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Background: 5-Fluorouracil (5-FU) is a cornerstone in treatment of colorectal cancer (CRC) and is usually combined with leucovorin (LV) to enhance the antitumour effect by increase thymidylate synthase (TS) inhibition, the key target enzyme for 5-FU. Arfolitixorin (Arfo) is an active form of the reduced folate, [6 R]-5,10-methylenetetrahydrofolate ([6 R]-MeTHF and in contrast to LV, does not need to be metabolized. The Modelle-001 was designed to explore whether a single intravenous bolus injection of Arfo as compared to LV, together with 5-FU increases the inhibition of TS, levels of folate concentrations and polyglutamylation in CRC liver metastases (CRLM) and liver parenchyma., Patients and Methods: Thirty patients with CRLM received either LV (60 mg/m 2 ) or Arfo (30 mg/m 2 or 120 mg/m 2 ) in combination with 5-FU preoperatively. Levels of folates and and TS inhibition were measured., Results: Significantly higher MeTHF levels and higher TS inhibition were measured in the Arfo groups compared to LV60, and there was a difference in folate poly-glutamylation between the groups., Conclusion: The Modelle-001 Trial demonstrated significantly higher levels of MeTHF in metastases following Arfo compared to LV. This resulted in a greater increase TS inhibition in metastases although not statistically significant., Competing Interests: Competing interests: The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: E. Odin, G. Carlsson, B. Gustavsson, and Y. Wettergren are registered inventors of patents held by Isofol Medical AB. Y. Wettergren, G. Carlsson and G. Peters have previously received honoraria for advisory board role. B Gustavsson is the founder of Isofol, and E. Odin and B. Gustavsson are shareholders. HT is a member of the Isofol Board. Ethical approval: The study was conducted according to the guidelines set forth in the Declaration of Helsinki and was approved by the Swedish Ethical Review Authority (2019-00962). Written informed consent was obtained from all included participants., (© 2024. The Author(s).)

Semen traces are considered important pieces of evidence in forensic investigations, especially those involving sexsual offenses. Recently, our research group developed a fluorescence-based technique to accurately determine the age of semen traces. However, the specific compounds resonsible for the fluoresescent behaviour of ageing semens remain unknown. As such, in this exploratory study, the aim is to identify the components associated with the fluorescent behavior of ageing semen traces. In this investigation semen stains and various biofluorophores commonly found in body fluids were left to aged for 0, 2, 4, 7, 14 and 21 days. Subsequently, thin-layer chromatography (TLC) and ultra-performance liquid chromatography (UPLC) mass spectrometry were performed to identify the biofluorophores present in semen. Several contributors to the autofluorescence could be identified in semen stain, these include tryptophan, kynurenine, kynurenic acid, and norharman. The study sheds light on the., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Isatin derivatives have attracted a lot of interest for their potential in the development of new anticancer drugs. A library of 38 isatin derivatives, created through an Ugi four-component reaction, underwent an initial screening in a panel of six human solid tumor cell lines. The four most active derivatives were then selected for further testing. These compounds showed selectivity towards the non-small cell lung cancer (NSCLC) cell line SW1573, whilst NSCLC A549 cells were barely affected. The combination of phenotypic assays, including wound healing, clonogenic and continuous live cell imaging provided a deeper understanding of the compounds' mode of action. In particular, the latter demonstrated that isatin derivatives were able to induce necroptosis in SW1573 cells. The kinetics of cell death showed that necroptosis appeared after 2.5 h of exposure, which could be delayed to 7 h when co-treated with necrostatin-1. Interaction between the isatin derivatives and the KRAS G12C protein variant was discarded after in silico studies. Further studies are warranted to identify the cellular target responsible for the observed selectivity among cell lines., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To investigate whether and how a single traumatic impact changes the mechanical properties of talar articular cartilage., Design: A marble was placed on the joint surface and a weight was dropped on both medial and lateral caprine talus to create a well-defined single focal impact. The mechanical properties of intact and impacted talar cartilage were measured with a micro-indenter. Elastic (storage) and viscous (loss) moduli were determined by oscillatory ramp and dynamic mechanical analysis protocols., Results: We found significant differences between ankles and within the same ankle joint, with the medial talus having significantly higher storage- and loss moduli than the lateral talus. The storage- and loss moduli of intact articular cartilage increased with greater indentation depths. However, postimpact the storage- and loss moduli were significantly and consistently lower in all specimens indicating immediate posttraumatic damage. The deeper regions of talar cartilage were less affected by the impact than the more superficial regions., Conclusions: A single traumatic impact results in an immediate and significant decrease of storage- and loss moduli. Further research must focus on the development of non- or minimally invasive diagnostic tools to address the exact microdamage caused by the impact. We speculate that the traumatic impact damaged the collagen fibers that confine the water-binding proteoglycans and thereby decreasing the hydrostatic pressure of cartilage. As part of the treatment directly after a trauma, one could imagine a reduction or restriction of peak loads to prevent the progression of the cascade towards PTOA of the ankle joint., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Sepsis remains a major cause of morbidity and mortality in both low- and high-income countries. Antibiotic therapy and supportive care have significantly improved survival following sepsis in the twentieth century, but further progress has been challenging. Immunotherapy trials for sepsis, mainly aimed at suppressing the immune response, from the 1990s and 2000s, have largely failed, in part owing to unresolved patient heterogeneity in the underlying immune disbalance. The past decade has brought the promise to break this blockade through technological developments based on omics-based technologies and systems medicine that can provide a much larger data space to describe in greater detail the immune endotypes in sepsis. Patient stratification opens new avenues towards precision medicine approaches that aim to apply immunotherapies to sepsis, on the basis of precise biomarkers and molecular mechanisms defining specific immune endotypes. This approach has the potential to lead to the establishment of immunotherapy as a successful pillar in the treatment of sepsis for future generations., (© 2024. Springer Nature America, Inc.)

Motivation: In many high-dimensional prediction or classification tasks, complementary data on the features are available, e.g. prior biological knowledge on (epi)genetic markers. Here we consider tasks with numerical prior information that provide an insight into the importance (weight) and the direction (sign) of the feature effects, e.g. regression coefficients from previous studies., Results: We propose an approach for integrating multiple sources of such prior information into penalized regression. If suitable co-data are available, this improves the predictive performance, as shown by simulation and application., Availability and Implementation: The proposed method is implemented in the R package transreg (https://github.com/lcsb-bds/transreg, https://cran.r-project.org/package=transreg)., (© The Author(s) 2023. Published by Oxford University Press.)

