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Alkanna tinctoria L. Tausch ("alkanet" or "alkanna") is a medicinal plant. Extracts from alkanet roots have applications as natural food coloring agents. In addition, they have proven antioxidant effects. Three classical solvents (ethanol and acidified ethanol/water) and four natural eutectic solvents (NADES)-choline chloride/urea; choline chloride/citric acid; choline chloride/lactic acid; and sodium acetate/formic acid-were compared for their effectiveness as "green" solvents for the extraction of the alkanet pigment. Notably, this study is the first to apply choline chloride-based NADESs for alkanet extraction, providing a comprehensive profile of key bioactive compounds and their contributions to antioxidant activity using UV/Vis and FT-IR spectrometry, GC-MS, and HPLC-PDA-MS. Among the classical solvents, 50% acidified ethanol showed the highest extraction capacity, as indicated by its total flavonoid (708 ± 32 mgCE/L) and total phenolic (1318 ± 63 mgGAE/L) content. However, this extract exhibited the highest total alkaloid content (256 ± 15 µg/L) compared to the other classical extraction solvents. Consequently, absolute ethanol was identified as a more suitable alternative. Among the NADES, the sodium acetate/formic acid (1:2 mol/mol, NADES4) extract was the only one to show the presence of alkannins. This extract also contained high levels of phenols (355 ± 21 mg GAE/L) and tannins (163 ± 10 mg CE/L), exhibited strong antioxidant potential (DPPH: 131 µmol TE/g dw, FRAP: 7.49 mg Fe(II)/mg dw), and contained significantly lower alkaloid levels (7.0 ± 0.5 µg/L). Comparative analyses indicated that the sodium acetate/formic acid extract outperformed those prepared with ethanolic solvents and other NADES. more...

Objective: Selective estrogen receptor modulators (SERMs) have demonstrated efficacy in the treatment of hypogonadism in males and male factor infertility. Two SERMs, clomiphene citrate and tamoxifen, are now prescribed for off-label use to treat both conditions in males. However, existing literature compares mixed protocols with active management. We aimed to conduct a meta-analysis to evaluate the effect of clomiphene and tamoxifen versus placebo on natural pregnancy rates., Methods: We conducted a comprehensive systematic review of electronic databases: MEDLINE, PubMed/PMC, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, Google Scholar, and Web of Science. Articles satisfying all selection criteria were analyzed. The primary outcome was the incidence of pregnancy after receiving the treatment. Secondary outcomes included serum follicle-stimulating hormone, luteinizing hormone, and testosterone levels, and sperm count and motility. We calculated the pooled odds ratio, risk ratio, and risk difference to ascertain possible alterations in the direction of the pooled effect size., Results: Ten randomized controlled trials were ultimately included and underwent data extraction. Clomiphene citrate and placebo groups had similar pregnancy rates (10.4% and 7.1%, respectively; odds ratio 1.30 [95% confidence interval 0.27-6.17]; p =0.74). No meta-analysis could be calculated for pregnancy rates in tamoxifen versus placebo groups. Heterogeneity among the studies of both SERMs ranged from low to high., Conclusion: Although clomiphene citrate and tamoxifen are often used off-label for the treatment of male infertility secondary to hypogonadism, studies of SERMs in the treatment of idiopathic male factor infertility are limited and heterogenous, preventing this meta-analysis from investigating the efficacy of SERMs on male infertility. The effect of clomiphene citrate or tamoxifen on the pregnancy rate remains uncertain., Competing Interests: The authors declare no conflict of interest., (© 2025 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.Vé.) more...

Competing Interests: Declaration of competing interest The authors certify that all of their affiliations and/or financial involvement with any organization, or any financial conflicts with the subject matter discussed in the manuscript are disclosed in the Acknowledgement section of the manuscript. more...

Background: High-intensity interval training (HIIT) in school settings has been much less studied in adolescents. The aim of this study was to examine the impact of HIIT on health-related fitness in adolescents., Methods: The total sample consisted of 60 adolescents (age 16.33 ± 0.62 years) from secondary Grammar school, randomly divided into two groups: the experimental (EG) (30) and the control group (CG) (30). The experimental program (12-weeks; 2 times per week) involved two Tabata sessions during one physical education class lasting 4 min each. Participants were tested for health-related fitness components-cardiorespiratory fitness (The Shuttle Run Test (SRT) and strength, hand grip test, standing long jump (SLJ) and counter movement jump (CMJ)., Results: Both the EG and the CG experienced significant positive changes in SRT (meters) and VO 2max values compared to baseline value ( p < 0.05), however, the increase in the EG was significantly higher than that in the CG (SRT - η p 2 = 0.111; VO 2max - η p 2 = 0.111, p < 0.01). The EG showed significant improvement in SRT (meters) and VO 2max values compared to the CG ( p < 0.01). Regarding the hand grip test results, a significant time × group interaction was found only for right hand ( p < 0.01). Moreover, the improvements in SLJ and CMJ values was greater in EG than that in the CG group (SLJ- η p 2 = 0.182; CMJ- η p 2 = 0.112, p < 0.01)., Conclusion: Findings indicate that HIIT implemented into physical education classes can result in significant improvements in selected health related fitness components in adolescents., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jovanović, Živković, Stanković, Zoretić and Trajković.) more...

