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To use phages in a personalized therapy and industrial applications, an accurate quantification is needed. The gold standard method, namely the culture-based double agar overlay (DAO) method, provides an accurate estimate of the number of infectious phages but is laborious and time-intensive. Quantitative polymerase chain reaction (qPCR) can be used as a fast alternative but tends to overestimate the number of infectious phage particles. Here we describe the use of a DNase treatment before quantification of the Staphylococcus aureus phage ISP with qPCR to obtain a more accurate estimate of the number of infectious phage particles. We showed that DNase treatment results in a significant decrease of the concentration when measured with qPCR although for two out of three tested ISP phage stocks, there was still a significant difference with the DAO method. We also showed that the discrepancy between quantification with qPCR and the DAO method is dependent on the storage period of the phage stock, with a larger discrepancy for older stocks. Additionally, we used negative contrast immune electron microscopy to confirm the presence of DNA in the medium of the phage stock and the impact of the DNase treatment on the free DNA. [ABSTRACT FROM AUTHOR]

Introduction Pain is a prevalent side effect seen in breast cancer survivors (BCS). Psychological factors are known role players in pain mechanisms. Both pain and psychological factors contribute to or interact with healthcare use (HCU). However, the association between psychological factors and HCU has never been investigated in BCS with pain, which is the aim of the present study. Methods Belgian BCS with pain (n  = 122) were assessed via the Medical Consumption Questionnaire, the Injustice Experienced Questionnaire, the Pain Catastrophizing Scale, the Pain Vigilance and Awareness Questionnaire, the Brief Illness Perceptions Questionnaire, and the Depression, Anxiety, and Stress Scale. Associations were analyzed with logistic and Poisson regressions. Results Opioid use was related to more catastrophizing and less psychological distress. Psychotropic drug use was related to more psychological distress. Endocrine therapy was related to less vigilance and awareness. Psychological distress was related to all types of healthcare provider (HCP) visits, with psychological distress negatively related to physiotherapy, psychology, and other primary HCP visits, and positively related to visiting a general practitioner or secondary HCP. Catastrophizing was related to more visiting behavior to a primary HCP, except to a general practitioner. Perceived injustice was related to more general practitioner and other primary HCP visits but to fewer psychology visits. Illness perceptions were related only to visiting other primary HCPs. Vigilance and awareness were related to more psychologist and secondary HCP visits. Conclusion Our findings underscore the complex interplay between HCU and psychological factors in BCS with pain. Psychological distress was overall the most important psychological factor related to HCU, whether catastrophizing and perceived injustice were the most relevant related to HCP visits. [ABSTRACT FROM AUTHOR]

To understand human learning and progress, it is crucial to understand curiosity. But how consistent is curiosity's conception and assessment across scientific research disciplines? We present the results of a large collaborative project assessing the correspondence between curiosity measures in personality psychology and cognitive science. A total of 820 participants completed 15 personality trait measures and 9 cognitive tasks that tested multiple aspects of information demand. We show that shared variance across the cognitive tasks was captured by a dimension reflecting directed (uncertainty-driven) versus random (stochasticity-driven) exploration and individual differences along this axis were significantly and consistently predicted by personality traits. However, the personality metrics that best predicted information demand were not the central curiosity traits of openness to experience, deprivation sensitivity, and joyous exploration, but instead included more peripheral curiosity traits (need for cognition, thrill seeking, and stress tolerance) and measures not traditionally associated with curiosity (extraversion and behavioral inhibition). The results suggest that the umbrella term "curiosity" reflects a constellation of cognitive and emotional processes, only some of which are shared between personality measures and cognitive tasks. The results reflect the distinct methods that are used in these fields, indicating a need for caution in comparing results across fields and for future interdisciplinary collaborations to strengthen our emerging understanding of curiosity. [ABSTRACT FROM AUTHOR]