Key unmet needs in multiple sclerosis (MS) include detection of early pathology, disability worsening independent of relapses, and accurate monitoring of treatment response. Collaborative approaches to address these unmet needs have been driven in part by industry-academic networks and initiatives such as the Grant for Multiple Sclerosis Innovation (GMSI) and Multiple Sclerosis Leadership and Innovation Network (MS-LINK ™ ) programs. We review the application of recent advances, supported by the GMSI and MS-LINK ™ programs, in neuroimaging technology to quantify pathology related to central pathology and disease worsening, and potential for their translation into clinical practice/trials. GMSI-supported advances in neuroimaging methods and biomarkers include developments in magnetic resonance imaging, positron emission tomography, ocular imaging, and machine learning. However, longitudinal studies are required to facilitate translation of these measures to the clinic and to justify their inclusion as endpoints in clinical trials of new therapeutics for MS. Novel neuroimaging measures and other biomarkers, combined with artificial intelligence, may enable accurate prediction and monitoring of MS worsening in the clinic, and may also be used as endpoints in clinical trials of new therapies for MS targeting relapse-independent disease pathology., Competing Interests: JO has received research funding from Biogen, Brain Canada, EMD Inc., Mississauga, Ontario, Canada, an affiliate of Merck KGaA, the MS Society of Canada, the National Institutes of Health, the National MS Society, and Roche; and has received personal compensation for consulting/speaking from Biogen, Bristol Myers Squibb, EMD Inc., Mississauga, Ontario, Canada, an affiliate of Merck KGaA, Eli Lilly, Novartis, Roche, and Sanofi. LA has received institutional research support from Genzyme, Merck, and Novartis; and personal compensation for lectures/advising from Biogen, Janssen, Merck, Novartis, Roche, and Sanofi. DH has received research funding from EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA and Roche Genentech; has received consulting honoraria from Horizon Therapeutics; and has received authorship fees/royalties from American College of Physicians and Up To Date, Inc. EJ is an employee of Merck OY, Espoo, Finland, an affiliate of Merck KGaA. TL is an employee of EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany. SL is a former employee of EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, and is currently an employee of Keros Therapeutics, Inc., Lexington, MA, USA. RM has received institutional research support from Hamad Medical Corporation and Qatar National Research Fund and personal compensation for lectures/advising from Eli Lilly, Novo Nordisk, Proctor & Gamble, and Sanofi. DO has received personal compensation for consulting/advisory services from Alexion, Biogen, Celgene/Bristol Myers Squibb, EMD Serono Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Genentech, Genzyme, Janssen, Novartis, Osmotica Pharmaceuticals, RVL Pharmaceuticals, Inc., TG Therapeutics, and Viela Bio, Inc.; has received research support from Biogen and EMD Serono Inc., Rockland, MA, USA, an affiliate of Merck KGaA; has issued national and international patents along with pending patents related to this current work and other developed technologies; and has received royalties for intellectual property licensed by The Board of Regents of The University of Texas System. PV holds stocks and has received consultancy fees from Accure Therapeutics, Attune Neurosciences, CLight, NeuroPrex, QMENTA, and Spiral Therapeutics. HV has received research funding/speaker fees from Merck. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Oh, Airas, Harrison, Järvinen, Livingston, Lanker, Malik, Okuda, Villoslada and de Vries.)

Background: Severe chronic kidney disease (CKD) in children and young adults has shown to be associated with abnormal brain development, which may contribute to neurocognitive impairments. We aimed to investigate risk factors for neurocognitive impairment and investigate the relation with structural brain abnormalities in young severe CKD patients., Methods: This cross-sectional study includes 28 patients with severe CKD (eGFR < 30), aged 8-30 years (median 18.5 years), on different treatment modalities (pre-dialysis [n = 8], dialysis [n = 8], transplanted [n = 12]). We assessed neurocognitive functioning using a comprehensive test battery and brain structure by magnetic resonance imaging metrics of brain volume and white matter integrity (fractional anisotropy [FA] and mean diffusivity [MD] measured with diffusion tensor imaging). Multivariate regression and mediation analyses were performed between clinical CKD parameters, brain structure, and neurocognitive outcome., Results: A combination of risk factors (e.g., longer time since kidney transplantation, longer dialysis duration and late CKD onset) was significantly associated with lower intelligence and/or worse processing speed and working memory. Lower FA in a cluster of white matter tracts was associated with lower intelligence and mediated the relation between clinical risk factors and lower intelligence., Conclusions: Young severe CKD patients with a prolonged duration of kidney replacement therapy, either dialysis or transplantation are at particular risk for impairments in intelligence, processing speed, and working memory. Disrupted white matter integrity may importantly contribute to these neurocognitive impairments. Prospective, longitudinal studies are needed to elucidate the mechanisms involved in CKD and treatment that affect white matter integrity and neurocognitive outcome in young patients. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s).)

Background: Late and moderate preterm (LMPT) infants are at risk for adverse later life outcomes. We determined the association between feeding method at enrolment and growth and body composition of LMPT infants until 3 months corrected age (3mCA)., Methods: Infants born between 32 +0 and 36 +6 weeks of gestation (n = 107) were enrolled up to 4 weeks corrected age and stratified according to feeding at enrolment. We performed anthropometric measurements at enrolment, term equivalent age (TEA) and 3mCA, including skinfold measurements and body composition using dual X-ray absorptiometry (DEXA)., Results: Feeding method at enrolment was associated with fat mass (FM) (breast 554.9 g, mixed 716.8 g, formula 637.7 g, p = 0.048), lean body mass (LM) (2512 g, 2853 g, 2722 g, respectively, p = 0.009) and lean mass index (LMI) (10.6 kg/m 2 , 11.6 kg/m 2 ,11.2 kg/m 2 respectively, p = 0.008) at TEA, but not 3mCA. Breastfed infants demonstrated greater increase in LM (breast 1707 g, mixed 1536 g, formula 1384 g, p = 0.03) and LMI (1.23 kg/m 2 , 0.10 kg/m 2 , 0.52 kg/m 2 , respectively, p = 0.022) between TEA and 3mCA., Conclusions: Breastfed LMPT infants have lower FM and greater LM increase and LMI increase up to 3mCA compared to formula or mixed-fed infants. These findings stress the importance of supporting breastfeeding in this population., Impact: Infants born late and moderate preterm age who are exclusively breastfed soon after birth gain more lean mass up to 3 months corrected age compared to mixed- or formula-fed infants. Breastfed infants have lower lean and fat mass at term equivalent age compared to mixed- and formula-fed infants. This is the first study exploring this population's growth and body composition in detail at 3 months corrected age. Our results underline the importance of supporting mothers to initiate and continue breastfeeding at least until 3 months corrected age., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: An imbalance of adipokines, hormones secreted by white adipose tissue, is suggested to play a role in the immunopathology of multiple sclerosis (MS). In people with MS (PwMS) of the same age, we aimed to determine whether the adipokines adiponectin, leptin, and resistin are associated with MS disease severity. Furthermore, we aimed to investigate whether these adipokines mediate the association between body mass index (BMI) and MS disease severity., Methods: Adiponectin, resistin, and leptin were determined in serum using ELISA. 288 PwMS and 125 healthy controls (HC) were included from the Project Y cohort, a population-based cross-sectional study of people with MS born in the Netherlands in 1966, and age and sex-matched HC. Adipokine levels and BMI were related to demographic, clinical and disability measures, and MRI-based brain volumes., Results: Adiponectin levels were 1.2 fold higher in PwMS vs. HC, especially in secondary progressive MS. Furthermore, we found a sex-specific increase in adiponectin levels in primary progressive (PP) male patients compared to male controls. Leptin and resistin levels did not differ between PwMS and HC, however, leptin levels were associated with higher disability (EDSS) and resistin strongly related to brain volumes in progressive patients, especially in several grey matter regions in PPMS. Importantly, correction for BMI did not significantly change the results., Conclusion: In PwMS of the same age, we found associations between adipokines (adiponectin, leptin, and resistin) and a range of clinical and radiological metrics. These associations were independent of BMI, indicating distinct mechanisms., (© 2022. The Author(s).)

Objectives: To investigate neurocognitive, psychosocial, and quality of life (QoL) outcomes in children with Multisystem Inflammatory Syndrome in Children (MIS-C) seen 3-6 months after PICU admission., Design: National prospective cohort study March 2020 to November 2021., Setting: Seven PICUs in the Netherlands., Patients: Children with MIS-C (0-17 yr) admitted to a PICU., Interventions: None., Measurements and Main Results: Children and/or parents were seen median (interquartile range [IQR] 4 mo [3-5 mo]) after PICU admission. Testing included assessment of neurocognitive, psychosocial, and QoL outcomes with reference to Dutch pre-COVID-19 general population norms. Effect sizes (Hedges' g ) were used to indicate the strengths and clinical relevance of differences: 0.2 small, 0.5 medium, and 0.8 and above large. Of 69 children with MIS-C, 49 (median age 11.6 yr [IQR 9.3-15.6 yr]) attended follow-up. General intelligence and verbal memory scores were normal compared with population norms. Twenty-nine of the 49 followed-up (59%) underwent extensive testing with worse function in domains such as visual memory, g = 1.0 (95% CI, 0.6-1.4), sustained attention, g = 2.0 (95% CI 1.4-2.4), and planning, g = 0.5 (95% CI, 0.1-0.9). The children also had more emotional and behavioral problems, g = 0.4 (95% CI 0.1-0.7), and had lower QoL scores in domains such as physical functioning g = 1.3 (95% CI 0.9-1.6), school functioning g = 1.1 (95% CI 0.7-1.4), and increased fatigue g = 0.5 (95% CI 0.1-0.9) compared with population norms. Elevated risk for posttraumatic stress disorder (PTSD) was seen in 10 of 30 children (33%) with MIS-C. Last, in the 32 parents, no elevated risk for PTSD was found., Conclusions: Children with MIS-C requiring PICU admission had normal overall intelligence 4 months after PICU discharge. Nevertheless, these children reported more emotional and behavioral problems, more PTSD, and worse QoL compared with general population norms. In a subset undergoing more extensive testing, we also identified irregularities in neurocognitive functions. Whether these impairments are caused by the viral or inflammatory response, the PICU admission, or COVID-19 restrictions remains to be investigated., Competing Interests: Dr. Buddingh’s institution received funding from Leids Universitair Fonds/ Bontiusstichting and ZonMw. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