Background: Despite the availability of evidence-based treatments for anorexia nervosa (AN), remission rates are moderate, and mortality is high. Olanzapine is used as adjunct therapy for AN in case of insufficient response to first-line treatments, even though the evidence is limited. Its effect on eating disorder (ED) psychopathology, its efficacy and tolerability, and its acceptability and adherence rate are unclear., Methods: We assessed the feasibility of a future definitive trial on olanzapine in young people with AN in an open-label, one-armed feasibility study that aimed to include 55 patients with AN or atypical AN aged 12-24 who gained < 2 kg within at least one month of treatment as usual (TAU) during outpatient, inpatient, or day-care treatment. Time points for assessments were at baseline, 8 weeks, 16 weeks, and 6 or 12 months. We estimated the following planning parameters: Recruitment rate (number of patients who agreed to take olanzapine/number eligible), adherence rate (number adhering to treatment/number recruited) and attrition rate (number completing study assessments/number recruited). In addition, two exploratory effect size parameters were estimated: Mean change in body mass index (BMI) and mean change in ED psychopathology., Results: Fifty-two people were pre-screened (June 2022 to May 2023; 10 study sites in England). 13 were ineligible at pre-screening . Of the 39  approached, 4 were found ineligible at screening. Of the remaining 35 eligible, 10 declined and 5 did not take part for other reasons. Thus, 20 participants were recruited and started olanzapine (recruitment rate: 20/35 = 57%). 15 out of 20 (75%) continued olanzapine for ≥ 16 weeks, and 13 participants (65%) remained in the trial until follow-up (either 6 or 12 months). Participants experienced, on average, a decrease over time in their Eating Disorder Examination Questionnaire (EDE-Q) Global scores (0.07 per week, N = 20) and an increase in BMI (0.08 kg/m 2 per week, N = 20) during treatment with olanzapine plus TAU., Conclusions: Possible reasons for the recruitment difficulties and low adherence rate include the high clinical workload of ED services during the COVID-19 pandemic and the reluctance of patients to agree to take olanzapine under the relatively restricted conditions of a clinical study., Trial Registration: International standard randomised controlled trial register number: ISRCTN80075010. Registration date: 27/04/2022., (© 2024. The Author(s).) more...

The aim of this study was to determine the effects of linear and change of direction high-intensity interval training (HIIT) on physical performance in elite female soccer players. Thirty elite female soccer players (age: 19.6 ± 4.6 years; height: 166.5 ± 4.8 cm; body weight: 60.5 ± 8.3 kg; BMI: 21.9 ± 2.9 kg/m 2 ) were randomly allocated to HIIT linear (HIIT LIN ) and HIIT change of direction (HIIT COD ) training groups. The HIIT LIN group performed linear running for 15, 20 or 25 s by keeping constant pace during the entire distance. In contrast, the HIIT COD group performed three changes of direction (COD) with a 180° turn during each interval run at 15, 20 or 25 s. Physical performance was assessed using sprinting, agility, vertical jumps, repeated sprint ability (RSA) and 30-15 Intermittent Fitness Test (30-15 IFT). In both groups, all physical performance measurements improved (p ≤ 0.05), except RSAbest in HIIT LIN (p = 0.45). Both interventions significantly improved speed over 10 m, 20 m, 30 m, Pro-agility, Zig-zag, RSAavg, fatigue index, maximal oxygen uptake, and velocity at 30-15 IFT, while moderate improvements were observed in countermovement jump (CMJ), CMJ with arm swing and squat jump. However, HIIT COD did not achieve superior improvements in any of the aforementioned measurements compared to HIIT LIN . Based on the obtained results, we concluded that different types of HIIT training have a positive effect on physical performance in elite female soccer players., Competing Interests: The authors declared no conflict of interest., (Copyright © Institute of Sport – National Research Instutite.) more...

Background: The OPEN feasibility trial testing olanzapine in anorexia nervosa (AN) in young people (YP) was not successful due to poor recruitment. This study aims to understand clinicians' views and experiences of using olanzapine in AN and the challenges in implementing the trial in National Health Service (NHS) clinical settings., Methods: We conducted qualitative interviews with eating disorders (ED) clinicians involved with the study (n = 11). Framework analysis was applied to qualitative data to identify barriers and facilitators to recruitment and study implementation. A web-based semi-structured Qualtrics survey was administered to ED clinicians (n = 24). Findings from the survey were used to corroborate and expand on the information derived from qualitative interviews., Results: Qualitative analysis identified four main themes: (1) Acknowledging Service User (SU) / Family Concerns, (2) Prioritising person-centred care, (3) Limited Service Capacity and (4) Study eligibility criteria. Subthemes are outlined accordingly. Clinicians appeared confident addressing SU concerns around olanzapine in clinical discussions, but timing was critical, and olanzapine was considered one aspect of treatment that needed to align with their holistic approach. Service pressures restricted opportunities for recruitment and the ability to offer regular review. At the same time, some YP were ineligible for the trial, as they were already taking olanzapine, or needed to be prescribed it more promptly than the study procedures allowed. Survey findings underlined confidence in prescribing and informing on olanzapine, the various possible benefits of olanzapine besides weight gain, and the importance of therapeutic alliances and informed consent. Both data sets highlight the need for further evidence on long-term safety, side effects and efficacy of olanzapine use for AN. Where clinical service capacity is at a premium, research implementation is not prioritised, particularly in intensive clinical settings., Conclusions: Findings provide first-hand insight into individual and systemic challenges with research implementation in the NHS, which need to be considered when designing future clinical research studies. We emphasise a person-centred approach when discussing olanzapine to consider a holistic recovery from AN beyond weight-gain as an isolated outcome for improvement., (© 2024. The Author(s).) more...

