routine diagnostics, on demand from the treating physicians. We compared viral detections and compared time to positive test results for each method.Findings: The FAP plus significantly reduced the turnaround time and was able to identify 95% patients with potential contagious viral RTI. Routine diagnostics ordered by the treating physician had a turnaround time of a median 22 h and detected 87% of patients with potential contagious viral RTI. In patients that had all three tests, the ID NOW2 detected 62% of patients with influenza.Conclusions: The FAP plus was able to rapidly and reliably identify patients with potential contagious viral RTIs; its use was feasible in the ED setting. Failing to test patients with viral RTI and using tests with long turnaround time may lead to nosocomial transmission of viral infections and adverse patient outcomes.

Hip and knee osteoarthritis (OA) are leading causes of global disability. Most research to date has focused on the knee, with results often extrapolated to the hip, and this extends to treatment recommendations in clinical guidelines. Extrapolating results from research on knee OA may limit our understanding of disease characteristics specific to hip OA, thereby constraining development and implementation of effective treatments. This review highlights differences between hip and knee OA with respect to prevalence, prognosis, epigenetics, pathophysiology, anatomical and biomechanical factors, clinical presentation, pain and non-surgical treatment recommendations and management. (c) 2021 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Background The COVID-19 pandemic was met with strict containment measures. We hypothesized that societal infection control measures would impact the number of hospital admissions for respiratory tract infections, as well as, the spectrum of pathogens detected in patients with suspected community acquired pneumonia (CAP). Methods This study is based on aggregated surveillance data from electronic health records of patients admitted to the hospitals in Bergen Hospital Trust from January 2017 through June 2021, as well as, two prospective studies of patients with suspected CAP conducted prior to and during the COVID-19 pandemic (pre-COVID cohort versus COVID cohort, respectively). In the prospective cohorts, microbiological detections were ascertained by comprehensive PCR-testing in lower respiratory tract specimens. Mann–Whitney’s U test was used to analyse continuous variables. Fisher’s exact test was used for analysing categorical data. The number of admissions before and during the outbreak of SARS-CoV-2 was compared using two-sample t-tests on logarithmic transformed values. Results Admissions for respiratory tract infections declined after the outbreak of SARS-CoV-2 (p Haemophilus influenzae was the most frequent bacterial detection in both cohorts, followed by Streptococcus pneumoniae in the pre-COVID and Staphylococcus aureus in the COVID cohort. Conclusion During the first year of the COVID-19 pandemic, the number of admissions with pneumonia and the microbiological detections in patients with suspected CAP, differed from the preceding year. This suggests that infection control measures related to COVID-19 restrictions have an overall and specific impact on respiratory tract infections, beyond reducing the spread of SARS-CoV-2.