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Purpose: To describe experiences of adolescents taking continuous drospirenone (DRSP-C) oral contraceptives, without placebo, for menstrual suppression, including breakthrough bleeding and other side-effects., Methods: This was a retrospective chart review of adolescents prescribed DRSP-C for menstrual suppression. Demographics and indications for DRSP-C were collected on the visit where DRSP-C was prescribed. Data through the final follow-up visit during the study period included documented effects and side-effects of DRSP-C and continuation of therapy. Statistical analyses were primarily descriptive., Results: Patients prescribed DRSP-C were included (n = 136). Dysmenorrhea was the most common indication for DRSP-C (58.8%, n = 80/136) followed by endometriosis (44.8%, n = 61/136). The median time on DRSP-C for the 116 patients who were able to initiate treatment was 12.3 months (interquartile range [IQR] 6.8, 17.4). Patients trialed, on average, 2 other forms of menstrual management before starting DRSP-C (IQR 1, 3). Pelvic pain or dysmenorrhea resolution or improvement was reported in 84.6% (44/52) of dysmenorrhea patients, and 77.8% (28/36) of pelvic pain patients. Almost half of patients reported breakthrough bleeding on DRSP-C (41.3%, n = 48/116); however, only 11 patients (42%, 11/26) discontinued DRSP-C because of it. Within the study period, 22.4% (n = 26/116) of patients discontinued DRSP-C, with a median treatment duration of 101 days (IQR 71, 157). Among patients who discontinued DRSP-C, the most common reason was breakthrough bleeding (42%, n = 11/26)., Discussion: DRSP-C for menstrual suppression was well tolerated in adolescents, with most patients reporting resolution or improvement of their indication for taking DRSP-C. Findings demonstrate DRSP-C is a viable option for menstrual suppression in adolescents., (Copyright © 2024 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Background: For patients with metastatic bladder cancer (mBC) palliative chemotherapy is one of the main treatment options. Real-world insights into outcomes are available, but a comprehensive overview of specific treatment details like number of chemotherapy cycles received and (reasons for) adjustments is lacking., Methods: A population-based study was conducted, including all patients diagnosed with mBC in the Netherlands between 2016 and 2021 who started chemotherapy as initial treatment. Data on patient, tumor, and treatment characteristics, including number of cycles, adjustments and reasons for adjustments, and survival were collected from the Netherlands Cancer Registry. Treatment patterns and outcomes were analyzed descriptively. Logistic regression analysis was used to identify factors associated with receiving the full guideline-recommended treatment (4-6 cycles)., Results: A total of 684 patients started first-line chemotherapy, mostly carboplatin-based (54%). Of these patients, 35% did not receive the full course of treatment. Among these patients who received <4 cycles, 24% died within one month of stopping treatment. Male sex and good performance status were independently associated with receiving the full course of treatment. Among patients who did receive a full course of treatment, half still had adjustments to their treatment schedule, which mainly included dose reductions due to side effects., Conclusions: Among patients with mBC starting first-line chemotherapy, only a small majority received the recommended number of cycles, and treatment adjustments were common. This suggests that adhering to recommended treatment is challenging, emphasizing the importance of integrating insights on treatment discontinuation and modifications into the shared decision-making process and guideline development., 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.)

Background: Cosyntropin has been suggested to decrease the incidence of post-dural puncture headache (PDPH) by increasing the production of cerebrospinal fluid. This study examined the association of prophylactic cosyntropin administration with the incidence of PDPH and its management with an epidural blood patch after an unintentional dural puncture (UDP)., Methods: We conducted a retrospective cohort study of cases with UDP during placement of neuraxial labor analgesia. Per institutional practice and at the discretion of the anesthesiologist, intravenous cosyntropin 1 mg may be administered for PDPH prophylaxis. PDPH, time from UDP to cosyntropin administration, time to development of PDPH, and management with epidural blood patch(es) were recorded., Results: Cosyntropin was administered in 164 of 234 (70%) cases with UDP. PDPH occurred 98/164 (60%) with cosyntropin and 45/70 (64%) without cosyntropin (p = 0.66). The PDPH adjusted incidence was 53% with cosyntropin and 62% without cosyntropin, difference 9% (95% CI -6% to 24%, p = 0.25). The adjusted epidural blood patch rate was 66% with cosyntropin and 78% without cosyntropin, difference of 12% (95% CI -5% to 28%, p = 0.17)., Conclusions: Prophylactic cosyntropin following UDP was not associated with a significant decrease in PDPH rate or use of epidural blood patch for management of PDPH. There was no significant difference in the rate of adverse hyperglycemic or hypertensive events amongst those who did or did not receive cosyntropin., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Pelvic carcinosarcoma is an aggressive malignancy with significant diagnostic and management hurdles due to its complex vascularity and potential for extensive local invasion. A 59-year-old female presented with severe abdominal pain and significant weight loss, leading to the discovery of a large, complex pelvic mass through CT scans, MRI, and PET CT, suggesting aggressive malignancy. Initial management included a robotic laparoscopic proximal sigmoid loop colostomy to alleviate obstruction. Significant vascularity led to consultations with Vascular Surgery and subsequent preoperative embolization. Definitive surgery involved a supralevator posterior exenteration for en bloc resection of the vagina, mass, and sigmoid colon, combined with a low anterior resection and an omental J flap in anticipation of potential postoperative radiation therapy. This case underscores the importance of integrated imaging and staged surgical interventions in managing pelvic carcinosarcoma, emphasizing a multidisciplinary approach to optimize outcomes and minimize complications., (© 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Apolipoprotein E (APOE) genetic variants are most notably known for their divergent impact on the risk of developing Alzheimer's disease. While APOE genotype has been consistently shown to modulate lipid metabolism in a variety of cellular contexts, the effect of APOE alleles on the lipidome in hepatocytes is unknown. In this study, we investigated the contribution of APOE alleles to lipidomic profiles of donor-derived primary human hepatocytes from 77 subjects. Lipidomic data obtained by liquid chromatography-mass spectrometry were analyzed across ε2/ε3, ε3/ε3, and ε3/ε4 genotypes to reveal how APOE modulates lipid relative levels over age and between groups. Hepatic APOE concentration, measured by ELISA, was assessed for correlation with lipid abundance in subjects grouped as per APOE genotype and sex. APOE genotype-specific differential lipidomic signatures associated with age for multiple lipid classes but did not differ between sexes. Compared to ε2/ε3, ε3/ε4 hepatocytes had higher abundance of acylcarnitines (AC) and acylphosphatidylglycerol (AcylPG) as a class, as well as higher medium and long-chain ACs, AcylPG, phosphatidylglycerol (PG), bis(monoacylglycerol)phosphate (BMP), monoacylglycerol (MG) and diacylglycerol (DG) species. The ε3/ε4 hepatocytes also exhibited a higher abundance of medium and long-chain ACs compared to the ε3/ε3 hepatocytes. Only in the ε3/ε4 hepatocytes, APOE concentration was lower and showed a negative correlation with BMP levels, specifically in females. APOE genotype dictates a differential lipidome in primary human hepatocytes. The lipids involved suggest mitochondrial dysfunction with accompanying alterations in neutral lipid storage, reflective of a general disturbance of free fatty acid metabolism in human hepatocytes with the ε4 allele., Competing Interests: Conflict of 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 Inc. All rights reserved.)