The Montreal Protocol is an international treaty that controls substances that deplete the ozone layer. Through the control of halogenated gases, it has been one of the most successful climate legislations to date. This success is driven by the interplay between chemical regulation and smart chemical design, demonstrating the positive impact chemistry can have on the world. This Article describes a group project that includes four assignments, a group presentation, and a writing task where students take on the role of consultants to assess the environmental friendliness of two fluorinated gases. Through the assignments students determine the global warming potential of two chemicals and pair this assessment with an evaluation of their potential to produce persistent products, such as trifluoroacetic acid, via atmospheric oxidation. Students worked together to take these, sometimes conflicting, pieces of evidence to make a final recommendation to their client as to the most "environmentally friendly" option in a mock Board of Directors meeting and then individually through a written recommendation. The project effectively addressed the learning goals of a third-year environmental chemistry class and was well received by students as a means of contextualizing the course material and providing students with a clear peer network in the class. This project is an effective application of fundamental chemistry topics (e.g., spectroscopy and the relationship between structure and reactivity) within a real-world context that emphasizes the ability of chemistry to have a positive impact on important environmental issues such as climate., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society and Division of Chemical Education, Inc.) more...

Background: Recognition of atypical anorexia nervosa (AAN) has challenged underweight as a defining factor of illness severity in anorexia nervosa (AN). The present study aimed to compare rates of medical instability in adolescents with underweight (AN) and non-underweight (AAN) anorexia nervosa., Methods: The study examined assessment data from specialist eating disorder services in the UK between January and December 2022. Participants (n = 205) aged 11-18 years were recruited across eight eating disorder clinics and diagnosed with AN (n = 113) or AAN (n = 92) after clinical assessment. Parameters associated with risk of medical instability were compared between AN and AAN groups, using t tests and regression analysis., Results: Rates of bradycardia and hypotension did not differ significantly between AN and AAN groups (p = 0.239 and p = 0.289). Although white blood cell counts were lower in the AN group, rates of leukopaenia could not be statistically compared as a result of there being too few counts in at least one group. No incidences of hypophosphataemia were found in the sample. A significant regression equation was found for percentage median body mass index, but not rate of weight loss, as a predictor of blood pressure, serum phosphorous and magnesium., Conclusions: Our findings indicate that medical instability occurs across a range of body weights in young people with AN and AAN. Although certain parameters of risk such as blood pressure, serum phosphorous and magnesium may be worsened at lower weight, both AN and AAN are serious mental health conditions that can lead to medical instability., (© 2024 The Author(s). Journal of Human Nutrition and Dietetics published by John Wiley & Sons Ltd on behalf of British Dietetic Association.) more...

Background: Multi-family Therapy (MFT) is being increasingly used in specialist eating disorder services internationally. Despite evidence of its efficacy, little is understood about the treatment mechanisms and what specifically promotes change. This study aimed to understand clinician perspectives on how change occurs during MFT., Methods: Clinicians with (a) 5 or more years' experience facilitating MFT and (b) who had facilitated a minimum of two MFT groups were eligible for this study. Two individual interviews and four semi-structured focus groups were conducted online. Recordings were transcribed verbatim and analysed using reflexive thematic analysis., Results: Twelve clinicians (five systemic/family psychotherapists, five clinical psychologists, and two consultant child and adolescent psychiatrists) from six different specialist services in the UK participated. Four main inter-connected themes describing how change is perceived to occur were generated; (1) Intensity and immediacy, (2) Flexibility, (3) New ideas and channels of learning and (4) Containment., Conclusions: Current data matches closely with young person and parent experiences of MFT and intensive day treatment and how they perceive change to occur. Quantitative data are now needed to evaluate the impact of these factors on outcome. Plain English Summary Multi-family Therapy (MFT) is being increasingly used in specialist eating disorder services internationally. While there is evidence that it is helpful, little is understood about how the treatment works and what specifically promotes change. This study aimed to understand how clinician believe change to occur during MFT for young people and their family members. Clinicians with (a) five or more years' experience facilitating MFT and (b) who had facilitated a minimum of two MFT groups were eligible for this study. Two individual interviews and four semi-structured focus groups were conducted online. Recordings were written out word-for-word and analysed using reflexive thematic analysis, a commonly used method for analysing this type of data. Twelve clinicians (five systemic/family psychotherapists, five clinical psychologists, and two consultant child and adolescent psychiatrists) from six different specialist services in the UK participated. Four related themes describing how change is perceived to occur were generated; (1) Intensity and immediacy, (2) Flexibility, (3) New ideas and channels of learning and (4) Containment. Current data matches closely with young person and parent experiences of MFT and intensive day treatment and how they perceive change to occur. These factors now need to be tested in future research., (© 2024. The Author(s).) more...

Algal biomass is a viable source of chemicals and metabolites for various energy, nutritional, medicinal and agricultural uses. While stresses have commonly been used to induce metabolite accumulation in microalgae in attempts to enhance high-value product yields, this is often very detrimental to growth. Therefore, understanding how to modify metabolism without deleterious consequences is highly beneficial. We demonstrate that low-doses (1-5 Gy) of ionizing radiation in the X-ray range induces a non-toxic, hormetic response in microalgae to promote metabolic activation. We identify specific radiation exposure parameters that give reproducible metabolic responses in Chlorella sorokiniana caused by transcriptional changes. This includes up-regulation of >30 lipid metabolism genes, such as genes encoding an acetyl-CoA carboxylase subunit, phosphatidic acid phosphatase, lysophosphatidic acid acyltransferase, and diacylglycerol acyltransferase. The outcome is an increased lipid yield in stationary phase cultures by 25% in just 24 hours, without any negative effects on cell viability or biomass., (© 2024. The Author(s).) more...