Objective: Medical treatments that aim to modify the appearance of the genitals in children who are born with a difference of sex development/intersex (DSD/I*) condition are highly controversial. Human Rights bodies worldwide have argued that such treatments are conflicting with the child's right of personal autonomy and should be legally restricted to the unique situation where the child's physical health is in danger. Design: We here review the current status of legal initiatives in Europe that have addressed the issue of medical treatments in minors who have a DSD for which they have not been able to give personal informed consent due to their young age. Patients: The management of a 3 years old child who has congenital adrenal hyperplasia (CAH) and grows up with atypical‐looking genitals is discussed. Results: In spite of extensive psychosocial support to the child and family from birth onwards, and good medical control of CAH, the child develops signs of emotional distress, suspected to be attributable to the genital difference. Our discussions include perspectives from the multidisciplinary DSD team caring for the child, a human rights specialist, and an intersex activist. From our discussions, we conclude that with evolving medical care, new ethical and human rights challenges are raised. A truly holistic human rights approach should not only consider physical but also mental health and psychosocial and psychosexual adaptation of the child to the medical condition, when reflecting on the acceptability of medical treatments in minors for which no personal informed consent can be obtained due to their young age. In addition it is paramount to include the meaningful participation of the child in the clinical management at the earliest possible stage. Conclusions: Continued convergence of clinical management and the human rights framework can be realised based on constructive discussions involving all stakeholders, and with the best interest of the child – and adult that they will become ‐ as a common goal. [ABSTRACT FROM AUTHOR]

Growth hormone (GH) deficiency (GHD) in children and adolescents can vary in severity and origin, with GH replacement therapy proving effective in achieving genetic target height. Optimal outcomes are seen in those treated early and with higher doses. As patients approach adult height, priorities shift towards optimizing metabolic effects, maintaining body composition, and enhancing bone mass and muscle strength. Transitioning from pediatric to adult care presents challenges, including accurately identifying candidates for continued GH therapy, reevaluating persistent GHD, and preventing treatment discontinuation. Assessing readiness for transition and self-management skills is crucial. This Policy and Practice Review provides a comprehensive overview of current policies, regulations, and guidelines pertinent to managing GHD transition in Belgium. We integrate perspectives from national academic and nonacademic clinical stakeholders in pediatric and adult endocrine care to provide an updated policy framework. This framework underscores the importance of sustained GH therapy during transition, particularly for individuals with persistent GHD, with the goal of optimizing practices and improving outcomes during this critical period. [ABSTRACT FROM AUTHOR]