The energy metabolism of tumor cells is considered one of the hallmarks of cancer because it is different from normal cells and mainly consists of aerobic glycolysis, fatty acid oxidation, and glutaminolysis. It is about one hundred years ago since Warburg observed that cancer cells prefer aerobic glycolysis even in normoxic conditions, favoring their high proliferation rate. A pivotal enzyme driving this phenomenon is lactate dehydrogenase (LDH), and this review describes prognostic and therapeutic opportunities associated with this enzyme, focussing on tumors with limited therapeutic strategies and life expectancy (i.e., pancreatic and thoracic cancers). Expression levels of LDH-A in pancreatic cancer tissues correlate with clinicopathological features: LDH-A is overexpressed during pancreatic carcinogenesis and showed significantly higher expression in more aggressive tumors. Similarly, LDH levels are a marker of negative prognosis in patients with both adenocarcinoma or squamous cell lung carcinoma, as well as in malignant pleural mesothelioma. Additionally, serum LDH levels may play a key role in the clinical management of these diseases because they are associated with tissue damage induced by tumor burden. Lastly, we discuss the promising results of strategies targeting LDH as a treatment strategy, reporting recent preclinical and translational studies supporting the use of LDH-inhibitors in combinations with current/novel chemotherapeutics that can synergistically target the oxygenated cells present in the tumor., Competing Interests: Declaration of Competing Interest All the authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: The long-term survival differences between endovascular repair (EVAR) and open repair for abdominal aortic aneurysms (AAAs) and specifically the impact of age on these differences remain a topic of debate. Therefore, we compared the long-term mortality between EVARand open abdominal aneurysm repair for patients of different ages., Methods: This was a retrospective cohort study of prospectively collected data from patients undergoing elective EVAR or open repair for infrarenal AAAs within the Vascular Quality Initiative multinational clinical registry (2003-2021). The primary outcome was long-term all-cause mortality comparing EVAR and open repair for patients aged less than 65 years, between 65 and 79 years, and those aged 80 and older. In addition, we investigated the interaction between repair modality and 10-year hazard of mortality for sex, aneurysm diameter, and several preoperative comorbid conditions within each age category. To account for the nonrandom assignment of treatment, we used propensity scores and inverse probability weighted Cox proportional hazard analysis., Results: We identified 48,074 patients undergoing elective infrarenal abdominal aneurysm repair (89% EVAR) within the study period, including 7940 patients aged less than 65, 29,555 aged between 65 and 79, and 10,579 aged 80 years or more. EVAR was associated with a higher propensity score-adjusted long-term hazard of mortality compared with open repair in the cohort aged less than 65 years (hazard ratio [HR], 1.39; 95% confidence interval [CI], 1.04-1.86; P = .026). The mortality was similar in the age cohort between 65 and 79 (HR, 0.94; 95% CI, 0.79-1.10; P = .43), whereas EVAR was associated with a lower hazard of mortality in the cohort aged 80 years or more (HR, 0.63; 95% CI, 0.46-0.86; P = .004). In patients aged less than 65 years, the hazard of mortality was higher with EVAR compared with open repair in those with female sex (HR, 4.40; 95% CI, 1.75-11.0), an aneurysm diameter of more than 65 mm (HR, 2.19; 95% CI, 1.11-4.34), and an absence of coronary artery disease (HR, 1.26; 95% CI, 0.83-1.91), congestive heart failure (HR, 1.41; 95% CI, 1.03-1.92), and renal dysfunction (HR, 1.46; 95% CI, 1.04-2.05). In the patient cohort aged 80 and older, a lower hazard of mortality for EVAR versus open repair was observed for male patients or those with small aneurysms or certain comorbidities., Conclusions: In a selected group of young patients with a substantial life expectancy, the long-term mortality is higher with EVAR compared with open repair for infrarenal AAAs. Long-term mortality with EVAR is similar in the middle cohort and lower in the elderly cohort compared with open repair., (Copyright © 2022 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Mutations in the ARPC1B isoform component of human actin-related protein 2/3 complex have been recently associated with an inborn error of immunity characterized by combined immunodeficiency, allergies, autoinflammation, and platelet abnormalities. Currently, indications on the management of this novel disease and information on its outcome are lacking. We report the first case series of 7 children with a homozygous mutation in ARPC1B gene who underwent allogeneic-HSCT (allo-HSCT). All patients presented an early clinical onset, characterized by recurrent infections, failure to thrive and gastrointestinal bleeding episodes complicated with neonatal hemorrhagic enteritis in 3 cases, and macrophage activating syndrome in 2. Allo-HSCT was performed at the median age of 1.83 years after a myeloablative conditioning regimen in all cases. Engraftment occurred in all patients with full donor chimerism in 6 out of 7. The clinical course after engraftment was uneventful in 3 out of 7 children; 2 patients developed a grade 1-2 acute graft-versus-host disease (GvHD), and 1 patient a grade 1 chronic-GvHD. JC virus-related progressive multifocal leukoencephalopathy was diagnosed in one patient 13 months after haploidentical-HSCT and successfully managed with donor-derived viral-specific T-cell infusion. Only one patient had a fatal outcome 3 months after HSCT because of sepsis, after veno-occlusive disease, and transplant-associated microangiopathy. At a median follow-up of 19 months (range 3-110), 6 out of 7 patients are alive and disease-free. The severity of the clinical phenotype at diagnosis and the high survival rate, with limited transplant-related morbidity, strongly support the indication to allo-HSCT for patients with this diagnosis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Unfractionated heparin has an unpredictable effect in an individual patient. The activated clotting time (ACT) can be used to measure the effect of heparin in the individual patient and guide additional heparin dosages. Previous cohort studies showed that a standardized bolus of 5,000 IU during noncardiac arterial procedures (NCAP) does not lead to an adequate ACT in the vast majority of patients. The aim of this study was to investigate whether an initial heparin dose of 100 IU/kg leads to an adequate but safe ACT, from 200 to 300 s., Methods: In this multicenter prospective study, 186 patients undergoing NCAP were enrolled and received an initial heparin dose of 100 IU/kg. Target ACT was set at ≥250 s initially; during the course of the study the target ACT was lowered to ≥200 s. After the initial heparin dose, additional heparin dosages were administered depending on the ACT values following a heparin dose protocol. ACT measurements and complications were monitored., Results: The mean baseline ACT was 134 ± 17 s. The mean ACT 5 minutes after the initial heparin dose was 227 ± 37 s. After the initial dose of heparin, 78 and 46% of patients reached an ACT of 200 and 250 s, respectively. Seven patients (4%) reached an ACT of 300 s or more. Ninety-four patients (51%) received at least one additional dose of heparin. After one additional dose of heparin, 91% of patients reached an ACT of 200 s and 13 patients (7%) reached an ACT of 300 s or more. Arterial thromboembolic complications occurred in 4.3% and bleeding complications occurred in 9.7%., Conclusions: A bolus of 100 IU/kg of heparin during NCAP results in adequate coagulation in most patients. ACT measurements enable accurate additional dosing, ensuring the individual patient tailored and safe coagulation., Key Words: anticoagulants; heparin; blood coagulation tests; vascular surgical procedures; peripheral vascular disease., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: This study investigates the relationship of child, caregiver, and caring context measurements with the care-related quality of life (CRQoL) and health-related quality of life (HRQoL) of caregivers of children with juvenile idiopathic arthritis (JIA)., Methods: We performed a cross-sectional analysis of baseline data on caregivers of children with JIA from Canada and the Netherlands collected for the "Canada-Netherlands Personalized Medicine Network in Childhood Arthritis and Rheumatic Diseases" study from June 2019 to September 2021. We used the CRQoL questionnaire (CarerQoL), adult EQ-5D-5L, and proxy-reported Youth 5-Level version of EuroQoL (EQ-5D-5L-Y) to assess caregiver CRQoL, caregiver HRQoL, and child HRQoL, respectively. We used a multivariate analysis to assess the relationship between both caregiver CRQoL and HRQoL and patient, caregiver, and caring context measurements., Results: A total of 250 caregivers were included in this study. Most of the caregivers were from the Netherlands (n = 178, 71%) and 77% were females (n = 193). The mean CarerQoL scores was 82.7 (standard deviation (SD) 11.4) and the mean EQ-5D-5L utility score was 0.87 (SD 0.16). Child HRQoL and employment had a positive relationship with both caregiver CarerQoL and EQ-5D-5L utility scores (p < 0.05), while receiving paid or unpaid help had a negative relationship with both scores (p < 0.05)., Conclusion: Our findings indicated that to understand the impact of JIA on families, we need to consider socio-economic factors, such as employment and support to carry caregiving tasks, in addition to child HRQoL., (© 2022. The Author(s).)