Background: Eating disorders (EDs) are serious, often chronic, conditions associated with pronounced morbidity, mortality, and dysfunction increasingly affecting young people worldwide. Illness progression, stages and recovery trajectories of EDs are still poorly characterised. The STORY study dynamically and longitudinally assesses young people with different EDs (restricting; bingeing/bulimic presentations) and illness durations (earlier; later stages) compared to healthy controls. Remote measurement technology (RMT) with active and passive sensing is used to advance understanding of the heterogeneity of earlier and more progressed clinical presentations and predictors of recovery or relapse., Methods: STORY follows 720 young people aged 16-25 with EDs and 120 healthy controls for 12 months. Online self-report questionnaires regularly assess ED symptoms, psychiatric comorbidities, quality of life, and socioeconomic environment. Additional ongoing monitoring using multi-parametric RMT via smartphones and wearable smart rings ('Ōura ring') unobtrusively measures individuals' daily behaviour and physiology (e.g., Bluetooth connections, sleep, autonomic arousal). A subgroup of participants completes additional in-person cognitive and neuroimaging assessments at study-baseline and after 12 months., Discussion: By leveraging these large-scale longitudinal data from participants across ED diagnoses and illness durations, the STORY study seeks to elucidate potential biopsychosocial predictors of outcome, their interplay with developmental and socioemotional changes, and barriers and facilitators of recovery. STORY holds the promise of providing actionable findings that can be translated into clinical practice by informing the development of both early intervention and personalised treatment that is tailored to illness stage and individual circumstances, ultimately disrupting the long-term burden of EDs on individuals and their families., (© 2024. The Author(s).) more...

Introduction: Antipsychotics are routinely prescribed off-label for anorexia nervosa (AN) despite limited evidence. This article presents a protocol of a study aiming to assess the feasibility of a future definitive trial on olanzapine in young people with AN., Methods and Analysis: In an open-label, one-armed feasibility study, 55 patients with AN or atypical AN, aged 12-24, receiving outpatient, inpatient or day-care treatment who are considered for olanzapine treatment will be recruited from NHS sites based in England. Assessments will be conducted at screening, baseline and at 8-, 16 weeks, 6- and 12 months. Primary feasibility parameters will be proportions of patients who agree to take olanzapine and who adhere to treatment and complete study assessments. Qualitative methods will be used to explore acceptability of the intervention and study design. Secondary feasibility parameters will be changes in body mass index, psychopathology, side effects, health-related quality of life, carer burden and proportion of participants who would enrol in a future randomised controlled trial. The study is funded by the National Institute for Health Research via Health Technology Assessment programme., Discussion: Olanzapine for young PEople with aNorexia nervosa will inform a future randomised controlled trial on the efficacy and safety of prescribing olanzapine in young people with AN., (© 2024 The Authors. European Eating Disorders Review published by Eating Disorders Association and John Wiley & Sons Ltd.) more...

Objective: We present the protocol of a feasibility randomised controlled trial (RCT) of intermittent theta burst stimulation (iTBS) for young people with anorexia nervosa (AN). Effective first-line psychological therapies exist for young people with AN, but little is known about how to treat those who do not respond. Non-invasive neuromodulation, such as iTBS, could address unmet treatment needs by targeting neurocircuitry associated with the development and/or maintenance of AN., Design: Sixty-six young people (aged 13-30 years) with persistent AN will be randomly allocated to receive 20 sessions of real or sham iTBS over the left dorsolateral prefrontal cortex in addition to their usual treatment. Outcomes will be measured at baseline, post-treatment (1-month post-randomisation) and 4-months post-randomisation (when unblinding will occur). Additional open follow-ups will be conducted at 12- and 24-months post-randomisation. The primary feasibility outcome is the proportion of participants retained in the study at 4-months. Secondary outcomes include AN symptomatology, other psychopathology, quality of life, service utilisation, neurocognitive processes, and neuroimaging measures., Discussion: Findings will inform the development of a future large-scale RCT. They will also provide exploratory data on treatment efficacy, and neural and neurocognitive predictors and correlates of treatment response to iTBS in AN., (© 2024 The Authors. European Eating Disorders Review published by Eating Disorders Association and John Wiley & Sons Ltd.) more...

Background: Although previous studies have reported that proprioceptive training methods (PTM) have positive effects, there is a relatively small number of studies regarding the impact of PTM in women's soccer. Therefore, there is a need to systematize the given results. In this regard, this systematic review aimed to investigate the effect of proprioceptive training methods in female soccer players., Methods: The studies' search and analysis were done according to the PRISMA guidelines. The following databases were checked (Google Scholar, PubMed Cochrane and ProQuest), with additional publication time criteria (2000-2023) using the following keywords: proprioceptive, balance, neuromuscular, training, exercise, intervention, method, activity, female football players, female soccer players, woman soccer players., Results: A total of 7 studies were included in the quantitative synthesis that meet all the criteria with the number of participants being 2.247. Based on the analysis of the previous research and detailed discussion, the main findings of the study resulted in the partial improvement of explosive strength (66%), strength (50%), muscle imbalance and flexibility (50%) and the prevention and reduction of lower extremity injuries in female soccer players (60%). Only one study reported no significant differences between groups, where rate of major injuries was higher in experimental group., Conclusion: The obtained results indicate the necessity to implement proprioceptive training in female soccer training programs, in order to influence the prevention and reduction of injuries and improve balance, proprioceptive ability and body control., (© 2024. The Author(s).) more...