Giardia duodenalis is the causative agent of the neglected diarrhoeal disease giardiasis. While often self-limiting, giardiasis is ubiquitous and impacts hundreds of millions of people annually. It is also a common gastro-intestinal disease of domestic pets, wildlife, and livestock animals. However, despite this impact, there is no vaccine for Giardia currently available. In addition, treatment relies on chemotherapies that are associated with increasing failure rates. To identify new treatment options for giardiasis we recently screened the Compounds Australia Scaffold Library for new chemotypes with selective anti-Giardia activity, identifying three compounds with sub-μM activity and promising selectivity. Here we extended these studies by examining the anti-Giardia activity of series CL9569 compounds. This compound series was of interest given the promising activity (IC 50 1.2 μM) and selectivity demonstrated by representative compound, SN00798525 (1). Data from this work has identified an additional three thieno [3,2-b]pyrrole 5-carboxamides with anti-Giardia activity, including 2 which displayed potent cytocidal (IC 50  ≤ 10 nM) and selective activity against multiple Giardia strains, including representatives from both human-infecting assemblages and metronidazole resistant parasites. Preclinical studies in mice also demonstrated that 2 is well-tolerated, does not impact the normal gut microbiota and can reduce Giardia parasite burden in these animals., Competing Interests: Declarations of competing interest CJS Hart, AG Riches, JH Ryan, and TS Skinner-Adams, are inventors on a PCT application that covers small molecule compounds derived from the compounds discussed in this manuscript., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Sleep problems (SP) are highly prevalent and seriously affect health and well-being in old age. The aim of this study was to examine the association between SP and happiness in an urban-dwelling older sample. The authors further explore the effects of generalized anxiety and depressive symptoms in the SP-happiness link using serial mediating modeling., Methods: Data came from the 2016 to 2018 Aging, Health, Psychological Well-being, and Health-seeking Behavior Study in Ghana (n = 661). The authors measured happiness with the cross-culturally validated item on a five-point scale. The GAD-7 and the CESD-8, respectively, assessed generalized anxiety and depressive symptoms. Participants reported nighttime and daytime SP in the last 30 days. The SPSS-based Hayes' PROCESS macro program (Model 6) was constructed to quantify the hypothesized mediation effect., Results: The analysis included 661 adults aged greater than or equal to 50 years (mean age = 65.53 [SD] = 11.89 years; 65.20% women). After full adjustment, path models showed that SP was negatively associated with happiness (β = -0.1277, 95%CI = -0.15950 to -0.096). Bootstrapping estimates revealed that the SP-happiness link was serially mediated via generalized anxiety representing 8.77%, depressive symptoms yielding 18.95%, and anxiety symptoms→depressive symptoms accounting for 26.70% of the total effect., Conclusion: Generalized anxiety and depressive symptoms may explain the negative association between SP and happiness in urban-dwelling older adults in the sub-Saharan African (SSA) context. Interventions, social and clinical, to improve happiness through sleep quality should include ways to improve mental health. Longitudinal and cross-cultural data are warranted to assess the bi-directionality of this relationship., (Copyright © 2023 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Vascular cognitive impairment (VCI) describes neurodegenerative disorders characterized by a vascular component. Pathologically, it involves decreased cerebral blood flow (CBF), white matter lesions, endothelial dysfunction, and blood-brain barrier (BBB) impairments. Molecularly, oxidative stress and inflammation are two of the major underlying mechanisms. Nitric oxide (NO) physiologically stimulates soluble guanylate cyclase (sGC) to induce cGMP production. However, under pathological conditions, NO seems to be at the basis of oxidative stress and inflammation, leading to a decrease in sGC activity and expression. The native form of sGC needs a ferrous heme group bound in order to be sensitive to NO (Fe(II)sGC). Oxidation of sGC leads to the conversion of ferrous to ferric heme (Fe(III)sGC) and even heme-loss (apo-sGC). Both Fe(III)sGC and apo-sGC are insensitive to NO, and the enzyme is therefore inactive. sGC activity can be enhanced either by targeting the NO-sensitive native sGC (Fe(II)sGC), or the inactive, oxidized sGC (Fe(III)sGC) and the heme-free apo-sGC. For this purpose, sGC stimulators acting on Fe(II)sGC and sGC activators acting on Fe(III)sGC/apo-sGC have been developed. These sGC agonists have shown their efficacy in cardiovascular diseases by restoring the physiological and protective functions of the NO-sGC-cGMP pathway, including the reduction of oxidative stress and inflammation, and improvement of vascular functioning. Yet, only very little research has been performed within the cerebrovascular system and VCI pathology when focusing on sGC modulation and its potential protective mechanisms on vascular and neural function. Therefore, within this review, the potential of sGC as a target for treating VCI is highlighted., Competing Interests: Declaration of Competing Interest JP has a proprietary interest in sGC agonists in the treatment of cognitive impairments. PS is a full time employee of Bayer AG, Pharmaceuticals. All other authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Fertility preservation (FP) is an important aspect of the care of transgender patients in whom Gender Affirming Medical Treatment (GAT) may begin before puberty is completed. While there are overall few studies that can be used to guide conversations about long-term effects of GAT, there are concerns that GAT could negatively impact fertility. Prior studies have shown low utilization of FP in this population, with avoidance of delay in starting GAT cited as one of the most common reasons for foregoing FP. It is possible that strategies to mitigate delay in commencement of GAT can facilitate higher FP utilization, maintaining options for future family building., Objective: To describe our institution's experience with Testicular Sperm Extraction (TESE) for FP and Histrelin Acetate (Supprelin) Subcutaneous Implantation for GAT commencement., Study Design: A retrospective review of transfeminine adolescents at our institution from 2010 to 2022 who underwent TESE for FP at the time of Supprelin placement for GAT (FP/SP). Outcomes of interest included successful sperm retrieval, age at first visit to our institution's Transgender Multispecialty Service Health clinic (GeMS), age at time of FP/SP, testicular volume, and Tanner stage at time of FP/SP, and age when GnRH agonist (GnRHa) therapy was prescribed. Testosterone, LH, FSH, and Inhibin B values prior to combination FP/SP were also obtained., Results: Ten patients from 2017 to 2022 underwent FP/SP after prescription of GnRHa based on Endocrine Society Guidelines. Successful sperm retrieval and storage was achieved in all patients. Median age at FP/SP was fourteen years 5.5 months (range 12y5m-16y8m). Median time from GnRHa prescription to FP/SP was two months (range 2-5 m). Mean testicular volume at time of FP/SP was 13.2 cc (SD 3.38 cc, range 8-17 cc), and median Tanner Stage was IV (range III-V). Average testosterone level was 301.60 (SD 173.04), LH 3.00 (SD 1.25), FSH 3.33 (SD 1.71), Inhibin B 208.50 (SD 87.44)., Conclusions: Performing TESE for FP is feasible for transgender youth undergoing Histrelin implant placement, leading to short delays in starting GAT. Testicular volume and endocrine markers can provide preoperative insight into likelihood of successful sperm retrieval during TESE, are needed to identify which patients will have successful sperm retrieval to ensure optimal counseling and informed decision making for providers, patients and families., (Copyright © 2023. Published by Elsevier Ltd.)

Ischemia reperfusion injury is a common precipitant of acute kidney injury that occurs following disrupted perfusion to the kidney. This includes blood loss and hemodynamic shock, as well as during retrieval for deceased donor kidney transplantation. Acute kidney injury is associated with adverse long-term clinical outcomes and requires effective interventions that can modify the disease process. Immunomodulatory cell therapies such as tolerogenic dendritic cells remain a promising tool, and here we tested the hypothesis that adoptively transferred tolerogenic dendritic cells can limit kidney injury. The phenotypic and genomic signatures of bone marrow-derived syngeneic or allogeneic, Vitamin-D3/IL-10-conditioned tolerogenic dendritic cells were assessed. These cells were characterized by high PD-L1:CD86, elevated IL-10, restricted IL-12p70 secretion and a suppressed transcriptomic inflammatory profile. When infused systemically, these cells successfully abrogated kidney injury without modifying infiltrating inflammatory cell populations. They also provided protection against ischemia reperfusion injury in mice pre-treated with liposomal clodronate, suggesting the process was regulated by live, rather than reprocessed cells. Co-culture experiments and spatial transcriptomic analysis confirmed reduced kidney tubular epithelial cell injury. Thus, our data provide strong evidence that peri-operatively administered tolerogenic dendritic cells have the ability to protect against acute kidney injury and warrants further exploration as a therapeutic option. This technology may provide a clinical advantage for bench-to-bedside translation to affect patient outcomes., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The evaluation of specific protein content in engineered tissues provides a gateway for developing regenerative medicine treatments. Since collagen type II, the major component of articular cartilage, is critical for the blossoming field of articular cartilage tissue engineering, the interest in this protein is growing rapidly. Accordingly, the need for quantification of collagen type II is increasing as well. In this study, we provide recent results for a new quantifying nanoparticle sandwich immunoassay technique for collagen type II. Since mesoporous palladium@platinum (Pd@Pt) nanoparticles have peroxidase-like catalytic activities, these nanoparticles were utilized in an enzyme-linked immunosorbent assay (ELISA)-like format to circumvent the need for traditional enzymes. These nanoparticles were easily conjugated with anti-collagen type II antibodies by the natural affinity interaction and used to develop a direct sandwich ELISA-like format for nanoparticle-linked immunosorbent assays. Using this method, we obtained a limit of detection of 1 ng mL -1 , a limit of quantification of 9 ng mL -1 . and a broad linear range between 1 ng mL -1 and 50 μg mL -1 for collagen type II with an average relative standard deviation of 5.5%, useable over a pH range of 7 - 9 at least. The assay was successfully applied to quantify collagen type II in cartilage tissues and compared with the results of commercial ELISAs and gene expression by reverse transcription-quantitative polymerase chain reaction. This method provides a thermally stable and cost-efficient alternative to traditional ELISAs. It also extends the application of nanoparticle-linked immunosorbent assays, thereby providing the potential to quantify other proteins and apply the technology in the medical, environmental, and biotechnology industry fields., 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 © 2023 Elsevier B.V. All rights reserved.)