To directly compare and describe the differences between juvenile idiopathic arthritis (JIA) patients and pediatric controls regarding features of the synovial and tenosynovial membrane on contrast-enhanced magnetic resonance imaging (MRI) of the wrist. T1-weighted contrast-enhanced MRI scans of 25 JIA patients with clinically active wrist arthritis and 25 children without a history of joint complaints nor any clinical signs of joint inflammation were evaluated by two readers blinded to clinical data. The synovium was scored at five anatomical sites based on thickening of the synovium (0-3 scale) and synovial enhancement (0-2 scale). Thickening and/or enhancement of the tenosynovium was scored at four anatomical sites using a 0-3 scale. Significantly higher scores for synovial thickening (median 4 vs. 1, p < 0.001) and synovial enhancement (median 4 vs. 1, p < 0.001) are found in the wrist of JIA patients as compared to controls. JIA patients experienced the highest synovial scores at the mid-/inter-carpal, 2nd -5th carpometacarpal, and radiocarpal joints. No significant difference in tenosynovial scores is found between both groups (median 0 vs. 0, p = 0.220). This study highlights the higher synovial thickening/enhancement scores on contrast-enhanced MRI of the wrist in JIA patients compared to pediatric controls. Tenosynovial thickening and/or enhancement was rarely present in both groups. In JIA patients, synovial thickening and enhancement were particularly present at three anatomical sites. These results substantially support rheumatologists and radiologists when navigating through MRI of the wrist in search for JIA disease activity., (© 2021. The Author(s).)

Sodium glucose cotransporter-2 (SGLT2) inhibitors have acquired a central role in the treatment of type 2 diabetes, chronic kidney disease including diabetic kidney disease, and heart failure with reduced ejection fraction. SGLT2 inhibitors lower glucose levels by inducing glycosuria. In addition, SGLT2 inhibitors improve cardiovascular outcomes (3-point MACE), end-stage kidney disease, hospitalization for heart failure, and cardiovascular mortality in people with and without diabetes. The mechanisms underlying these benefits have been extensively investigated, but remain poorly understood. In this review, we first summarize recent trial evidence and subsequently focus on (1) the mechanisms by which SGLT2 inhibitors improve kidney outcomes and (2) the potential role of the kidneys in mediating the cardioprotective effects of SGLT2 inhibitors., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Empirical evidence and clinical observations suggest a strong -yet under acknowledged-link between anorexia nervosa (AN) and non-suicidal self-injurious behavior (NSSI). By reviewing the literature on the psychopathology and neurobiology of AN and NSSI, we shed light on their relationship. Both AN and NSSI are characterized by disturbances in affect regulation, dysregulation of the reward circuitry and the opioid system. By formulating a reward-centered hypothesis, we explain the overlap between AN and NSSI. We propose three approaches understanding the relationship between AN and NSSI, which integrate psychopathology and neurobiology from the perspective of self-destructiveness: (1) a nosographical approach, (2) a research domain (RDoC) approach and (3) a network analysis approach. These approaches will enhance our knowledge of the underlying neurobiological substrates and may provide groundwork for the development of new treatment options for disorders of self-destructiveness, like AN and NSSI. In conclusion, we hypothesize that self-destructiveness is a new, DSM-5-transcending concept or psychopathological entity that is reward-driven, and that both AN and NSSI could be conceptualized as disorders of self-destructiveness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Oudijn, Linders, Mocking, Lok, van Elburg and Denys.)

Background: The pathophysiology of neurological dysfunction in severe chronic kidney disease (CKD) in children and young adults is largely unknown. We aimed to investigate brain volumes and white matter integrity in this population and explore brain structure under different treatment modalities., Methods: This cross-sectional study includes 24 patients with severe CKD (eGFR < 30) aged 8-30 years (median = 18.5, range = 9.1-30.5) on different therapy modalities (pre-dialysis, n = 7; dialysis, n = 7; transplanted, n = 10) and 21 healthy controls matched for age, sex, and parental educational level. Neuroimaging targeted brain volume using volumetric analysis on T1 scans and white matter integrity with tract-based spatial statistics and voxel-wise regression on diffusion tensor imaging (DTI) data., Results: CKD patients had lower white matter integrity in a widespread cluster of primarily distal white matter tracts compared to healthy controls. Furthermore, CKD patients had smaller volume of the nucleus accumbens relative to healthy controls, while no evidence was found for abnormal volumes of gray and white matter or other subcortical structures. Longer time since successful transplantation was related to lower white matter integrity. Exploratory analyses comparing treatment subgroups suggest lower white matter integrity and smaller volume of the nucleus accumbens in dialysis and transplanted patients relative to healthy controls., Conclusions: Young CKD patients seem at risk for widespread disruption of white matter integrity and to some extent smaller subcortical volume (i.e., nucleus accumbens). Especially patients on dialysis therapy and patients who received a kidney transplant may be at risk for disruption of white matter integrity and smaller volume of the nucleus accumbens., (© 2021. The Author(s).)

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) lower blood pressure (BP). When SGLT2i and GLP-1RA are combined, synergistic effects on BP have been observed. The mechanisms underlying these BP reductions are incompletely understood. The aim of this study was to assess the mechanisms underlying the BP reduction with the SGLT2i dapagliflozin, GLP-1RA exenatide, and dapagliflozin-exenatide compared with placebo in people with obesity and type 2 diabetes., Methods: Sixty-six people with type 2 diabetes were randomized to 16 weeks of dapagliflozin 10 mg/day, exenatide 10 µg twice daily, dapagliflozin-exenatide, or placebo treatment. The effect of treatments on estimates of: (1) plasma volume (calculated by Strauss formula, bioimpedance spectroscopy, hematocrit, (2) autonomic nervous system activity (heart rate variability), (3) arterial stiffness (pulse wave applanometry), (4) systemic hemodynamic parameters including peripheral vascular resistance, cardiac output and stroke volume (all derived from non-invasively systemic hemodynamic monitoring), and (5) natriuresis (24-hour urine collection) were assessed after 10 days and 16 weeks of treatment., Results: After 10 days, dapagliflozin reduced systolic BP (SBP) by - 4.7 mmHg, and reduced plasma volume. After 16 weeks, dapagliflozin reduced SBP by - 4.4 mmHg, and reduced sympathetic nervous system (SNS) activity. Exenatide had no effect on SBP, but reduced parasympathetic nervous system activity after 10 days and 16 weeks. After 10 days, dapagliflozin-exenatide reduced SBP by - 4.2 mmHg, and reduced plasma volume. After 16 weeks, dapagliflozin-exenatide reduced SBP by - 6.8 mmHg, and the reduction in plasma volume was still observed, but SNS activity was unaffected., Conclusions: The dapagliflozin-induced plasma volume contraction may contribute to the initial SBP reduction, while a reduction in SNS activity may contribute to the persistent SBP reduction. Dapagliflozin-exenatide resulted in the largest decrease in SBP. The effect on plasma volume was comparable to dapagliflozin monotherapy, and SNS activity was not reduced, therefore other mechanisms are likely to contribute to the blood pressure lowering effect of this combination, which need further investigation. Trial registration Clinicaltrials.gov, NCT03361098., (© 2022. The Author(s).)