The objective of this research was to analyze and elucidate the sagittal spinal posture status in older elementary school children, considering their gender and grade differences. The study involved 484 school children (252 males and 232 females) from grades V to VIII, assessed for sagittal spinal posture using the Formetric 4D System. The analysis, employing the Chi-squared test of independence along with the Z-test, did not reveal significant grade-related differences ( p < 0.52) in the incidence of normal sagittal alignment or diagnosed outliers. However, within grade levels, no significant difference was observed for male participants ( p < 0.80), while a significant difference was identified for females ( p < 0.01). Examining gender differences across grades, a disparity was noted only among seventh graders concerning normal spine alignment and outlier existence ( p < 0.01), favoring male participants. Regardless of the grade, a significant gender difference emerged in the location of diagnosed outliers: kyphosis (M = 108 vs. F = 72), lordosis (M = 5 vs. F = 14), kypholordosis (M = 18 vs. F = 66), and flatback outlier of the lumbar spine (M = 27 vs. F = 11). These findings suggest potential adjustments to the curriculum and highlight the need to tailor physical education instruction based on this study's outcomes. Consequently, these results imply the importance of a differentiated approach in preventing sagittal plane outliers of the spine in adolescent children. more...

Background: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignant epithelial tumor endemic to Southern China and Southeast Asia. While previous studies have revealed a low frequency of gene mutations in NPC, its epigenomic aberrations are not fully elucidated apart from DNA hypermethylation. Epigenomic rewiring and enhancer dysregulation, such as enhancer hijacking due to genomic structural changes or extrachromosomal DNA, drive cancer progression., Methods: We conducted Hi-C, 4C-seq, ChIP-seq, and RNA-seq analyses to comprehensively elucidate the epigenome and interactome of NPC using C666-1 EBV(+)-NPC cell lines, NP69T immortalized nasopharyngeal epithelial cells, clinical NPC biopsy samples, and in vitro EBV infection in HK1 and NPC-TW01 EBV(-) cell lines., Findings: In C666-1, the EBV genome significantly interacted with inactive B compartments of host cells; the significant association of EBV-interacting regions (EBVIRs) with B compartment was confirmed using clinical NPC and in vitro EBV infection model. EBVIRs in C666-1 showed significantly higher levels of active histone modifications compared with NP69T. Aberrant activation of EBVIRs after EBV infection was validated using in vitro EBV infection models. Within the EBVIR-overlapping topologically associating domains, 14 H3K4me3(+) genes were significantly upregulated in C666-1. Target genes of EBVIRs including PLA2G4A, PTGS2 and CITED2, interacted with the enhancers activated in EBVIRs and were highly expressed in NPC, and their knockdown significantly reduced cell proliferation., Interpretation: The EBV genome contributes to NPC tumorigenesis through "enhancer infestation" by interacting with the inactive B compartments of the host genome and aberrantly activating enhancers., Funding: The funds are listed in the Acknowledgements section., Competing Interests: Declaration of interests MJF declares two patents on methodologies related to ChIA-PET. The remaining authors have no conflict of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.) more...

Hospital admissions for eating disorders (ED) are rapidly increasing. Limited research exists evidencing the factors that lead to hospital admissions or their outcomes. The current study aimed to identify predictors of hospital admission in adolescents with anorexia nervosa (AN) or atypical anorexia nervosa (AAN). Prospective observational study including participants (n = 205) aged 11-18 and diagnosed with AN or AAN at initial ED assessment, across eight London clinics. Physical health parameters at assessment, including heart rate, blood pressure, temperature and rate of weight loss, were compared between adolescents who were admitted to a paediatric ward following assessment and those who were not admitted. The mean rate of weight loss prior to assessment was significantly higher, and mean energy intake significantly lower, in the admitted vs not admitted groups (1.2 vs 0.6kg/week, p < 0.001 and 565 kcal/day vs 857 kcal/day, p < 0.001), independent of degree of underweight. No significant differences were identified between groups in all other parameters of physical risk. Underweight adolescents with AN were equally likely to be admitted as non-underweight adolescents with AAN.  Conclusion: This study provides evidence on predictors of hospital admission, from a sample representing the London area. The assessment of weight loss speed, duration and magnitude are recommended as priority parameters that inform the risk of deterioration and the likelihood of hospital admission in adolescent AN and AAN. Further research investigating outcomes of these hospital admission is needed. What is Known: • Hospital admissions for eating disorders (ED) are rapidly increasing. • Limited research exists evidencing the factors that lead to hospital admissions, or their outcomes. What is New: • This study provides evidence on predictors of hospital admission in young people with typical and atypical anorexia nervosa. • Weight loss speed, duration, and magnitude are recommended as priority parameters that inform the risk of deterioration and the likelihood of hospital admission in this patient group., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.) more...