Over the past ten years, there has been a rapid increase in the availability and use of mobile electroencephalography (mEEG) in research. Indeed, researchers using mEEG have recorded EEG and event-related brain potentials in a wide range of environments - for example, while walking (Debener et al., 2012), riding a bike (Scanlon et al., 2020), or even in a shopping mall (Krigolson et al., 2021). However, given that low-cost, ease-of-use, and setup speed provide the primary advantages of an mEEG system over large array traditional EEG systems, an important and unresolved question is just how many electrodes does an mEEG system need to collect research-quality EEG data? Here, we tested whether or not a two-channel forehead-mounted mEEG system - the "Patch" - could measure event-related brain potentials within their established amplitude and latency characteristics (Luck, 2014). In the present study, participants performed a visual oddball task while we recorded EEG data from the Patch. Our results demonstrated that we could capture and quantify the N200 and P300 event-related brain potential components using a minimal electrode array forehead-mounted EEG system. Our data further support the idea that mEEG can be used for quick and rapid EEG-based assessments, such as measuring the impact of concussions on the sports field (Fickling et al., 2021) or assessing the impact of stroke severity in a hospital (Wilkinson et al., 2020)., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: Research shows that health professionals should adapt their communication when addressing patients with limited health literacy (HL). However, the extent to which physiotherapists apply recommended communication techniques is unclear., Methods: We conducted a two phase mixed-method study, first holding focus group interviews among patients and experts on communication to explore the need for adjusted communication in physiotherapist-patient interaction. Second, we manually coded audio recordings of primary care physiotherapy consultations to investigate the extent to which physiotherapists applied these recommended communication techniques, and adjusted their communication towards patients with lower education., Results: Focus group interviews identified four categories of communication elements: the teach-back method, medical jargon explanation, summarizing patient's narratives, and checking patient's understanding. In 50 audio recordings we identified 2670 clauses. We report limited use of the recommended communication techniques; the teach-back method was used in 2% of consultations (95%CI: 0.4%-10.5%) while medical jargon explanation was used in 84% (95%CI: 71.5%-91.7%). Mixed effects logistic regression models showed no association between lower education and communication techniques., Conclusion: Although physiotherapists need to adjust their communication to patients with lower education, they rarely apply the recommended communication techniques., Practice Implications: Knowledge about limited HL among physiotherapists needs to be increased., 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 © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The combined effects of multiple environmental toxicants and social stressor exposures are widely recognized as important public health problems, likely contributing to health inequities. However, US policy makers at state and federal levels typically focus on one stressor exposure at a time and have failed to develop comprehensive strategies to reduce multiple co-occurring exposures, mitigate cumulative risks and prevent harm. This research aimed to move from considering disparate environmental stressors in isolation to mapping the links between environmental, economic, social and health outcomes as a dynamic complex system using children's exposure to neurodevelopmental toxicants as an illustrative example. Such a model can be used to support a broad range of child developmental and environmental health policy stakeholders in improving their understanding of cumulative effects of multiple chemical, physical, biological and social environmental stressors as a complex system through a collaborative learning process., Methods: We used system dynamics (SD) group model building to develop a qualitative causal theory linking multiple interacting streams of social stressors and environmental neurotoxicants impacting children's neurodevelopment. A 2 1/2-day interactive system dynamics workshop involving experts across multiple disciplines was convened to develop the model followed by qualitative survey on system insights., Results: The SD causal map covered seven interconnected themes: environmental exposures, social environment, health status, education, employment, housing and advocacy. Potential high leverage intervention points for reducing disparities in children's cumulative neurotoxicant exposures and effects were identified. Workshop participants developed deeper level of understanding about the complexity of cumulative environmental health risks, increased their agreement about underlying causes, and enhanced their capabilities for integrating diverse forms of knowledge about the complex multi-level problem of cumulative chemical and non-chemical exposures., Conclusion: Group model building using SD can lead to important insights to into the sociological, policy, and institutional mechanisms through which disparities in cumulative impacts are transmitted, resisted, and understood., 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 © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The spatial architecture of the tumour microenvironment and phenotypic heterogeneity of tumour cells have been shown to be associated with cancer prognosis and clinical outcomes, including survival. Recent advances in highly multiplexed imaging, including imaging mass cytometry (IMC), capture spatially resolved, high-dimensional maps that quantify dozens of disease-relevant biomarkers at single-cell resolution, that contain potential to inform patient-specific prognosis. Existing automated methods for predicting survival, on the other hand, typically do not leverage spatial phenotype information captured at the single-cell level. Furthermore, there is no end-to-end method designed to leverage the rich information in whole IMC images and all marker channels, and aggregate this information with clinical data in a complementary manner to predict survival with enhanced accuracy. To that end, we present a deep multimodal graph-based network (DMGN) with two modules: (1) a multimodal graph-based module that considers relationships between spatial phenotype information in all image regions and all clinical variables adaptively, and (2) a clinical embedding module that automatically generates embeddings specialised for each clinical variable to enhance multimodal aggregation. We demonstrate that our modules are consistently effective at improving survival prediction performance using two public breast cancer datasets, and that our new approach can outperform state-of-the-art methods in survival prediction., 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 © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Rheumatoid arthritis is the most common autoimmune disease worldwide and requires long-term treatment to suppress inflammation. Currently, treatment is started when arthritis is clinically apparent. We aimed to evaluate whether earlier intervention, in the preceding phase of arthralgia and subclinical joint inflammation, could prevent the development of clinical arthritis or reduce the disease burden., Methods: We conducted a randomised, double-blind, placebo-controlled, proof-of-concept-trial at the Leiden University Medical Centre, Leiden, Netherlands. Adults aged 18 years or older with arthralgia clinically suspected of progressing to rheumatoid arthritis and MRI-detected subclinical joint inflammation were eligible for enrolment across 13 rheumatology outpatient clinics in the southwest region of the Netherlands and randomly assigned (1:1) to a single intramuscular glucocorticoid injection (120 mg) and a 1-year course of oral methotrexate (up to 25 mg/week), or placebo (single injection and tablets for 1 year). Participants and investigators were masked to group assignment. Follow-up continued for 1 year after the end of the 1-year treatment period. The primary endpoint was development of clinical arthritis (fulfilling the 2010 rheumatoid arthritis classification criteria or involving two or more joints) that persisted for at least 2 weeks. Patient-reported physical functioning, symptoms, and work productivity were secondary endpoints, which were measured every 4 months. Additionally, the course of MRI-detected inflammation was studied. All participants entered the intention-to-treat analysis. This trial is registered with EudraCT, 2014-004472-35, and the Netherlands Trial Register, NTR4853-trial-NL4599., Findings: Between April 16, 2015, and Sept 11, 2019, 901 patients were assessed for eligibility and 236 were enrolled and randomly assigned to active treatment (n=119) or placebo (n=117). At 2 years, the frequency of the primary endpoint was similar between the groups (23 [19%] of 119 participants in the treatment group vs 21 [18%] of 117 in the placebo group; hazard ratio 0·81, 95% CI 0·45 to 1·48). Physical functioning improved more in the treatment group during the first 4 months and remained better than in the placebo group (mean between-group difference in Health Assessment Questionnaire disability index over 2 years: -0·09, 95% CI -0·16 to -0·03; p=0·0042). Similarly, pain (on scale 0-100, mean between-group difference: -8, 95% CI -12 to -4; p<0·0001), morning stiffness of joints (-12, -16 to -8; p<0·0001), presenteeism (-8%, -13 to -3; p=0·0007), and MRI-detected joint inflammation (-1·4 points, -2·0 to -0·9; p<0·0001) showed sustained improvement in the treatment group compared with the placebo group. The number of serious adverse events was equal in both groups; adverse events were consistent with the known safety profile for methotrexate., Interpretation: Methotrexate, the cornerstone treatment of rheumatoid arthritis, initiated at the pre-arthritis stage of symptoms and subclinical inflammation, did not prevent the development of clinical arthritis, but modified the disease course as shown by sustained improvement in MRI-detected inflammation, related symptoms, and impairments compared with placebo., Funding: Dutch Research Council (NWO; Dutch Arthritis Society)., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Context: Clinical guidelines are available to enhance symptom management during cancer treatment but often are not used in the practice setting. Clinical decision support can facilitate the implementation and adherence to clinical guidelines. and improve the quality of cancer care., Objectives: Clinical decision support offers an innovative approach to integrate guideline-based symptom management into oncology care. This study evaluated the effect of clinical decision support-based recommendations on clinical management of symptoms and health-related quality of life (HR-QOL) among outpatients with lung cancer., Methods: Twenty providers and 179 patients were allotted in group randomization to attention control (AC) or Symptom Assessment and Management Intervention (SAMI) arms. SAMI entailed patient-report of symptoms and delivery of recommendations to manage pain, fatigue, dyspnea, depression, and anxiety; AC entailed symptom reporting prior to the visit. Outcomes were collected at baseline, two, four and six-months. Adherence to recommendations was assessed through masked chart review. HR-QOL