Study Objectives: (1) To investigate if drug-induced sleep endoscopy (DISE) findings are predictive of surgical response for patients undergoing maxillomandibular advancement (MMA) for obstructive sleep apnea (OSA) and (2) to investigate the predictive value of the jaw thrust maneuver during DISE in terms of surgical response to MMA., Methods: A retrospective cohort study was conducted in patients with OSA who underwent a baseline polysomnography (PSG) and DISE followed by MMA and a 3- to 6-month follow-up PSG between September 1, 2011, and September 30, 2020., Results: Sixty-four patients with OSA (50 males [78.1%]; mean ± SD age = 51.7 ± 9.5 years; mean ± SD apnea-hypopnea index = 49.0 ± 20.8 events/h) were included. Thirty-nine patients were responders, and 25 were nonresponders. Adjusting for baseline characteristics and surgical characteristics (eg, age, baseline apnea-hypopnea index, degree of maxillary advancement), patients with complete anteroposterior epiglottic collapse had 0.239 times lower odds for response to MMA (95% confidence interval, 0.059-0.979; P = .047). No significant relationship was found between complete concentric velum collapse and MMA response. There was no statistically significant association between effect of jaw thrust maneuver during DISE on upper airway patency and treatment outcome of MMA., Conclusions: This study indicates that DISE is a promising tool to identify patients who will or will not respond to MMA for treating OSA. Patients with complete anteroposterior epiglottic collapse may be less suitable candidates for MMA., Citation: Zhou N, Ho J-PTF, de Vries N, Bosschieter PFN, Ravesloot MJL, de Lange J. Evaluation of drug-induced sleep endoscopy as a tool for selecting patients with obstructive sleep apnea for maxillomandibular advancement. J Clin Sleep Med . 2022;18(4):1073-1081., (© 2022 American Academy of Sleep Medicine.)

Human papillomavirus (HPV)-induced anal intraepithelial neoplasia (AIN, graded 1-3) is highly prevalent in HIV-positive (HIV+) men who have sex with men (MSM), but only a minority of lesions progresses to cancer. Our study aimed to characterise comprehensively anal tissue samples from a cross-sectional series (n = 104) of HIV+ MSM and longitudinal series (n = 40) of AIN2/3 progressing to cancer using different biomarkers. The cross-sectional series consisted of 8 normal, 26 AIN1, 45 AIN2, 15 AIN3 and 10 anal squamous cell carcinoma. Tissue sections were immunohistochemically (IHC) stained for p16 (viral transformation marker), Ki-67 (cellular proliferation marker) and HPV-E4 (viral production marker). We evaluated the expression of IHC markers and compared it with DNA methylation, a marker for malignant transformation. E4 positivity decreased, whereas p16 and Ki-67 scores and methylation marker positivity increased (P values < .001) with increasing severity of anal lesions. Within AIN2, a heterogeneous biomarker pattern was observed concerning E4, p16 and methylation status, reflecting the biological heterogeneity of these lesions. In the longitudinal series, all AIN2/3 and carcinomas showed high p16 and Ki-67 expression, strong methylation positivity and occasional E4 positivity. We earlier showed that high methylation levels are associated with progression to cancer. The observed E4 expression in some AIN2/3 during the course of progression to cancer and absence of E4 in a considerable number of AIN1 lesions make the potential clinical significance of E4 expression difficult to interpret. Our data show that IHC biomarkers can help to characterise AIN; however, their prognostic value for cancer risk stratification, next to objective methylation analysis, appears to be limited., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Introduction: Anxiety disorders occur in approximately one third of people with Parkinson's disease (PD), and have a major impact on patient and caregiver wellbeing. In order to better understand and diagnose anxiety in PD patients, we investigated the generalizability of the results of a previous factor analysis on anxiety symptoms to a sample of PD patients with neuropsychiatric symptoms., Methods: In this cross-sectional study, anxiety symptoms were measured with the Beck Anxiety Inventory (BAI) in 123 PD patients who were referred for neuropsychiatric diagnostics and treatment. Subscales of anxiety were analyzed through principal component analysis of BAI items. The associations between BAI subscales and symptoms of motor and cognitive function and depression were assessed through regression analyses., Results: Similar to the previous factor analysis, we found one psychological (affective) and four somatic subscales of anxiety in the BAI. The affective subscale was the principal component explaining 35.9% of the variance. The scores on the total BAI and the affective subscale were significantly associated with depressive symptoms. In a post-hoc analysis, the affective subscale had equal power as compared to the total BAI in predicting whether or not participants were diagnosed with an anxiety disorder after psychiatric evaluation., Conclusion: In this study, we replicated our previous findings of one affective and multiple somatic subscales of the BAI. The 7-item affective subscale of the BAI shows potential as a screening tool for non-episodic anxiety in PD. However, in clinical practice, we recommend evaluating anxiety symptoms in the context of other PD symptoms, including motor, autonomic, and other (neuro)psychiatric symptoms., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered: Odile A. van den Heuvel received speakers’ honorarium from BENECKE., (© 2021 The Author(s).)