Background and Aim: Anti-aminoacyl-tRNA synthetase (ARS) antibodies form a condition called Antisynthetase syndrome (ASSD). While interstitial lung disease (ILD) is a particularly frequent manifestation of ASSD and is closely associated with morbidity and mortality, few studies have been conducted on its characteristics on high-resolution computed tomography (HRCT). In this study, we clarified the HRCT findings in patients with anti-ARS antibody-positive ILD (ARS-ILD).  Methods: The HRCT findings at the time of the ILD diagnosis in 24 ARS-ILD patients were retrospectively evaluated by 2 pulmonologists and one radiologist. We also assessed the clinical symptoms, physical examination findings, and laboratory data including the type of anti-ARS antibodies. For a further analysis, the data of patients were divided into two groups: the polymyositis (PM)/dermatomyositis (DM) group and the non-PM/DM group., Results: The ratio of men to women was almost 1:1. The median age at the time of the diagnosis was 53 years old. Anti-glycyl (anti-EJ) and anti-histidyl (anti-Jo-1) antibodies were more common than others. An analysis of the HRCT patterns of 23 ARS-ILD patients showed that the most common pattern was the nonspecific interstitial pneumonia (NSIP) pattern. The second most common pattern was the usual interstitial pneumonia (UIP) pattern. Between the PM/DM and non-PM/DM groups, no clear trends were noted in the age, sex ratio, proportion of HRCT patterns, or type of anti-ARS antibodies., Conclusions: This retrospective study demonstrated that ARS-ILD patients, regardless of myositis symptoms, most often showed the NSIP pattern on HRCT, as previously reported. However, unlike previous reports, the UIP pattern on HRCT was not rare. more...

Background: Despite dietitians being important members of the multidisciplinary team delivering family therapy for anorexia nervosa (FT-AN), their specific responsibilities and roles are unclear and their involvement in the treatment can be a contentious issue., Methodology: Clinicians ( n = 20) experienced in the delivery of FT-AN who were working at a specialist child and adolescent eating disorder service responded to an online survey about their experience of including a dietitian in FT-AN and how they understand the role. Both categorical and open-ended questions were used. Reflexive thematic analysis was used to analyse the qualitative free-text responses of clinician perspectives on the role of the dietitian in FT-AN., Results: All clinicians agreed that dietetics had a role within FT-AN and most frequently sought dietetic involvement in the early phases of FT-AN. Reflexive thematic analysis of responses identified three main themes. These were (1) collaboration is key, (2) confidence as a core consideration and (3) case-by-case approach. These themes evidenced the role of the dietitian within FT-AN and highlighted both the benefits and concerns of this involvement., Conclusions: This study demonstrated that dietitians can take a core role as collaborators within therapy-led teams that facilitate joint working and sharing of expertise. However, dietetic input should be considered on a case-by-case basis, given its potential for creating an over-focus on nutrition and potentially diminishing parental confidence in feeding. When indicated for selected cases, nutritional counselling should be offered in joint sessions with the therapist rather than separately. The findings of the study were limited by the small sample size of participants recruited from a single centre and heterogeneity in the professional background of respondents. Although the integration of dietetics within the multidisciplinary team and the ability of dietitians to individualise patient care can enhance FT-AN treatment, potential benefits and disbenefits should be considered for each case. more...

Background: Family therapy for anorexia nervosa (FT-AN) is the first line recommended treatment for child and adolescent anorexia nervosa. Despite evidence of its efficacy, little is understood about the treatment mechanisms. This study aimed to understand how young people who have received FT-AN perceive change to occur across treatment., Method: Fifteen adolescents (age 12-18 years) completed individual semi-structured interviews online. Recordings were transcribed verbatim and analysed using reflexive thematic analysis., Results: Four inter-connected themes describing the process of change during treatment were generated; (1) relationships as the vehicle for change, (2) an awakening, (3) through, not around - no way out, (4) the life beyond., Conclusions: Current data match relatively closely with theoretical models of FT-AN and emphasise the importance of building trust with all family members, including the young person. Additionally, supporting the family to create a trusting context in which there is a sense that the only way out of the illness is by going through it (rather than avoiding it) is critical. Empirical investigation of each of the described mechanisms is needed., (© 2024. The Author(s).) more...

Matrix metalloproteinase-9 (MMP-9) is a secreted zinc-dependent endopeptidase that degrades the extracellular matrix and basement membrane of neurons, and then contributes to synaptic plasticity by remodeling the extracellular matrix. Inhibition of MMP-9 activity has therapeutic potential for neurodegenerative diseases such as fragile X syndrome. This paper reports the molecular design, synthesis, and in vitro studies of novel indole derivatives as inhibitors of proMMP-9 activation. High-throughput screening (HTS) of our internal compound library and subsequent merging of hit compounds 1 and 2 provided compound 4 as a bona-fide lead. X-ray structure-based design and subsequent lead optimization led to the discovery of compound 33, a highly potent and selective inhibitor of proMMP-9 activation., 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 Ltd. All rights reserved.) more...

Background: Prosocial behaviour can promote positive social interactions and it is a key skill in adolescence. People with emotional problems or psychiatric disorders, such as people with eating disorders might have impairments in prosocial behaviour, due to broader documented difficulties in underlying processes (e.g., mentalizing)., Methods: The aim of this study was to examine prosocial behaviour in adolescents with eating disorders compared to healthy controls, using a computerised behavioural task. Adolescents (N = 123) including patients with eating disorders (n = 61) and healthy adolescents (n = 62) played a four-player computerised Prosocial Cyberball Game with three pre-programmed avatar players. During the task, participants witnessed the exclusion of one of the players, and subsequently had the opportunity to compensate for this by throwing the ball more often to the excluded player. Throughout the game, participants rated the level of negative emotion in themselves and in the excluded player., Results: Patients made significantly fewer ball tosses towards the excluded player during the compensation round compared to healthy controls (large effect size). Patients reported a significantly smaller increase in negative emotion after witnessing the exclusion and a significantly smaller decrease in negative emotion following the compensation round (large effect sizes). Patients also estimated a smaller decrease in negative emotion in the excluded player following the compensation round (medium effect size). There were no significant associations between these outcomes and eating disorder psychopathology in patients., Conclusions: Compared to healthy adolescents, adolescent patients with eating disorders demonstrated less prosocial compensatory behaviour towards a computerised victim of social exclusion. In addition, they reported flatter negative emotion in themselves in response to witnessing and compensating for exclusion, and in the excluded player following compensation. If these findings are replicated, interventions to target these difficulties might contribute to improvements in social functioning in this patient group., (© 2023. The Author(s).) more...