was measured by the Functional Assessment of Cancer Therapy-Lung questionnaire. Descriptive statistics with linear and logistic regression accounting for the clustering structure of the design and a modified chi-square test were used for analyses., Results: Median age of patients was 63 years, 58% female, 88% white, and 32% ≤high school education. Significant differences in clinical management were evident in SAMI vs. AC for all target symptoms that passed threshold. Patients in SAMI were more likely to receive sustained-release opioids for constant pain, adjuvant medications for neuropathic pain, opioids for dyspnea, stimulants for fatigue and mental health referrals for anxiety. However, there were no statistically significant differences in HR-QOL at any time point., Conclusion: SAMI improved clinical management for all target symptoms but did not improve patient outcomes. A larger study is warranted to evaluate effectiveness., (Copyright © 2021 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Junctional ectopic tachycardia (JET) is a common arrhythmia after congenital heart disease surgery. There is variability in the choice of antiarrhythmic therapy, with amiodarone used commonly. Intravenous (IV) sotalol is a newly available agent that may be useful for JET., Objective: The purpose of this study was to evaluate the safety and efficacy of IV sotalol for postoperative JET and compare outcomes with IV amiodarone., Methods: This is a retrospective single-center study of all patients who received IV sotalol or IV amiodarone for postoperative JET at Texas Children's Hospital from December 15, 2015, to December 15, 2020. Data included antiarrhythmic efficacy, hemodynamics, and adverse effects. Successful JET control was defined as a decrease in JET rate to <170 beats/min (or decrease by >20%), or conversion to sinus rhythm, with persistent control over 24 hours without requiring alternative antiarrhythmics or mechanical support., Results: A total of 32 patients (median age 71 days; interquartile range 17-221 days) received IV amiodarone (n = 20 [62%]) or IV sotalol (n = 12 [38%]) for postoperative JET. Amiodarone was successful in treating JET in 75% of cases; sotalol was successful in 83%. The JET rate decreased faster over the first 90 minutes after a sotalol bolus (25 beats/min per hour) than after an amiodarone bolus (8 beats/min per hour) (P < .01); no heart rate difference was seen after 24 hours. Amiodarone infusion was discontinued early because of hypotension/bradycardia in 2 patients; this was not required in any patients receiving sotalol., Conclusion: For children with postoperative JET, both IV sotalol and amiodarone are safe and efficacious. IV sotalol may lead to a faster improvement in heart rate., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objectives: This longitudinal case-control study aimed to determine the frequency of polymicrobial enteric detections in Ghanaian infants with and without diarrhoea., Methods: Infants aged 1-12 months with and without diarrhoea attending the outpatient department of a peri-urban Ghanaian hospital were prospectively assessed and stool samples were collected on days 0, 6 and 28 and analysed for 18 enteric pathogens with PCR., Results: At least one enteric pathogen was detected in 100 of 107 cases with diarrhoea (93%) and in 82 of 97 controls (85%). The number of pathogens was higher in cases than in controls (median three versus two pathogens, p 0.001). The adjusted attributable fraction (AF) for diarrhoea was highest for enterotoxigenic Escherichia coli (7.2%, 95% CI -2.0% to 16.3%), rotavirus (4.1%, 95% CI 0.6%-7.5%), Giardia lamblia (2.3%, 95% CI -0.7 to 5.3%) and astrovirus (2.3%, 95% CI -2.9 to 7.5%). In cases, a higher pathogen number was significantly associated with watery stool consistency (median 3, interquartile range (IQR) 2-5 versus median 2.5, IQR 1-4, p 0.014), stool frequency five or more per day (median 4, IQR 3-5 versus median 3, IQR 2-4, p 0.048) and vomiting (median 4, IQR 3-5 versus median 3, IQR 2-4, p 0.025). During follow-up, 94% (78/83) of cases and 85% (67/79) of controls had acquired at least one new pathogen without developing a new episode of diarrhoea., Conclusion: Enteric pathogens could be identified in the stool of the vast majority of Ghanaian infants, whereby pathogens were very frequently acquired without resulting in new episodes of diarrhoea during follow-up. A higher number of co-occurring pathogens may increase the risk of diarrhoea and disease severity., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Menopause represents an endocrine challenge to urogenital health, as oestrogens deprivation and androgens decline significantly contributes to age-related involution of vulvovaginal tissues and lower urinary tract. Genitourinary syndrome of menopause (GSM) is a clinical entity including the chronic and progressive condition of vulvovaginal atrophy (VVA) and encompassing both anatomical and functional consequences of menopause. The term GSM describes genital, sexual and urinary symptoms with a detrimental impact on quality of life (QOL). Several treatment options are available, but many barriers are still present to adequately diagnose and treat GSM. This review aims to present current evidences about epidemiology, aetiology, diagnosis and treatment of GSM, with a focus on prescription medications [low-dose local oestrogen therapy (LET), prasterone (DHEA) and the SERM ospemifene] for urogenital symptoms in healthy postmenopausal women and in special populations, including women with premature ovarian insufficiency (POI) and breast cancer survivors (BCS)., Competing Interests: Declaration of competing interest The present work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. R.E.N. had past financial relationships (lecturer, member of advisory boards, and/or consultant) with Boehringer Ingelheim, Eli Lilly, Endoceutics, Gedeon Richter, HRA Pharma, Merck Sharpe & Dohme, Procter & Gamble Co, TEVA Women's Health Inc, and Zambon SpA. At present, she has on-going relationships with Abbott, Astellas, Bayer HealthCare AG, Exceltis, Fidia, Gedeon Richter, Novo Nordisk, Organon & Co, Palatin Technologies, Pfizer Inc, Shionogi Limited, and Theramex. L.C. declare no competing interests for the present work., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Higher maternal cow-milk intake during pregnancy is associated with higher fetal growth measures and higher birth weight., Objective: The aim of this study was to assess the associations of maternal milk intake during pregnancy with body fat measures and cardiometabolic risk factors at the age of 10 y., Methods: In a population-based cohort of Dutch mothers and their children (n = 2466) followed from early pregnancy onwards, we assessed maternal first-trimester milk intake (milk and milk drinks) by food-frequency questionnaire. Maternal milk intake was categorized into 0-0.9, 1-1.9, 2-2.9, 3-3.9, 4-4.9, and ≥5 glasses/d, with 1 glass equivalent to 150 mL milk. For children at the age of 10 y, we calculated BMI and obtained detailed measures of body and organ fat by DXA and MRI. We also measured blood pressure and lipid, insulin, and glucose concentrations. Data were analyzed using linear and logistic regression models., Results: Compared with children whose mothers consumed 0-0.9 glass of milk/d during their pregnancy, those whose mothers consumed ≥5 glasses of milk/d had a 0.29 SD (95% CI: 0.10, 0.48) higher BMI, 0.27 SD (95% CI: 0.08, 0.47) higher fat mass, 0.26 SD (95% CI: 0.07, 0.46) higher lean mass, 0.30 SD (95% CI: 0.09, 0.50) higher android-to-gynoid fat mass ratio and 0.38 SD (95% CI: 0.09, 0.67) higher abdominal visceral fat mass. After correction for multiple comparisons, groups of maternal milk intake were not associated with pericardial fat mass index, liver fat fraction, blood pressure, or lipid, insulin, or glucose concentrations (P values >0.0125)., Conclusions: Our results suggest that maternal first-trimester milk intake is positively associated with childhood general and abdominal visceral fat mass and lean mass, but not with other cardiometabolic risk factors., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

No literature is available on the benign versus malignant breast lesion ratio in trans women (male sex assigned at birth, female gender identity). As hormone treatment in trans women results in breast tissue histologically comparable with cis (non-trans) women, breast pathology may be expected. Previously, an increased breast cancer risk compared with cis men have been observed. We aimed to investigate the frequency and outcomes of breast biopsies in trans women. Therefore, we retrospectively examined the medical files of 2616 trans women. To gain data on breast lesions, we linked our cohort to a national pathology database. In this study we found that 126 people (5%) had one or more breast biopsies (n = 139). Of these, 21 trans women had a breast biopsy before the start of hormone treatment, and 53 after the start of hormone treatment. Breast biopsies were performed predominantly because of abnormalities during physical examination (37%, n = 51/139 biopsies), or because of capsular formation or contraction (28%, n = 16/57 biopsies) in trans women with breast implants. The most common breast lesions after the start of hormone treatment were fibroadenomas (n = 20), breast cancer (n = 6), fibrosis (n = 5), cysts (n = 4), and infections (n = 4). The benign versus malignant breast biopsy ratio was 88:12, which is comparable to the ratio in cis women (90:10). This study shows breast lesions in a limited number of trans women. Since the indications and outcomes of biopsies in trans women were similar to those in cis women, it seems reasonable to follow breast care guidelines as developed for cis women., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Media attention to marine plastic pollution is increasing, yet it is unclear which topics are being discussed. This paper analyses all 2019 news articles referencing marine plastics in the four leading UK online newspapers. Examining 943 articles in a structural topic model, this is the first analysis to depict what is being reported and how this varied according to political alignment (right vs. left-wing), type (broadsheet vs. tabloid), and publication date. We identified 36 topics, suggesting a large variety in the coverage, with plastic pollution ranging from the primary focus to only mentioned in passing. Greater emphasis was on explaining current issues of marine plastics, with limited reference to actionable reduction measures or producer responsibility. Many topics' prevalence varied across the media outlets. We discuss how this coverage varies across media outlets, and how it relates to a broader context (i.e. potential links to behaviour and current policy efforts)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Heart failure (HF) patients experience a high burden of symptoms and functional limitations, and morbidity and mortality remain high despite successful therapies. The majority of HF drugs in the United States are approved for reducing hospitalization and mortality, while only a few have indications for improving quality of life, physical function, or symptoms. Patient-reported outcomes that directly measure patient's perception of health status (symptoms, physical function, or quality of life) are potentially approvable endpoints in drug development. This paper summarizes the history of endpoints used for HF drug approvals in the United States and reviews endpoints that measure symptoms, physical function, or quality of life in HF patients., (Copyright © 2020. Published by Elsevier Inc.)