Background : Vancomycin is a commonly prescribed antibiotic to treat serious Gram-positive infections in children. The efficacy of vancomycin is known to be directly related to the pharmacokinetic/pharmacodynamic (PK/PD) index of the area under the concentration–time curve (AUC) divided by the minimal inhibitory concentration (MIC) of the pathogen. In most countries, steady-state plasma concentrations are used as a surrogate parameter for this target AUC/MIC, but this practice has some drawbacks. Hence, AUC-based dosing using model-informed precision dosing (MIPD) tools has been proposed for increasing the target attainment rate and reducing vancomycin-related nephrotoxicity. Solid scientific evidence for these claimed benefits is lacking in children. This randomized controlled trial aims to investigate the large-scale utility of MIPD dosing of vancomycin in critically ill children. Methods: Participants from 14 neonatal intensive care, pediatric intensive care, and pediatric hemo-oncology ward units from 7 hospitals are randomly allocated to the intervention or standard-of-care comparator group. In the intervention group, a MIPD dosing calculator is used for AUC-based dosing, in combination with extra sampling for therapeutic drug monitoring in the first hours of treatment, as compared to standard-of-care. An AUC24h between 400 and 600 is targeted, assuming an MIC of 1 mg/L. Patients in the comparator group receive standard-of-care dosing and monitoring according to institutional guidelines. The primary endpoint is the proportion of patients reaching the target AUC24h/MIC of 400–600 between 24 and 48 h after the start of vancomycin treatment. Secondary endpoints are the proportion of patients with (worsening) acute kidney injury during vancomycin treatment, the proportion of patients reaching target AUC24h/MIC of 400–600 between 48 and 72 h after the start of vancomycin treatment, time to clinical cure, ward unit length-of-stay, hospital length-of-stay, and 30-day all-cause mortality. Discussion: This trial will clarify the propagated benefits and provide new insights into how to optimally monitor vancomycin treatment in critically ill children. Trial registration: Eudract number: 2019–004538-40. Registered on 2020–09-08 ClinicalTrials.gov NCT046666948. Registered on 2020–11-28 [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does RXFP2 disruption impair male fertility? SUMMARY ANSWER We identified biallelic variants in RXFP2 in patients with male infertility due to spermatogenic arrest at the spermatid stage, supporting a role of RXFP2 in human spermatogenesis, specifically in germ cell maturation. WHAT IS KNOWN ALREADY Since RXFP2, the receptor for INSL3, plays a crucial role in testicular descent during prenatal development, biallelic variants lead to bilateral cryptorchidism, as described in four families to date. While animal models have also suggested a function in spermatogenesis, the postnatal functions of RXFP2 and its ligand INSL3, produced in large amounts by the testes from puberty throughout adulthood, are largely unknown. STUDY DESIGN, SIZE, DURATION A family with two male members affected by impaired fertility due to spermatogenic maturation arrest and a history of bilateral cryptorchidism underwent clinical, endocrinological, histological, genomic, in vitro cellular, and in silico investigations. PARTICIPANTS/MATERIALS, SETTING, METHODS The endocrinological and histological findings were correlated with publicly available single-cell RNA sequencing (scRNA-seq) data. The genomic defects have been characterized using long-read sequencing and validated with in silico modeling and an in vitro cyclic AMP reporter gene assay. MAIN RESULTS AND THE ROLE OF CHANCE An intragenic deletion of exon 1–5 of RXFP2 (NM_130806.5) was detected in trans with a hemizygous missense variant c.229G>A, p.(Glu77Lys). The p.(Glu77Lys) variant caused no clear change in cell surface expression or ability to bind INSL3, but displayed absence of a cAMP signal in response to INSL3, indicating a loss-of-function. Testicular biopsy in the proband showed a maturation arrest at the spermatid stage, corresponding to the highest level of RXFP2 expression in scRNA-seq data, thereby providing a potential explanation for the impaired fertility. LIMITATIONS, REASONS FOR CAUTION Although this is so far the only study of human cases that supports the role of RXFP2 in spermatogenic maturation, this is corroborated by several animal studies that have already demonstrated a postnatal function of INSL3 and RXFP2 in spermatogenesis. WIDER IMPLICATIONS OF THE FINDINGS This study corroborates RXFP2 as gene implicated in autosomal recessive congenital bilateral cryptorchidism due to biallelic variants, rather than autosomal-dominant cryptorchidism due to monoallelic RXFP2 variants. Our findings also support that RXFP2 is essential in human spermatogenesis, specifically in germ cell maturation, and that biallelic disruption can cause male infertility through spermatogenic arrest at the spermatid stage. STUDY FUNDING/COMPETING INTEREST(S) Funding was provided by the Bellux Society for Pediatric Endocrinology and Diabetology (BELSPEED) and supported by a Research Foundation Flanders (FWO) senior clinical investigator grant (E.D.B. 1802220N) and a Ghent University Hospital Special Research Fund grant (M.C. FIKO-IV institutional fund). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Aims: Type 1 diabetes mellitus (T1DM) is characterised by insulin deficiency. Due to perceived physical activity (PA)‐related hypoglycaemia, a minority of people with T1DM exercise regularly. However, the relationship between T1DM and PA remains poorly understood. Our aim was to summarise the existing literature on the effects of PA on short‐term glucose control (glycated haemoglobin or time in range) in people with T1DM. Methods: We searched seven electronic databases (PubMed, Embase, Cochrane library, Cinahl, SPORTDiscus, PEDro and Web Of Science) and two sources of the grey literature (ClinicalTrials.gov and ICTRP). All reviews were screened via title/abstract and full text by two independent reviewers (LE and HT), conflicts were solved by a third independent reviewer (DDC). We excluded animal studies, case reports, non‐English articles, qualitative studies, conference abstracts and articles without full‐text access. A meta‐analysis using random effects model was performed to study the effect of PA on haemoglobin A1c (HbA1c) levels in people with T1DM. Results: We obtained 19,201 unique references across nine different electronic databases. After screening and snowballing, 68 articles were found investigating the effect of PA on glycaemic control in people with T1DM. Overall, HbA1c levels in the PA group (mean difference = 0.29% (0.20%–0.39%)), were lower compared with the control group. Conclusion: An overall small beneficial effect of PA on glycaemic control in people with T1DM was found. Caution is advised when interpreting the results of this meta‐analysis, given variations in study type, duration, frequency and intensity of physical activity across included studies. [ABSTRACT FROM AUTHOR]