Objectives: Arterial thrombo-embolic complications (ATEC) are still common during and after non-cardiac arterial procedures (NCAP) despite the administration of (a fixed bolus of) heparin. These ATEC could be due to existing individual differences in heparin sensitivity. The purpose of this study was to evaluate the feasibility and safety of an ACT guided heparin dose protocol and to evaluate if a more effective target ACT can be achieved during NCAP., Methods: In this multi-center prospective study, 194 patients undergoing elective and non-elective NCAP were enrolled and received heparin according to a heparin dose protocol which aimed to obtain a target ACT of 250 seconds (s.), measured by the Medtronic HMS Plus. Patients received a standardized bolus of 5 000 IU followed by additional boluses depending on the actual ACT. Primary outcome was the ACT value reached. Secondary outcomes were incidence of all ATEC and haemorrhagic complications., Results: The mean baseline ACT was 138 ± 17 s. The mean ACT five minutes after the initial heparin bolus of 5 000 IU was 197 ± 31 s. 48% of patients reached an ACT of 200 s. and six per cent of patients reached an ACT of 250 s. Additional dosages of heparin were administered in 72% of patients. With this ACT guided heparin protocol 86% of patients reached an ACT of 200 s. and 26% of patients reached an ACT of 250 s. A negative correlation was found between body weight and the ACT at T1 (P ˂ 0.001). ATEC and haemorrhagic complications occurred in 11.3% and 16.5% of patients. The lowest incidence of ATEC was found in patients with peak ACT between 200 and 250 s, namely 6.3%., Conclusion: This ACT guided heparin protocol proved to be feasible, safe and more patients reached an ACT > of 200 s. compared to a standardized heparin bolus of 5 000 IU. Further research is needed to investigate if ACT guided heparin administration could be preferable over not monitoring the anticoagulant effect of peri-procedural heparin and results in a lower incidence of ATEC, without an increase in haemorrhagic complications., (Copyright © 2021. Published by Elsevier Inc.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Dupilumab is a relatively new treatment option for patients with moderate to severe atopic dermatitis. There is a lack of knowledge about the effects of treatment with dupilumab during conception for both men and women, as well as during pregnancy and lactation in women. We report four patients (two men, two women) who expressed a wish to conceive during treatment with dupilumab in daily practice. Both men conceived during dupilumab treatment, while the two women discontinued dupilumab because of anticipated pregnancy. Apart from disease flares in both of the patients who discontinued treatment, no complications were reported concerning the ability to conceive, the course of the pregnancy or the fetal outcome. We present an overview of the current available literature on dupilumab during conception, pregnancy and lactation, which can guide considerations for patients on dupilumab wishing to conceive a child. Until more data are available, preference should be given to treatment with topical corticosteroids, phototherapy, systemic corticosteroids and ciclosporin., (© 2021 The Authors. Clinical and Experimental Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Objectives: For selection of high-risk systemic lupus erythematosus (SLE) patients it is necessary to obtain indicators of disease severity that predict disease damage. As in systemic sclerosis, nailfold capillary abnormalities could be such a biomarker in SLE. The primary objective of this cross-sectional study is to describe capillary abnormalities in childhood-onset SLE (cSLE) cohort (onset < 18 years) and compare them with matched healthy controls. The secondary objective is to correlate the observed capillary abnormalities with demographical variables in both cohorts and with disease-specific variables in cSLE patients., Methods: Healthy controls were matched for ethnic background, age and gender. Videocapillaroscopy was performed in eight fingers with 2-4 images per finger. Quantitative and qualitative assessments of nailfold capillaroscopy images were performed according to the definitions of the EULAR study group on microcirculation in Rheumatic Diseases., Results: Both groups (n = 41 cSLE-patients and n = 41 healthy controls) were comparable for ethnic background (p = 0.317). Counted per mm, cSLE-patients showed significantly more 'giants' (p = 0.032), 'abnormal capillary shapes' (p = 0.003), 'large capillary hemorrhages' (p < 0.001) and 'pericapillary extravasations' (p < 0.001). Combined 'abnormal capillary shapes and pericapillary extravasations' (in the same finger) were detected in 78% (32/41 patients). By qualitative analysis, 'microangiopathy' was detected in 68.3% (28/41) and a 'scleroderma pattern' in 17.1% (7/41) of the cSLE-patients (without scleroderma symptoms). The difference of percentage positive anti-RNP antibodies in the group with or without a scleroderma pattern was not significant (p = 0.089). The number of 'abnormal capillary shapes per mm' was significantly correlated with treatment-naivety. The number of 'large pathological hemorrhages per mm' was significantly correlated with SLEDAI score and presence of nephritis. Compared to healthy controls, 'pericapillary extravasations' were found in significantly higher numbers per mm (p < 0.001) as well as in percentage of patients (p < 0.001)., Conclusions: Our observations confirm that giants, abnormal capillary morphology and capillary hemorrhages are also observed in cSLE, as was already known for adults with SLE. Number of capillary hemorrhages in cSLE was significantly correlated with disease activity. A high frequency and total amount of "pericapillary extravasations" was observed in cSLE patients, possibly revealing a new subtype of capillary hemorrhage that might reflect endothelial damage in these pediatric patients.

Background: Over the past decades, the preterm birth rate has increased, mostly due to a rise in late and moderate preterm (LMPT, 32-36 weeks gestation) births. LMPT birth affects 6-7% of all births in the United Kingdom and is associated with increased morbidity risk after birth in infancy as well as in adulthood. Early life nutrition has a critical role in determining infant growth and development, but there are limited data specifically addressing LMPT infants, which was the rationale for the design of the current study. Objective: The Feeding Late and Moderate Infants and Growth Outcomes (FLAMINGO) study aims to improve understanding of the longitudinal growth, nutritional needs, and body composition of LMPT infants as well as their microbiome development and neurodevelopment. In addition, having a nested non-inferiority trial enables evaluation of the nutritional adequacy of a concept IMF with large milk phospholipid-coated lipid droplets comprising dairy and vegetable lipids. The primary outcome of this RCT is daily weight gain until 3 months corrected age. Methods: A total of 250 healthy LMPT infants (32+0-36+6 weeks gestational age) with birth weight 1.25-3.0 kg will be recruited to the cohort, of which 140 infants are anticipated to be enrolled in the RCT. During six visits over the first 2 years of life, anthropometry, body composition (using dual energy X-Ray absorptiometry), feeding behavior, and developmental outcomes will be measured. Saliva and stool samples will be collected for oral and gut microbiota assessment. Discussion: The FLAMINGO study will improve understanding of the longitudinal growth, body composition development, and feeding characteristics of LMPT infants and gain insights into their microbiome and neurodevelopment. Study Registration: www.isrctn.com; Identifier ISRCTN15469594., Competing Interests: MA-B is an employee of Danone. RMvE was previously an employee of Danone. NDE declares research funding from Danone Early Life Nutrition and Prolacta Biosciences US, and lecture honoraria from Nestle Nutrition Institute. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kakaroukas, Abrahamse-Berkeveld, Berrington, McNally, Stewart, Embleton and van Elburg.)

Objective: To assess the effect of sialendoscopy of the major salivary glands on salivary flow and xerostomia in patients with Sjögren's syndrome (SS)., Methods: Forty-five patients with SS were randomly assigned to a control group (no irrigation, control, n = 15), to irrigation of the major salivary glands with saline (saline, n = 15) or to irrigation with saline followed by corticosteroid application (triamcinolone acetonide in saline, saline/TA, n = 15). Unstimulated whole saliva flow (UWSF), chewing-stimulated whole saliva flow (SWSF), citric acid-stimulated parotid flow, Clinical Oral Dryness Score (CODS), Xerostomia Inventory (XI) and EULAR SS Patient Reported Index (ESSPRI) scores were obtained 1 week before (T0), and 1, 8, 16, 24, 36, 48 and 60 weeks after sialendoscopy. Data were analysed using linear mixed models., Results: Irrespective of the irrigation protocol used, sialendoscopy resulted in an increased salivary flow during follow-up up to 60 weeks. Significant between-group differences in the longitudinal course of outcomes were found for UWSF, SWSF, XI and ESSPRI scores (P = 0.028, P = 0.001, P = 0.03, P = 0.021, respectively). UWSF at 60 weeks was higher compared with T0 in the saline group (median: 0.14 vs median: 0.10, P = 0.02) and in the saline/TA group (median: 0.20, vs 0.13, P = 0.035). In the saline/TA group SWSF at 48 weeks was higher compared with T0 (median: 0.74 vs 0.38, P = 0.004). Increase in unstimulated salivary flow was also reflected in improved CODS, XI and ESSPRI scores compared with baseline., Conclusion: Irrigation of the major salivary glands in patients with SS increases salivary flow and reduces xerostomia., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Fibrosis is a hallmark of adverse cardiac remodeling, which promotes heart failure, but it is also an essential repair mechanism to prevent cardiac rupture, signifying the importance of appropriate regulation of this process. In the remodeling heart, cardiac fibroblasts (CFs) differentiate into myofibroblasts (MyoFB), which are the key mediators of the fibrotic response. Additionally, cardiomyocytes are involved by providing pro-fibrotic cues. Nuclear receptor Nur77 is known to reduce cardiac hypertrophy and associated fibrosis; however, the exact function of Nur77 in the fibrotic response is yet unknown. Here, we show that Nur77-deficient mice exhibit severe myocardial wall thinning, rupture and reduced collagen fiber density after myocardial infarction and chronic isoproterenol (ISO) infusion. Upon Nur77 knockdown in cultured rat CFs, expression of MyoFB markers and extracellular matrix proteins is reduced after stimulation with ISO or transforming growth factor-β (TGF-β). Accordingly, Nur77-depleted CFs produce less collagen and exhibit diminished proliferation and wound closure capacity. Interestingly, Nur77 knockdown in neonatal rat cardiomyocytes results in increased paracrine induction of MyoFB differentiation, which was blocked by TGF-β receptor antagonism. Taken together, Nur77-mediated regulation involves CF-intrinsic promotion of CF-to-MyoFB transition and inhibition of cardiomyocyte-driven paracrine TGF-β-mediated MyoFB differentiation. As such, Nur77 provides distinct, cell-specific regulation of cardiac fibrosis.