Acute kidney injury (AKI) is a major clinical concern in sickle cell disease (SCD). Clinical evidence suggests that red cell alarmins may cause AKI in SCD, however, the sterile inflammatory process involved has hitherto not been defined. We discovered that hemopexin deficiency in SCD is associated with a compensatory increase in α-1-microglobulin (A1M), resulting in an up to 10-fold higher A1M-to-hemopexin ratio in SCD compared with healthy controls. The A1M-to-hemopexin ratio is associated with markers of hemolysis and AKI in both humans and mice with SCD. Studies in mice showed that excess heme is directed to the kidneys in SCD in a process involving A1M causing AKI, whereas excess heme in controls is transported to the liver as expected. Using genetic and bone marrow chimeric tools, we confirmed that hemopexin deficiency promotes AKI in sickle mice under hemolytic stress. However, AKI was blocked when hemopexin deficiency in sickle mice was corrected with infusions of purified hemopexin prior to the induction of hemolytic stress. This study identifies acquired hemopexin deficiency as a risk factor of AKI in SCD and hemopexin replacement as a potential therapy., (© 2020 by The American Society of Hematology.)

Background: ABO blood group antigens in the liver are expressed mainly on endothelial cells or biliary epithelial cells but not on hepatocytes. This suggests that ABO-incompatible hepatocyte transplantation (ABOi-HTx) is theoretically feasible. However, the effects of stress on ABO blood group antigen expression caused by isolation and intraportal infusion require thorough investigation before ABOi-HTx can be implemented in clinical settings., Methods: Human hepatocytes were isolated from liver tissue obtained from liver resection or deceased donor livers. The expression of blood group antigens on cryopreserved human liver tissues and isolated hepatocyte smear specimens were examined by immunofluorescent staining. The effect of proinflammatory cytokines on blood group antigen expression of hepatocytes was evaluated by flow cytometry. Instant blood-mediated inflammatory reaction after hepatocyte incubation with ABO-incompatible whole blood was examined using the tubing loop model., Results: Blood group antigens were mainly expressed on vessels in the portal area. In hepatocyte smear specimens, isolated hepatocytes did not express blood group antigens. In contrast, a subset of cells in the smear specimens of nonparenchymal liver cells stained positive. In the flow cytometry analysis, isolated hepatocytes were negative for blood group antigens, even after 4-h incubation with cytokines. Platelet counts and complement activation were not significantly different in ABO-identical versus ABO-incompatible settings in the tubing loop model., Conclusion: Our study showed that blood group antigens were not expressed on hepatocytes, even after isolation procedures or subsequent incubation with cytokines. This finding is an important step toward removing the restriction of ABO matching in hepatocyte transplantation. Our results suggest that ABOi-HTx is a feasible therapeutic option, especially in patients who require urgent treatment with freshly isolated hepatocytes, such as those with acute liver failure., (© 2019 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objective: This study examined the role of migration and acculturation in the diet of Ghanaian migrants in Europe by (1) comparing food intake of Ghanaian migrants in Europe with that of Ghanaians living in Ghana and (2) assessing the association between acculturation and food intake., Design: Data from the cross-sectional multicenter study Research on Obesity and Diabetes among African Migrants were used. Food intake was assessed using a Ghana-specific food propensity questionnaire (134 items and 14 food groups); foods were grouped based on a model of dietary change proposed by Koctürk-Runefors., Setting: Ghana, London, Amsterdam, and Berlin., Participants: A total of 4,534 Ghanaian adults living in Ghana and Europe, with complete dietary data. Of these, 1,773 Ghanaian migrants had complete acculturation data., Main Outcome Measure: Food intake (the weighted intake frequency per week of food categories)., Analysis: Linear regression., Results: Food intake differed between Ghanaians living in Ghana and Europe. Among Ghanaian migrants in Europe, there were inconsistent and small associations between acculturation and food intake, except for ethnic identity, which was consistently associated with intake only of traditional staples., Conclusions and Implications: Findings indicate that migration is associated with dietary changes that cannot be fully explained by ethnic, cultural, and social acculturation. The study provides limited support to the differential changes in diet suggested by the Koctürk-Runefors' model of dietary change., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Different treatment options for patients with arthrogenous Temporomandibular Disorders (TMDs) have been reported. However, evidence regarding the most effective intervention using network meta-analysis (NMA) has not been performed. Thus, we conducted a NMA of randomized clinical trials (RCTs) to identify the most effective treatment of arthrogenous TMDs with respect to pain reduction and improved mouth opening, and to generate a ranking according to their effectiveness., Material and Methods: An electronic search on three major databases was undertaken to identify RCTs published before August 2019, comparing up to fourteen different treatments against control/placebo patients for arthrogenous TMDs with respect to pain reduction and improved mouth opening. The treatment variables were controls/placebo, conservative treatment (muscle exercises and occlusal splint therapy), occlusal splint therapy alone, intraarticular injection (IAI) of hyaluronic acid (HA) or corticosteroid (CS), arthrocentesis with or without HA, CS and platelet-rich plasma (PRP), arthroscopy with or without HA and PRP, open joint surgery, and physiotherapy. Frequentist NMA was performed using STATA software. Studies meeting the inclusion criteria were divided according to the length of follow-up (short-term (≤5 months) and intermediate-term (≥6 months to 4 years) and type of TMJ arthrogenous disorders; internal derangement (ID) and TMJ osteoarthritis (OA). The standardized mean differences (SMD) in post-treatment pain reduction and maximum mouth opening (MMO) were analysed., Results: Thirty-six RCTs were identified that performed comparative outcome assessments for pain and 33 RCTs for MMO. At the short term (≤5 months), IAI-HA (SMD = -2.8, CI: -3.7 to -1.8) and IAI-CS (SMD = -2.11, CI: -2.9 to -1.2) (all very low quality evidence) achieved a substantially greater pain reduction than control/placebo. At intermediate term (≥6 months), a statistically significant decrease in posttreatment pain intensity was observed following Arthroscopy-PRP (SMD = -3.5, CI: -6.2 to -0.82), Arthrocentesis-PRP (SMD = -3.08, CI: -5.44 to -0.71), Arthroscopy-HA (SMD = -3.01, CI: -5.8 to -0.12), TMJ surgery (SMD = -3, CI: -5.7 to -0.28), IAI-HA (SMD = -2.9, CI: -4.9 to -1.09) (all very low quality evidence), Arthroscopy-alone (SMD = -2.6, CI: -5.1 to -0.07, low quality evidence) and Arthrocentesis-HA (SMD = -2.3, CI: -4.5 to -018, moderate-quality evidence) when compared to the control/placebo groups. Relative to MMO, the most effective treatments for short- and intermediate-term improvement were the arthroscopy procedures (PRP > HA > alone, all very low-quality evidence) followed by Arthrocentesis-PRP (very low-quality evidence) and Arthrocentesis-HA (moderate-quality evidence). The non-invasive procedures of occlusal splint therapy, physical therapy, conservative therapy, placebo/control provided significantly lower quality outcomes relative to pain and MMO., Conclusion: The results of the present meta-analysis support a paradigm shift in arthrogenous TMJ disorder treatment. There is a new evidence (though on a very low to moderate quality level) that minimally invasive procedures, particularly in combination with IAI of adjuvant pharmacological agents (PRP, HA or CS), are significantly more effective than conservative treatments for both pain reduction and improvement of MMO in both short (≤5 months) and intermediate term (6 months-4 years) periods. In contrast to traditional concepts mandating exhaustion of conservative treatment options, minimally invasive procedures, therefore, deserve to be implemented as efficient first-line treatments (e.g. IAIs and/or arthrocentesis) or should be considered rather early, i.e. as soon as patients do not show a clear benefit from an initial conservative treatment., (Copyright © 2019 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Brain volumes computed from magnetic resonance images have potential for assisting with the diagnosis of individual dementia patients, provided that they have low measurement error and high reliability. In this paper we describe and validate icobrain dm, an automatic tool that segments brain structures that are relevant for differential diagnosis of dementia, such as the hippocampi and cerebral lobes. Experiments were conducted in comparison to the widely used FreeSurfer software. The hippocampus segmentations were compared against manual segmentations, with significantly higher Dice coefficients obtained with icobrain dm (25-75th quantiles: 0.86-0.88) than with FreeSurfer (25-75th