Proline, which is a predominant amino acid in grape musts, is involved in the taste and flavor of foods and beverages. The yeast Saccharomyces cerevisiae poorly utilizes proline in wine-making processes, leading to a nitrogen deficiency during fermentation and proline accumulation in wine. Previous studies have shown that the protein kinase A (PKA) pathway is involved in inhibitory mechanisms of proline utilization. In this study, we screened the PKA pathway-related genes that regulate proline utilization. Using a yeast culture collection of disrupted strains associated with the downstream of the PKA cascade, we revealed that the stress-responsive transcription factor genes MSN2/4 regulate proline utilization. Moreover, we found that Msn2/4 up-regulate the SHY1 gene during the cell growth of the wine fermentation model, which may cause the inhibition of proline utilization. The SHY1-deleted strain of the commercial wine yeast clearly showed proline consumption and average ethanol production under the wine fermentation model. The present data indicate that the PKA-Msn2/4-Shy1 cascade controls the inhibition of proline utilization under wine-making processes. Our study could hold promise for the development of wine yeast strains that can efficiently reduce proline during wine fermentation., (Copyright © 2023 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.) more...

Background: Total pelvic exenteration (TPE) in men is a surgical procedure to treat genitourinary and colorectal malignancies. Despite improvement in multimodal strategies and technology, mortality is still high and literature is limited about perioperative outcomes comparison to other radical procedures., Methods: We analyzed National Surgical Quality Improvement Program (NSQIP) baseline database of all male patients undergoing cystectomy, low anterior resection/abdominoperineal resection (LAR/APR) or TPE from January 1, 2005 to December 31, 2016. Postoperative complications within 30 days after surgery were measured including: Wound infection, septic complications, deep vein thrombosis, cardiovascular events, and return to the operating room or mortality, etc. Differences between groups were analyzed using analysis of variance (ANOVA) tests., Results: A total of 7,375 patients underwent radical cystectomy, 49,762 underwent LAR/APR and 792 underwent TPE. Cystectomy patients were on average older compared to TPE or LAR/APR patients (P<0.001). In univariable and multivariable analysis, patients undergoing TPE had greater infectious and septic complications compared to cystectomy (odds ratio =1.09; 95% confidence interval (CI): 1.06-1.12) and LAR/APR (odds ratio =1.08; 95% CI: 1.05-1.11). Moreover, TPE had a slightly higher mortality within the 30-day postoperatively than those who underwent LAR/APR (odds ratio =1.01; 95% CI: 1.00-1.02) and cystectomy (odds ratio =1.01; 95% CI: 1.00-1.01)., Conclusions: Men undergoing TPE had greater rates of infections and postoperative complications compared to those undergoing radical cystectomy and LAR/APR. From a clinical standpoint, TPE has high morbidity that could provide opportunity for quality improvement projects with the goal of mitigating high complication rates., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-23-266/coif). The authors have no conflicts of interest to declare., (2023 Translational Andrology and Urology. All rights reserved.) more...

Introduction: Multi-family therapy for anorexia nervosa (MFT-AN) is a novel, group-based intervention that intensifies single-family therapy for anorexia nervosa (FT-AN), with the aim of improving outcomes. The current study explored treatment moderators in a randomised controlled trial (N = 167) of FT-AN and MFT-AN for young people (adolescents/emerging adults aged 13-20 years) with anorexia nervosa., Methods: Data were analysed using multiple linear regression. Six hypothesised baseline participant and parent factors were tested as possible moderators of treatment effect on end-of-treatment and follow-up percentage of median Body Mass Index (%mBMI); age, eating disorder symptom severity, perceived family conflict (young person and parent ratings) and parent-rated experiences of caregiving (positive and negative)., Results: Greater parent-rated positive caregiving experiences moderated treatment outcomes at follow-up (β = -0.47, 95%CI: -0.91, -0.03, p = 0.04), but not end-of-treatment. Participants who had fewer parent-rated positive caregiving experiences at baseline had higher weight at follow-up if they had MFT-AN compared to FT-AN. No other hypothesised baseline factors moderated treatment outcome (p's > 0.05)., Discussion: The current study suggests MFT-AN may be indicated for families who present with fewer positive caregiving experiences to treatment. The MFT-AN group context may help to promote mentalisation and hope for these families, which may be harder to achieve in single-family treatment. Future research is needed to empirically evaluate how and why MFT-AN supports this group more., Trial Registration: ISRCTN registry: ISRCTN11275465, registered 29 January 2007., (© 2023 The Authors. European Eating Disorders Review published by Eating Disorders Association and John Wiley & Sons Ltd.) more...