The relationship between 'bulky' locoregional lymphadenopathy and survival has not been investigated in the setting of esophageal adenocarcinoma (EAC). This study aimed to explore whether bulky regional lymphadenopathy at diagnosis affected survival outcomes in patients with EAC treated with neoadjuvant chemotherapy and en bloc resection. A single-center retrospective review of a prospectively maintained upper GI cancer surgical database was performed between January 2012 and December 2019. Patients with locally advanced EAC (cT2-3, N+, M0) treated with neoadjuvant docetaxel-based chemotherapy and transthoracic en bloc esophagogastrectomy were identified. Computed tomography scans from before the initiation of treatment were reviewed, and patients were stratified according to whether bulky loco-regional lymph nodes were present. This was defined as lymphadenopathy >2 cm in any axis. Overall survival was compared, and a Cox multivariate regression model was calculated. Two hundred twenty-five of the eight hundred seventy patients identified met the inclusion criteria. Forty-eight (21%) had bulky lymphadenopathy, leaving 177 allocated to the control group. More patients with bulky lymphadenopathy had ypN3 disease (18/48, 38% vs. 39/177, 20%, P  = 0.025). Among patients with bulky lymphadenopathy, overall survival was generally worse (32.6 vs. 59.1 months, P  = 0.012). However, among the 9/48 (19%) patients with bulky lymphadenopathy who achieved ypN− status survival outcomes were similar to those with non-bulky lymphadenopathy who also achieved lymph node sterilization. Poor differentiation (HR 1.8, 95% CI 1.0–2.9, P  = 0.034), ypN+ (HR 1.9, 95% CI 1.1–3.6, P  = 0.032), and bulky lymphadenopathy were independently associated with an increased risk of death (HR 1.7, 1.0–2.9, P  = 0.048). Bulky regional lymphadenopathy is associated with a poor prognosis. Efforts to identify the ideal treatment regimen for these patients are urgently required. [ABSTRACT FROM AUTHOR]

Background It is unclear whether targeted monitoring of acute adrenal insufficiency (AI) related adverse events (AE) such as sick day episodes (SDEs) and hospitalization rate in congenital adrenal hyperplasia (CAH) is associated with a change in the occurrence of these events. Aim Study temporal trends of AI related AE in the I-CAH Registry. Methods In 2022, data on the occurrence of AI-related AE in children aged <18 years with 21-hydroxylase deficiency CAH were compared to data collected in 2019. Results In 2022, a total of 513 children from 38 centers in 21 countries with a median of 8 children (range 1-58) per center had 2470 visits evaluated over a 3-year period (2019-2022). The median SDE per patient year in 2022 was 0 (0-2.5) compared to 0.3 (0-6) in 2019 (P =.01). Despite adjustment for age, CAH phenotype and duration of study period, a difference in SDE rate was still apparent between the 2 cohorts. Of the 38 centers in the 2022 cohort, 21 had also participated in 2019 and a reduction in SDE rate was noted in 13 (62%), an increase was noted in 3 (14%), and in 5 (24%) the rate remained the same. Of the 474 SDEs reported in the 2022 cohort, 103 (22%) led to hospitalization compared to 299 of 1099 SDEs (27%) in the 2019 cohort (P =.02). Conclusion The I-CAH Registry can be used for targeted monitoring of important clinical benchmarks in CAH. However, changes in reported benchmarks need careful interpretation and longer-term monitoring. [ABSTRACT FROM AUTHOR]