quantiles: 0.80-0.83). Other brain structures were also compared against manual delineations, with icobrain dm showing lower volumetric errors overall. Test-retest experiments show that the precision of all measurements is higher for icobrain dm than for FreeSurfer except for the parietal cortex volume. Finally, when comparing volumes obtained from Alzheimer's disease patients against age-matched healthy controls, all measures achieved high diagnostic performance levels when discriminating patients from cognitively healthy controls, with the temporal cortex volume measured by icobrain dm reaching the highest diagnostic performance level (area under the receiver operating characteristic curve = 0.99) in this dataset., Competing Interests: Declaration of Competing Interest The following authors are employed (or have been employed at the time of performing the work relevant for this paper) by icometrix: Hanne Struyfs, Diana M. Sima, Annemie Ribbens, Nuno Pedrosa de Barros, Thanh Vân Phan, Lene Claes, Maria Ines Ferraz Meyer, Wim Van Hecke, Dirk Smeets. Melissa Wittens and Ellis Niemantsverdriet have no competing interests. Sebastiaan Engelborghs has received unrestricted research grants from Janssen Pharmaceutica NV and ADx Neurosciences (paid to institution)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: This survey-based study was undertaken to investigate how total debt loads are impacting the personal and professional decisions made by graduating oral and maxillofacial surgery (OMS) residents. The aim of this study was to evaluate differences in total debt load on graduating residents and analyze the effects of this debt on career, family, and lifestyle choices after graduation., Study Design: This study was a cross-sectional, web-based survey of all graduating OMS residents in accredited OMS residency programs in the United States. Participation in the survey was optional, and all responses were anonymously collected and the data analyzed by using Qualtrics software. The respondents were analyzed as a collective, with the predictor of the study being program training length and the outcome being total debt load, with independent analysis of select other financial variables., Results: For the 246 deliverable emails, there were 120 respondents (48.7% response rate). The average graduating OMS resident was a Caucasian male (median age 32 years), living with a significant other or spouse who independently earned money, and had no dependents. The average range of accumulated debt of graduating residents was between $300,000 and $350,000, with 50.83% of the respondents having $350,000 or less in overall debt and 49.17% of the respondents having $350,000 or greater in accumulated debt. For those respondents completing 4-year programs, the average range of accumulated debt was between $250,000 and $300,000, and for those respondents completing 6-year programs, the average range of accumulated debt was between $400,000 and $450,000 (P < .08)., Conclusions: Graduating OMS residents carry with them a significant amount of debt whether graduating from a 4-year program or a 6-year program. However, when subjectively queried, most of these residents stated they would again choose OMS as a career choice., (Copyright © 2019. Published by Elsevier Inc.)

Background and Aims: African populations have a favourable lipid profile compared to European populations. However, the extent to which they differ between rural and urban settings in Africa and upon migration to Europe is unknown. We assessed the lipid profiles of Ghanaians living in rural- and urban-Ghana and Ghanaian migrants living in three European countries., Methods: We used data from a multi-centre, cross-sectional study among Ghanaian adults residing in rural- and urban-Ghana and London, Amsterdam and Berlin (n = 5482). Dyslipidaemias were defined using the 2012 European Guidelines on Cardiovascular Prevention. Comparisons between groups were made using age-standardised prevalence and prevalence ratios (PRs) with adjustments for important covariates., Results: In both sexes, the age-standardised prevalence of high total cholesterol (TC) and LDL-cholesterol (LDL-C) was lower in rural- than in urban-Ghana and Ghanaian migrants in Europe. Adjusted PRs of high TC and LDL-C were higher in urban-Ghana (TC PR = 2.15, 95%confidence interval 1.69-2.73) and Ghanaian migrant men (TC PR = 2.03 (1.56-2.63)) compared to rural-Ghana, but there was no difference between rural- and Ghanaian migrant women (TC PR = 1.01 (0.84-1.22)). High triglycerides levels were as prevalent in rural-Ghana (11.6%) as in urban-Ghana (12.8%), but were less prevalent in Ghanaian migrant women (2.0%). In both sexes, low HDL-cholesterol was most prevalent in rural-Ghana (50.1%) and least prevalent in Europe (12.9%)., Conclusion: The lipid profile varied among ethnically homogeneous African populations living in different geographical locations in Africa and Europe. Additional research is needed to identify factors driving these differential risks to assist prevention efforts., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The Water Framework Directive (WFD) is a pioneering piece of legislation that aims to protect and enhance aquatic ecosystems and promote sustainable water use across Europe. There is growing concern that the objective of good status, or higher, in all EU waters by 2027 is a long way from being achieved in many countries. Through questionnaire analysis of almost 100 experts, we provide recommendations to enhance WFD monitoring and assessment systems, improve programmes of measures and further integrate with other sectoral policies. Our analysis highlights that there is great potential to enhance assessment schemes through strategic design of monitoring networks and innovation, such as earth observation. New diagnostic tools that use existing WFD monitoring data, but incorporate novel statistical and trait-based approaches could be used more widely to diagnose the cause of deterioration under conditions of multiple pressures and deliver a hierarchy of solutions for more evidence-driven decisions in river basin management. There is also a growing recognition that measures undertaken in river basin management should deliver multiple benefits across sectors, such as reduced flood risk, and there needs to be robust demonstration studies that evaluate these. Continued efforts in 'mainstreaming' water policy into other policy sectors is clearly needed to deliver wider success with WFD goals, particularly with agricultural policy. Other key policy areas where a need for stronger integration with water policy was recognised included urban planning (waste water treatment), flooding, climate and energy (hydropower). Having a deadline for attaining the policy objective of good status is important, but even more essential is to have a permanent framework for river basin management that addresses the delays in implementation of measures. This requires a long-term perspective, far beyond the current deadline of 2027., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Typhoid fever, caused by the bacterium Salmonella enterica subsp. enterica serovar Typhi, is an important cause of blood stream infections in the tropics, for which easy-to-apply molecular diagnostic approaches are desirable. The diagnostic performance of a newly introduced and a previously described loop-mediated isothermal amplification (LAMP) approach using different primer sets on a Genie II Mk2 device for the identification of Salmonella enterica ssp. enterica ser. Typhi was evaluated with well-characterized residual materials from the tropics in a case control-based approach. After in-vitro confirmation of binding characteristics of both LAMP primer sets with culture isolates (n = 112), sensitivity and specificity were 100% for the newly designed new LAMP primer set 1 with incubated blood culture materials, while specificity was reduced to 97.1% for primer set 2. For 170 EDTA blood samples, sensitivity and specificity were 10% and 98.3% for primer set 1 as well as 38.0% and 83.3% for primer set 2, respectively; qPCR from EDTA blood did not score much better with 10% sensitivity and 100% specificity. LAMP using a Genie II Mk2 device is suitable for the identification of Salmonella enterica spp. enterica ser. Typhi from incubated blood culture materials. Sensitivity and specificity were insufficient for diagnosis directly from EDTA blood samples but LAMP showed similar sensitivity as qPCR., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Disease-modifying treatment trials are increasingly advanced to the prodromal or preclinical phase of Alzheimer's disease (AD), and inclusion criteria are based on biomarkers rather than clinical symptoms. Therefore, it is of great interest to determine which biomarkers should be combined to accurately predict conversion from mild cognitive impairment (MCI) to AD dementia. However, up to date, only few studies performed a complete A/T/N subject characterization using each of the CSF and imaging markers, or they only investigated long-term (≥ 2 years) prognosis. This study aimed to investigate the association between cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), amyloid- and 18 F-FDG positron emission tomography (PET) measures at baseline, in relation to cognitive changes and conversion to AD dementia over a short-term (12-month) period. We included 13 healthy controls, 49 MCI and 16 AD dementia patients