The global COVID-19 pandemic has put enormous stress on healthcare systems and hospital staffing. However, through all this, families will continue to become pregnant, give birth, and breastfeed. Unfortunately, care of the childbearing family has been de-prioritized during the pandemic. Additionally, many healthcare practices during the pandemic have not been positive for the childbearing family or breastfeeding. Despite recommendations from the World Health Organization to promote early, direct breastfeeding and skin to skin contact, these and other recommendations are not being followed in the clinical setting. For example, some mothers have been forced to go through labor and birth alone in some institutions whilst some hospitals have limited or no parental visitation to infants in the NICU. Furthermore, hospitals are discharging mothers and their newborns early, limiting the amount of time that families receive expert lactation care, education, and technical assistance. In addition, some hospitals have furloughed staff or transferred them to COVID-19 wards, further negatively impacting direct care for families and their newborns. We are concerned that these massive changes in the care of childbearing families will be permanently adopted. Instead, we must use the pandemic to underscore the importance of human milk and breastfeeding as lifesaving medical interventions. We challenge healthcare professionals to change the current prenatal and post-birth practice paradigms to protect lactation physiology and to ensure that all families in need receive equal access to evidence-based lactation education, care and technical assistance., Competing Interests: JG serves as member of the National Health Council and is also director of the Dutch national Human Milk Bank. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Spatz, Davanzo, Müller, Powell, Rigourd, Yates, Geddes, van Goudoever and Bode.)

A major function of the nervous system is to maintain a relatively constant internal environment. The distinction between our external environment (i.e., the environment that we live in and that is subject to major changes, such as temperature, humidity, and food availability) and our internal environment (i.e., the environment formed by the fluids surrounding our bodily tissues and that has a very stable composition) was pointed out in 1878 by Claude Bernard (1814-1878). Later on, it was indicated by Walter Cannon (1871-1945) that the internal environment is not really constant, but rather shows limited variability. Cannon named the mechanism maintaining this limited variability homeostasis. Claude Bernard envisioned that, for optimal health, all physiologic processes in the body needed to maintain homeostasis and should be in perfect harmony with each other. This is illustrated by the fact that, for instance, during the sleep-wake cycle important elements of our physiology such as body temperature, circulating glucose, and cortisol levels show important variations but are in perfect synchrony with each other. These variations are driven by the biologic clock in interaction with hypothalamic target areas, among which is the paraventricular nucleus of the hypothalamus (PVN), a core brain structure that controls the neuroendocrine and autonomic nervous systems and thus is key for integrating central and peripheral information and implementing homeostasis. This chapter focuses on the anatomic connections between the biologic clock and the PVN to modulate homeostasis according to the daily sleep-wake rhythm. Experimental studies have revealed a highly specialized organization of the connections between the clock neurons and neuroendocrine system as well as preautonomic neurons in the PVN. These complex connections ensure a logical coordination between behavioral, endocrine, and metabolic functions that helps the organism maintain homeostasis throughout the day., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective : To evaluate the oncological outcome at 5-year follow-up after laparoscopic cryoablation (LCA) for small renal masses (SRMs), as there is an increasing interest in ablative therapy for cT1a renal tumours due to the rising incidence of SRMs, the trend towards minimally invasive nephron-sparing treatments, and the ageing population. Patients and methods : Between 2004 and 2015, 233 consecutive LCA were performed in 219 patients for SRMs at two referral centres. We only included those patients with ≥5 years of follow-up ( n = 165) in a prospectively maintained database. A descriptive analysis was conducted for pre-, peri- and postoperative characteristics. A Kaplan-Meier analysis assessed overall (OS), disease-specific (DSS), and recurrence-free survival (RFS). Results : The median (interquartile range [IQR]) age of our patient cohort was 68 (60.5-76) years. The median (IQR) body mass index was 26.2 (23.8-29) kg/m 2 , and the median (IQR) Charlson Comorbidity Index score corrected for age was 4 (2.5-6). The median (IQR) tumour diameter was 28 (21-33) mm. In all, 15% developed a complication in the first 30 days after LCA, of which 1% had a major complication (Clavien-Dindo Grade ≥III). The median (IQR) preoperative estimated glomerular filtration rate (eGFR) was 82.5 (65-93.75) mL/min/1.73 m 2 . The median eGFR decreased by 16.4% and 15.2% at the 3-month and 5-year follow-up, respectively. Persistence was found in 1%, local recurrence in 2%, and systemic progression in 4%. The OS, DSS, and RFS were 74%, 96.9% and 95.4%, respectively. Conclusion : LCA is a safe and effective treatment for SRMs in selected cases and shows good oncological outcomes after 5 years of follow-up, with only 1% developing a major complication., Competing Interests: All authors declare that they have no conflicts of interest., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Objectives: Isotopic analyses using human dental enamel provide information on the mobility and diet of individuals in forensic and archeological studies. Thus far, no study has systematically examined intraindividual coupled strontium (Sr), oxygen (O), and carbon (C) isotope variation in human enamel or the effect that caries have on the isotopic integrity of the enamel. The inadequate quantification of isotopic variation affects interpretations and may constrain sample selection of elements affected by caries. This study aims to quantify the intraindividual isotopic variation and provides recommendations for enamel sampling methods., Material and Methods: This study presents the first systematic results on intraindividual variation in Sr-O-C isotope composition and Sr concentration in modern human dental enamel of third molars (affected and unaffected by caries). A multiloci sampling approach (n = 6-20) was used to analyze surface and inner enamel, employing thermal ionization mass spectrometry (TIMS) and isotope ratio mass spectrometry (IRMS). Third molars were analyzed from 47 individuals from the Netherlands, Iceland, the United States, the Caribbean, Colombia, Somalia, and South Africa., Results: Intradental isotopic variation in modern Dutch dental elements was recorded for Sr, O, and C and exceeded the variation introduced by the analytical error. Single loci and bulk sampling approaches of third molars established that a single analysis is only representative of the bulk Sr isotope composition in 60% of the elements analyzed. Dental elements affected by caries showed twice the variation seen in unaffected dental elements. Caries did not consistently incorporate the isotopic composition of the geographical environment in which they developed., Discussion: The isotopic variability recorded in unaffected inner enamel indicates that variations greater than 0.000200 for 87 Sr/ 86 Sr and larger than 2‰ for δ 18 O and δ 13 C are required to demonstrate changes in modern Dutch human diet or geographic location., (© 2020 The Authors. American Journal of Physical Anthropology published by Wiley Periodicals, Inc.)

Enteroviruses (EVs) are highly prevalent viruses worldwide. Recombination is known to occur frequently in EVs belonging to species Enterovirus A , Enterovirus B , and Enterovirus C . Although many recombinant vaccine-derived poliovirus (VDPV) strains have been reported, our knowledge on recombination in non-polio EVs in the species Enterovirus C is limited. Here, we combined a dataset consisting of 11 newly generated full-length Enterovirus C sequences and 180 publicly available sequences to study recombination dynamics in non-polio EVs. To identify recombination patterns, maximum likelihood phylogenetic trees of different genomic regions were constructed, and segregation analyses were performed. Recombination was observed between members of the same 3DPol cluster, but was rarely observed between members of different clusters. We hypothesize that this restriction may have arisen through their different compartmentalization in respiratory and enteric tracts related to differences in cellular tropisms so that the opportunity to recombine may not be available.