Abstract Background Assessing prognosis is challenging for many physicians in various medical fields. Research shows that physicians who perform disability assessments consider six areas when evaluating a prognosis: disease, treatment, course of the disease, external information, patient-related and physician-related aspects. We administered a questionnaire to evaluate how physicians rate the importance of these six prognosis areas during work disability evaluation and to explore what kind of support they would like during prognosis assessment. Methods Seventy-six physicians scored the importance of 23 prognostic aspects distributed over six prognosis areas. Participants scored the importance of each aspect both “in general” and from the perspective of a case vignette of a worker with a severe degenerative disease. The questionnaire also covered needs and suggestions for support during the evaluation of prognoses. Results Medical areas that are related to the disease, or the treatment or course of the disease, appeared important (scores of 7.0–9.0), with less differing opinions among participants (IQR 1.0–3.0). Corresponding verbatim remarks supported the importance of disease and treatment as prognostic aspects. In comparison, patient- and physician-related aspects scored somewhat lower, with more variability (range 4.0–8.0, with IQR 2.0–5.0 for patient- and physician-related considerations). Participants indicated a need for a tool or online database that includes prognostic aspects and prognostic evidence. Conclusions Despite some variation in scores, the physicians rated all six prognosis areas as important for work disability evaluations. This study provides suggested aids to prognosis assessment, including an online support tool based on evidence-based medicine features.

BackgroundThe Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry.Methods and resultsA total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P

BackgroundThe hypothesis that dopamine plays an important role in the pathophysiology of pathological gambling is pervasive. However, there is little to no direct evidence for a categorical difference between pathological gamblers and healthy control subjects in terms of dopamine transmission in a drug-free state. Here we provide evidence for this hypothesis by comparing dopamine synthesis capacity in the dorsal and ventral parts of the striatum in 13 pathological gamblers and 15 healthy control subjects.MethodsThis was achieved using [18F]fluoro-levo-dihydroxyphenylalanine dynamic positron emission tomography scans and striatal regions of interest that were hand-drawn based on visual inspection of individual structural magnetic resonance imaging scans.ResultsOur results show that dopamine synthesis capacity was increased in pathological gamblers compared with healthy control subjects. Dopamine synthesis was 16% higher in the caudate body, 17% higher in the dorsal putamen, and 17% higher in the ventral striatum in pathological gamblers compared with control subjects. Moreover, dopamine synthesis capacity in the dorsal putamen and caudate head was positively correlated with gambling distortions in pathological gamblers.ConclusionsTaken together, these results provide empirical evidence for increased striatal dopamine synthesis in pathological gambling.

Dopamine is central to a number of cognitive functions and brain disorders. Given the cost of neurochemical imaging in humans, behavioural proxy measures of dopamine have gained in popularity in the past decade, such as spontaneous eye blink rate (sEBR). Increased sEBR is commonly associated with increased dopamine function based on pharmacological evidence and patient studies. Yet, this hypothesis has not been validated using in vivo measures of dopamine function in humans. To fill this gap, we measured sEBR and striatal dopamine synthesis capacity using [18 F]DOPA PET in 20 participants (nine healthy individuals and 11 pathological gamblers). Our results, based on frequentist and Bayesian statistics, as well as region-of-interest and voxel-wise analyses, argue against a positive relationship between sEBR and striatal dopamine synthesis capacity. They show that, if anything, the evidence is in favour of a negative relationship. These results, which complement findings from a recent study that failed to observe a relationship between sEBR and dopamine D2 receptor availability, suggest that caution and nuance are warranted when interpreting sEBR in terms of a proxy measure of striatal dopamine.

Cellular therapies with CD4+ T regulatory cells (Tregs) hold promise of efficacious treatment for the variety of autoimmune and allergic diseases as well as posttransplant complications. Nevertheless, current manufacturing of Tregs as a cellular medicinal product varies between different laboratories, which in turn hampers precise comparisons of the results between the studies performed. While the number of clinical trials testing Tregs is already substantial, it seems to be crucial to provide some standardized characteristics of Treg products in order to minimize the problem. We have previously developed reporting guidelines called minimum information about tolerogenic antigen-presenting cells, which allows the comparison between different preparations of tolerance-inducing antigen-presenting cells. Having this experience, here we describe another minimum information about Tregs (MITREG). It is important to note that MITREG does not dictate how investigators should generate or characterize Tregs, but it does require investigators to report their Treg data in a consistent and transparent manner. We hope this will, therefore, be a useful tool facilitating standardized reporting on the manufacturing of Tregs, either for research purposes or for clinical application. This way MITREG might also be an important step toward more standardized and reproducible testing of the Tregs preparations in clinical applications.