with a clinical-based diagnosis and a complete A/T/N characterization at baseline. Global cortical amyloid-β (Aβ) burden was quantified using the 18 F-AV45 standardized uptake value ratio (SUVR) with two different reference regions (cerebellar grey and subcortical white matter), whereas metabolism was assessed based on 18 F-FDG SUVR. CSF measures included Aβ 1-42 , Aβ 1-40 , T-tau, P-tau 181 , and their ratios, and MRI markers included hippocampal volumes (HV), white matter hyperintensities, and cortical grey matter volumes. Cognitive functioning was measured by MMSE and RBANS index scores. All statistical analyses were corrected for age, sex, education, and APOE ε4 genotype. As a result, faster cognitive decline was most strongly associated with hypometabolism (posterior cingulate) and smaller hippocampal volume (e.g., Δstory recall: β = +0.43 [p < 0.001] and + 0.37 [p = 0.005], resp.) at baseline. In addition, faster cognitive decline was significantly associated with higher baseline Aβ burden only if SUVR was referenced to the subcortical white matter (e.g., Δstory recall: β = -0.28 [p = 0.020]). Patients with MCI converted to AD dementia at an annual rate of 31%, which could be best predicted by combining neuropsychological testing (visuospatial construction skills) with either MRI-based HV or 18 F-FDG-PET. Combining all three markers resulted in 96% specificity and 92% sensitivity. Neither amyloid-PET nor CSF biomarkers could discriminate short-term converters from non-converters., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the effect of temporomandibular joint (TMJ) disc repositioning and post-operative functional splint for the treatment of anterior disc displacement (ADD) in juvenile patients with Class II malocclusion., Materials and Methods: Juvenile patients (≤20 years) who had bilateral TMJ ADD with and Class II malocclusion treated by disc repositioning and functional splints were included in the study. Magnetic resonance imaging (MRI) and cephalometric radiographs before surgery (T0), immediately after surgery (T1) and more than 3 months after surgery (T3) were obtained in all patients. Cephalometric values including condylar height, overjet, SNA, SNB and pogonion position etc. were measured and compared before and after disc repositioning by statistical analysis. Fourteen patients (13 female, 1 male) were included in this study. Their average age was 16.7 years (range, 12-20 years)., Results: Seven patients with 14 joints had an MRI at least 6 months (6-24 months, mean 14.3) prior to disc repositioning. When compared to the MRI taken just prior to surgery, of those 14 joints, 9 condyles (64.3%) had evidence of bone resorption, 5 condyles (35.7%) had new bone formation mostly at the posterior part of the condyle (21.4%). These MRIs showed the condylar height was reduced 0.81 mm ± 0.61 (P = 0.013). Pre-operative cephalometric radiographs showed increased overjet (P = 0.039). The mean post-operative follow-up was 9.4 months (range, 4-13 months). Postoperative MRI showed the condylar height increased 1.74 ± 0.98 mm after disc repositioning (P < 0.001). Newly generated bone was observed on all condyles. 84.6% of the new bone was formed on the superior and posterior-anterior surfaces. Postoperative cephalometric radiographs showed the SNB angle increased 1.83 ± 1.56°(P < 0.001), pogonion position (pg'-G') moved anteriorly 2.18 ± 3.13 mm (P = 0.028) and incisor overjet decreased 3.55 ± 1.86 mm (P < 0.001), whereas significant changes were not found in SNA, Sn - G Vert, Y-Axis, U1 SN, IMPA (L1-MP) and U1-L1 (P > 0.05)., Conclusion: Conservative treatment for ADD with Class II malocclusion in juvenile patients may cause condyle resorption and aggravate the dentofacial deformity. Disc repositioning combined with post-operative functional splints can effectively promote condylar growth and help correct the dentofacial deformity., (Copyright © 2018 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Overhauser-enhanced Magnetic Resonance Imaging (OMRI) is a double resonance technique applied for oxygen imaging in aqueous samples and biological tissues. In this report, we present an improved OMRI approach of oxygen measurement using the single line "Finland" trityl spin probe. Compared to a traditional approach, we introduced an additional mechanism of leakage of spin polarization due to an interaction of a spin system with oxygen. The experimental comparison of the new approach with an oxygen-dependent leakage factor to a traditional approach performed in phantom samples in vitro, and mouse tumor model in vivo, shows improved accuracy of determination of oxygen and contrast agent concentrations., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: The aim of the study was to compare bone adaptation after design modification in Biomet stock prostheses., Materials and Methods: Computed tomography (CT) data of the patients treated with a Biomet TMJ replacement from 2010 to 2016 were recruited. Fossa prosthesis with a bulge and 4 types of condyle-ramus angle prostheses were virtually designed and implanted by computer-assisted simulation. The amount of bone trimming including fossa, mandibular ramus and bone graft were measured by ProPlan CMF 1.4 software. The differences between the original and modified prostheses were compared by SPSS 17.0 software for statistical analysis., Results: There were 54 patients' CT data included in the study. The amount of fossa bone trimming was 150.20 mm 3 in the modified prosthesis and 281.82 mm 3 in the original one. The amount of ramus bone trimming was 103.86 mm 3 in the modified prosthesis and 229.45 mm 3 in the original one. The amount of fossa bone grafting was 95.88 mm 3 in the modified prosthesis and 263.03 mm 3 in the original one. There were significant differences between them (p = 0.000)., Conclusions: The modified Biomet prostheses design requires less bone trimming and grafting for implantation., (Copyright © 2018 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

The African Programme for Onchocerciasis Control (APOC), which focused on annual mass treatment with ivermectin, was launched in 1995 and was replaced by the Expanded Special Project for Neglected Tropical Diseases (ESPEN) by the end of 2015. In Ghana, the Community Directed Treatment with Ivermectin (CDTI) was introduced in 1999. After a decade, biannual reinforcement was introduced during which the Ghana Health Service (GHS) recorded coverage rates through routine data collection. Transmission studies conducted in the Upper Denkyira East Municipal (UDEM) of the forest zone of Ghana in 2002 and 2006 had shown that annual treatments with ivermectin had hardly any effect on the transmission of Onchocerca volvulus by the vector Simulium sanctipauli. In order to establish whether or not this was due to an insufficient compliance to the CDTI programme, an additional questionnaire survey was carried out in 2013 following those conducted in 2002 and 2006. The repeat transmission survey conducted in 2013 in the same area revealed that the vector S. sanctipauli had apparently disappeared from the rivers Ofin and Pra due to gold mining activities. In 2006 and 2013, we conducted surveys using structured questionnaires to address issues related to compliance and to compare results on the effectiveness of CDTI. A total of 692 individuals from 7 villages and 447 individuals from 9 villages were interviewed in 2006 and 2013 respectively. Questions asked included whether or not they had taken the ivermectin and reasons for not doing so when that was the case. Results were compared with the previous investigations conducted in 2002. Whereas official reported coverage rates ranged from 59 to 85% in 2006 and from 88 to 97% in 2013, compliance rates decreased from 36% in 2006 to 21% in 2013. Factors affecting compliance included fear of unpleasant side effects (pruritus and oedema), which decreased from 36% to 21% for the same period. Lack of awareness of CDTI sharply increased from 12% to 46% for the same period. Participants believed that treatments were no longer necessary due to the absence of vectors observed in 2013. There seems to be a considerable difference between coverage and compliance rates in the study communities. The difference can be attributed to the performance of the Community-Directed Distributors (CDDs) and the absence of the vector population observed in 2013. Discussions with CDDs suggested that factors that led to non-compliance were mostly side effects, unawareness of the disease by immigrants and lack of financial motivation for the CDDs. Also included was the fact that they needed to complete distribution of the drugs in the entire village, covering all households within just one week irrespective of the size of the catchment area. This, they thought was too much work for a short period of time. We propose to intensify the training of CDDs by the national Neglected Tropical Diseases Programme (NTDP) and to include the Community-based Health and Planning Services (CHPS) concept into onchocerciasis control efforts for awareness creation while the vector population and the transmission should be further monitored. The population should be made aware that the side effects they experienced from previous treatments or had heard about had reduced significantly. They also should be in the known that vector flies may return and so the risk of transmission remains., (Copyright © 2018. Published by Elsevier B.V.)