Custom-made polymethyl methacrylate (PMMA) bone cement is used to treat cranial bone defects but whether it is cytotoxic is still unsure. Possible PMMA-induced adverse effects in vivo affect mesenchymal stem cells and osteoblasts at the implant site. We aimed to investigate whether PMMA affects osteogenic and osteoclast activation potential of human mesenchymal stem cells and/or osteoblasts. Immediately after polymerization, PMMA was added to cultured human adipose stem cells (hASCs) or human osteoblasts (hOBs). Medium lactate dehydrogenase was measured (day 1), metabolic activity, proliferation, osteogenic and osteoclast-activation marker expression (day 1 and 7), and mineralization (day 14). PMMA did not affect lactate dehydrogenase, KI67 gene expression, or metabolic activity in hASCs and hOBs. PMMA transiently decreased DNA content in hOBs only. PMMA increased COL1 gene expression in hASCs, but decreased RUNX2 in hOBs. PMMA did not affect osteocalcin or alkaline phosphatase (ALP) expression, ALP activity, or mineralization. Only in hOBs, PMMA decreased RANKL/OPG ratio. In conclusion, PMMA is not cytotoxic and does not adversely affect the osteogenic potential of hASCs or hOBs. Moreover, PMMA does not enhance production of osteoclast factors by hASCs and hOBs in vitro. Therefore, PMMA bone cement seems highly suitable to treat patients with cranial bone defects., (© 2019 The Authors. Journal of Biomedical Materials Research Part B: Applied Biomaterials published by Wiley Periodicals, Inc.)

Sexual concerns are common after haematopoietic cell transplantation (HCT). Exposure to total body irradiation (TBI), alkylating agent and graft versus host disease (GvHD) can all affect sexual function, leading to problems in sexual desire, arousal and the orgasm phase of the sexual response cycle. In high-risk haematological malignancies, such as acute leukaemia and myelodysplastic syndromes, HCT often offers the highest chance for long-term survival. In addition, these haematological diseases and HCT can have an impact on body image, self-esteem, (sexual) relationship and psychosocial factors, all of which are able to affect sexuality and sexual function. Five years post HCT, 80% of the female survivors and 46% of the male survivors report sexual dysfunction. It has been shown that these patients cope better after having discussed sexual health. While healthcare providers (HCPs) have the responsibility to address sexual issues, it has been demonstrated that 48%-82% HCT recipients reported not having discussed sexual issues with their HCPs and that only one-third of the HCPs routinely discussed sexual issues with their patients. HCPs describe a lack of knowledge and being uncomfortable with the topic as the most important reasons for not addressing sexual functioning. Even so, it would help >90% HCPs if the patient initiated discussing sexual issues. However, to empower patients addressing sexual issues, adequate comprehensive patient information is needed. In an effort to better meet the patients' need, a patient information sheet: 'Information for patients undergoing Hematopoietic Cell Transplantation: the impact of the disease and treatment on sexual function and sexuality', has been created. In this review, we describe what is known about the impact of HCT on sexual function and briefly the management of sexual problems., Competing Interests: The authors declare that they have no conflicts of interest., (© the authors; licensee ecancermedicalscience.)

Fracture repair is characterized by cytokine production and hypoxia. To better predict cytokine modulation of mesenchymal stem cell (MSC)-aided bone healing, we investigated whether interleukin 4 (IL-4), IL-6, and their combination, affect osteogenic differentiation, vascular endothelial growth factor (VEGF) production, and/or mammalian target of rapamycin complex 1 (mTORC1) activation by MSCs under normoxia or hypoxia. Human adipose stem cells (hASCs) were cultured with IL-4, IL-6, or their combination for 3 days under normoxia (20% O 2 ) or hypoxia (1% O 2 ), followed by 11 days without cytokines under normoxia or hypoxia. Hypoxia did not alter IL-4 or IL-6-modulated gene or protein expression by hASCs. IL-4 alone decreased runt-related transcription factor 2 (RUNX2) and collagen type 1 (COL1) gene expression, alkaline phosphatase (ALP) activity, and VEGF protein production by hASCs under normoxia and hypoxia, and decreased mineralization of hASCs under hypoxia. In contrast, IL-6 increased mineralization of hASCs under normoxia, and enhanced RUNX2 gene expression under normoxia and hypoxia. Neither IL-4 nor IL-6 affected phosphorylation of the mTORC1 effector protein P70S6K. IL-4 combined with IL-6 diminished the inhibitory effect of IL-4 on ALP activity, bone nodule formation, and VEGF production, and decreased RUNX2 and COL1 expression, similar to IL-4 alone, under normoxia and hypoxia. In conclusion, IL-4 alone, but not in combination with IL-6, inhibits osteogenic differentiation and angiogenic stimulation potential of hASCs under normoxia and hypoxia, likely through pathways other than mTORC1. These results indicate that cytokines may differentially affect bone healing and regeneration when applied in isolation or in combination., (© 2019 Wiley Periodicals, Inc.)

HIV-1 entry into cells is mediated by the envelope glycoprotein (Env) and represents an attractive target for therapeutic intervention. Two drugs that inhibit HIV entry are approved for clinical use: the membrane fusion-inhibitor T20 (Fuzeon, enfuvirtide) and the C-C chemokine receptor type 5 (CCR5) blocker maraviroc (Selzentry). Another class of entry inhibitors supposedly target the fusion peptide (FP) and are termed anchor inhibitors. These include the VIRIP peptide and VIRIP derivatives such as VIR165, VIR353, and VIR576. Here, we investigated the mechanism of inhibition by VIR165. We show that substitutions within the FP modulate sensitivity to VIR165, consistent with the FP being the drug target. Our results also revealed that VIR165 acts during an intermediate post-CD4-binding entry step that is overlapping but not identical to the step inhibited by fusion inhibitors such as T20. We found that some but not all resistance mutations to heptad repeat 2 (HR2)-targeting fusion inhibitors can provide cross-resistance to VIR165. In contrast, resistance mutations in the HR1-binding site for the fusion inhibitors did not cause cross-resistance to VIR165. However, Env with mutations located outside this binding site and thought to affect fusion kinetics, exhibited decreased sensitivity to VIR165. Although we found a strong correlation between Env stability and resistance to HR2-based fusion inhibitors, such correlation was not observed for Env stability and VIR165 resistance. We conclude that VIRIP analogs target the FP during an intermediate, post-CD4-binding entry step that overlaps with but is distinct from the step(s) inhibited by HR2-based fusion inhibitors., (© 2019 Eggink et al.)

Background: A patient's physical function plays a leading role in the treatment prescription for patients with cancer. Objective assessments of physical function may be more predictive for treatment tolerability and survival than frequently used subjective measures, such as the Eastern Cooperative Oncology Group/World Health Organization (ECOG/WHO) performance score. The use of smartphones to measure physical activity and fitness may provide an excellent opportunity to objectively estimate a patient's physical function against low costs and little time. We investigated feasibility, validity and reliability of smartphone measurements of step count and physical fitness in patients with cancer., Methods: In total, 72 patients participated. They wore a smartphone for 14 days to measure the mean number of steps per day, concomitant with an accelerometer during the first 7 days. Patients performed a six-minute walk test (6MWT) twice outdoors via a smartphone application and once in a test environment in the hospital. Feasibility was evaluated by the proportion of patients who completed the study as well as smartphone assessments of step count and physical fitness. Validity was assessed with the intraclass correlation coefficient (ICC) between the accelerometer and the first week of the smartphone for step count, and between the 6MWT in the hospital and via the application for physical fitness. Test-retest reliability was assessed with the ICC between step count levels of the first and second week of smartphone assessments, and between the first and second six-minute walk test in the home environment., Results: The completeness of smartphone measurements was approximately 90% for step count and 64% for physical fitness assessments. Validity was excellent for step count (ICC = 0.97, p < 0.001) and fair for fitness (ICC = 0.47, p < 0.001). We found excellent test-retest reliability for step count (ICC = 0.91, p < 0.001) and physical fitness (ICC = 0.88, p < 0.001)., Conclusions: This study showed that objective smartphone measurements of step count in clinical practice are feasible, valid and reliable. These findings indicate that the use of smartphones to objectively assess physical activity in clinical cancer practice is promising and may be used to select patients for treatment and study participation, to monitor patients during treatment and to guide treatment decisions.