Purpose: The purpose of this study was to identify whether the incidence of systematically identified or incidentally encountered facial nerve branches during dissection to approach condylar fractures increases risk of transient and/or permanent facial nerve weakness., Methods: A systematic review and meta-analysis were performed that included several databases with specific keywords, a reference search, and a manual search for suitable articles. The inclusion criteria were all clinical trials, with the aim of assessing the rate of facial nerve injuries when open reduction and internal fixation (ORIF) of condylar process fractures was performed using different surgical approaches. The articles had to have documented the number of encountered facial nerve branches during ORIF. The main outcome variable was transient and permanent facial nerve injury. The dependent variable was the event and/or number of encountered facial nerve branches during surgery, and how they were handled (i.e. dissected, retracted, etc.)., Results: A total of 1202 mandibular condylar fractures were enrolled in 29 studies. Rate of transient facial nerve injury (TFNI) was 11.3 % (136/1202). The number of facial nerve branches encountered intraoperatively was 543, namely buccal, marginal mandibular, zygomatic and temporal nerve branches. There was a significant correlation suggesting that there is a strong positive linear relationship between TFNI and encountered facial nerve branches (Coef = 0.1916, P = 0.001). There was no significant relationship between permanent facial nerve injury and encountered facial nerve branches (P = 0.808). TFNI was 4.3% and 18.7% for those studies expressly reporting that facial nerve branches were encountered incidentally without dissection and with dissection, respectively. For studies reporting deliberate and systematic facial nerve dissection, TFNI was 20.9%. Finally, studies that did not report any encounters of facial nerve branches, TFNI was 7.9 %., Conclusion: This meta-analysis demonstrated that manipulation of the facial nerve during different surgical approaches causes different incidences of facial nerve injury. The choice of surgical approach for a given fracture should take this into consideration., (Copyright © 2018 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Background: Bile acid homeostasis is essential and imbalance may lead to liver damage and liver failure. The bile acid induced intestinal factor fibroblast growth factor 19 (FGF19) has been identified as a key protein for mediating negative feedback inhibition of bile acid synthesis. The aim of the study was to define FGF19 and bile acid concentrations in portal and systemic blood in the fasted and postprandial state. We also addressed the question if physiological portal levels of FGF19 can be extrapolated from the concentration in systemic blood., Methods: Portal and systemic blood was collected from 75 fasted patients undergoing liver surgery and from three organ donors before and after enteral nutrition. Serum concentration of FGF19 was determined with ELISA and bile acid concentration with gas chromatography-mass spectrometry., Results: Concentration of bile acids was twice as high in portal compared to systemic blood in the fasted group and 3-5 times higher in the postprandial group. FGF19 increased after enteral nutrition but did not differ between portal and systemic blood, in either group. In addition, a strong, positive correlation between bile acids and FGF19 was found., Conclusion: Our results confirm that bile acids drive the postprandial increase of circulating FGF19 but a hepatic clearance of FGF19 is unlikely. We conclude that systemic concentrations of FGF19 reflect portal concentrations of FGF19.

Background: Although brain atrophy is considered to be a downstream marker of Alzheimer's disease (AD), subtle changes may allow to identify healthy subjects at risk of developing AD. As the ability to select at-risk persons is considered to be important to assess the efficacy of drugs and as MRI is a widely available imaging technique we have recently developed a reliable segmentation algorithm for the corpus callosum (CC). Callosal atrophy within AD has been hypothesized to reflect both myelin breakdown and Wallerian degeneration., Methods: We applied our fully automated segmentation and feature extraction algorithm to two datasets: the OASIS database consisting of 316 healthy controls (HC) and 100 patients affected by either mild cognitive impairment (MCI) or Alzheimer's disease dementia (ADD) and a second database that was collected at the Memory Clinic of Hospital Network Antwerp and consists of 181 subjects, including healthy controls, subjects with subjective cognitive decline (SCD), MCI, and ADD. All subjects underwent (among others) neuropsychological testing including the Mini-Mental State Examination (MMSE). The extracted features were the callosal area (CCA), the circularity (CIR), the corpus callosum index (CCI) and the thickness profile., Results: CIR and CCI differed significantly between most groups. Furthermore, CIR allowed us to discriminate between SCD and HC with an accuracy of 77%. The more detailed callosal thickness profile provided little added value towards the discrimination of the different AD stages. The largest effect of normal ageing on callosal thickness was found in the frontal callosal midbody., Conclusions: To the best of our knowledge, this is the first study investigating changes in corpus callosum morphometry in normal ageing and AD by exploring both summarizing features (CCA, CIR and CCI) and the complete CC thickness profile in two independent cohorts using a completely automated algorithm. We showed that callosal circularity allows to discriminate between an important subgroup of the early AD spectrum (SCD) and age and sex matched healthy controls.

Purpose: Reconstruction of orbital wall fractures is demanding and has improved dramatically with the implementation of new technologies. True-to-original accuracy of reconstruction has been deemed essential for good clinical outcome, and reasons for unfavorable clinical outcome have been researched extensively. However, no detailed analysis on the influence of plate position and surface contour on clinical outcome has yet been published., Materials and Methods: Data from a previous study were used for an ad-hoc analysis to identify predictors for unfavorable outcome, defined as diplopia or differences in globe height and/or globe projection of >2 mm. Presumed predictors were implant surface contour, aberrant implant dimension or position, accuracy of reconstructed orbital volume, and anatomical fracture topography according to the current AO classification., Results: Neither in univariable nor in multivariable regression models were unfavorable clinical outcomes associated with any of the presumed radiological predictors, and no association of the type of implant, i.e., standard preformed, CAD-based individualized and non-CAD-based individualized with its surface contour could be shown., Conclusion: These data suggest that the influence of accurate mechanical reconstruction on clinical outcomes may be less predictable than previously believed, while the role of soft-tissue-related factors may have been underestimated., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Adoptive transfer of donor-derived T cells can be applied to improve immune reconstitution in immune-compromised patients after allogeneic stem cell transplantation. The separation of beneficial T cells from potentially harmful T cells can be achieved by using the major histocompatibility complex (MHC) I-Streptamer isolation technology, which has proven its feasibility for the fast and pure isolation of T-cell populations with a single specificity. We have analyzed the feasibility of the simultaneous isolation of multiple antigen-specific T-cell populations in one procedure by combining different MHC I-Streptamers., Methods: First, the effect of combining different amounts of MHC I-Streptamers used in the isolation procedure on the isolation efficacy of target antigen-specific T cells and on the number of off-target co-isolated contaminating cells was assessed. The feasibility of this approach was demonstrated in large-scale validation procedures targeting both high and low frequent T-cell populations using the Good Manufacturing Practice (GMP)-compliant CliniMACS Plus device., Results: T-cell products targeting up to 24 different T-cell populations could be isolated in one, simultaneous MHC I-Streptamer procedure, by adjusting the amount of MHC I- Streptamers per target antigen-specific T-cell population. Concurrently, the co-isolation of potentially harmful contaminating T cells remained below our safety limit. This technology allows the reproducible isolation of high and low frequent T-cell populations. However, the expected therapeutic relevance of direct clinical application without in vitro expansion of these low frequent T-cell populations is questionable., Discussion: This study provides a feasible, fast and safe method for the generation of highly personalized MHC I-Streptamer isolated T-cell products for adoptive immunotherapy., (Copyright © 2018 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Validated absolute risk equations are currently recommended as the basis of cardiovascular disease (CVD) risk stratification in prevention and control strategies. However, there is no consensus on appropriate equations for sub-Saharan African populations. We assessed agreement between different cardiovascular risk equations among Ghanaian migrant and home populations with no overt CVD., Methods: The 10-year CVD risks were calculated for 3586 participants aged 40-70years in the multi-centre RODAM study among Ghanaians residing in Ghana and Europe using the Framingham laboratory and non-laboratory and Pooled Cohort Equations (PCE) algorithms. Participants were classified as low, moderate or high risk, corresponding to <10%, 10-20% and >20% respectively. Agreement between the risk algorithms was assessed using kappa and correlation coefficients., Results: 19.4%, 12.3% and 5.8% were ranked as high 10-year CVD risk by Framingham non-laboratory, Framingham laboratory and PCE, respectively. The median (25th-75th percentiles) estimated 10-year CVD risk was 9.5% (5.4-15.7), 7.3% (3.9-13.2) and 5.0% (2.3-9.7) for Framingham non-laboratory, Framingham laboratory and PCE, respectively. The concordance between PCE and Framingham non-laboratory was better in the home Ghanaian population (kappa=0.42, r=0.738) than the migrant population (kappa=0.24, r=0.732) whereas concordance between PCE and Framingham laboratory was better in migrant Ghanaians (kappa=0.54, r=0.769) than the home population (kappa=0.51, r=0.758)., Conclusion: CVD prediction with the same algorithm differs for the migrant and home populations and the interchangeability of Framingham laboratory and non-laboratory algorithms is limited. Validation against CVD outcomes is needed to inform appropriate selection of risk algorithms for use in African ancestry populations., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)