Objective: Multi-family therapy (MFT-AN) is a promising group-based treatment for adolescent anorexia nervosa. This study aimed to explore how young people and parents perceived change to occur during MFT treatment., Methods: Young people (10-18 years) diagnosed with anorexia nervosa or atypical anorexia nervosa and their parents who completed MFT-AN alongside family therapy for anorexia nervosa within the preceding 2 years were eligible for this study. Semi-structured qualitative interviews were conducted. Recordings were transcribed verbatim and analysed using reflexive thematic analysis., Results: Twenty-three participants (8 young people, 10 mothers and 5 fathers) completed interviews. Five main themes were identified; (1) Powerful connection, (2) Intensity, (3) New learning and perspective shifts, (4) Comparisons, and (5) Discharge is not recovery. There was a strong sense that being with others in a similar position in an intense environment were key factors in promoting change. Comparisons were inevitable and could promote insight and foster motivation, but could also be unhelpful at times. Participants spoke about how recovery continues beyond service use and requires ongoing attention and support., Conclusions: Through the mechanisms of connection, intensity, new learning and comparisons change is perceived to occur in MFT-AN. Some of these are considered unique to this treatment format., (© 2023 Eating Disorders Association and John Wiley & Sons Ltd.) more...

The aim of this study was to determine urban-rural and regional differences in anthropometric characteristics among adolescents aged 12-14, as well as to present the prevalence of weight status. A total of 534 adolescents aged 12-14 from primary schools across Montenegro participated in this cross-sectional study (283 boys, aged 13.52 ± 0.42, body height 169.43 ± 8.89, body weight 60.54 ± 13.47; 251 girls, aged 13.51 ± 0.40, body height 165.54 ± 6.67, body weight 55.28 ± 9.27). The sample was divided by geographic region in Montenegro into northern, central, and coastal regions, and according to settlement type into urban and rural inhabitants. Anthropometric characteristics were assessed using a battery of seven variables: arm span (AS); body height (BH); body weight (BW); waist circumference (WC); hip circumference (HC); body mass index (BMI); and waist-to-hip ratio (WHR). BMI was categorized based on the World Health Organization's (WHO) cut-offs. The results indicate that girls from urban areas exhibited significantly greater body height and lower BMI values compared to their rural counterparts. Similarly, boys from urban areas also demonstrated lower BMI values compared to their rural peers. However, no statistically significant differences were observed in other anthropometric characteristics between these two groups of adolescents. Based on analysis of variance (ANOVA) and post-hoc analysis, it was found that girls from central areas had significantly greater body height compared to those from northern and coastal areas. Likewise, boys from northern areas showed higher body mass and BMI values compared to those from central areas. Additionally, both boys and girls from central areas had higher values compared to those from coastal areas. Nevertheless, no significant differences were detected in other anthropometric characteristics among adolescents from these regions. This study identified significant differences in anthropometric parameters among participants based on urban-rural status and within regional divisions. However, further research encompassing a larger sub-sample and a broader array of anthropometric variables is needed to draw a more comprehensive conclusion. more...

Heparanase-1 (HPSE1) is an endo-β-d-glucuronidase that is the only mammalian enzyme known to cleave heparan sulfate (HS) of heparan sulfate proteoglycans (HSPG), a key component of the glycocalyx layer of the vascular endothelium matrix. Inhibition of HPSE1 has therapeutic potential for cancer and proteinuric kidney diseases. We previously reported that 2 showed a moderate potency as an HPSE1 inhibitor and an issue of selectivity against exo-β-d-glucuronidase (GUSβ) and glucocerebrosidase (GBA) remained. A structure-based lead optimization of 2 using X-ray co-crystal structure analysis and fragment molecular orbital calculation resulted in 4e, which showed a more than 7-fold increase in HPSE1 inhibitory activity. The subsequent introduction of a methyl group into the 6-hydroxy group of 4e resulted in 18 with reduced inhibitory activities against GUSβ and GBA while maintaining the inhibitory activity against HPSE1. The inhibitory activities of 18 against serum HPSE1 in mice were significant and lasted for 4 h at doses of 3, 30, and 100 mg/kg. Compound 18 could be a novel lead compound for HPSE1 inhibitors with improved inhibitory activity against HPSE1 and increased HPSE1 selectivity over GUSβ and GBA., 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 Ltd. All rights reserved.) more...

Urothelial carcinoma of the upper tract (UTUC) is a malignancy that accounts for 5-10% of all urothelial carcinomas. Radical surgery is the primary treatment option due to the high rate of invasive stages at the time of diagnosis. Nephroureterectomy (NU) with bladder cuff excision is the current standard of care. While laparoscopic NU has been established since 1991, many centres still perform open surgery due to the complexity of laparoscopic instrumentation and the steep learning curve for excising the bladder cuff. With the increasing adoption of the multi-port (MP) robotic surgery, NU has increasingly been performed using this platform. The use of MP robotic systems for NU has been challenged by the need for patient repositioning and/or redocking of the robot, which can consume valuable operative time. The transition from the daVinci Si to the daVinci Xi system has seen a noticeable reduction in redocking and patient repositioning. However, owing to the multi-quadrant nature of the surgery in question, the use of multiple ports and external instrument clashing are still persistent problems. Moreover, there is a growing interest in utilizing a retroperitoneal approach for robot-assisted NU due to its potential benefits such as improved control of hilar structures, reduction of blood loss, shorter operative time and hospital stay, reduced complications and decreased postoperative discomfort. The application of the daVinci single-port (SP) robotic platform during radical NU for UTUC is feasible and has the potential to improve the current surgical approach. Indeed, the use of a SP platform may solve the problem of patient repositioning and redocking of the robot, improve superficial aesthetic outcome and minimize external instrument clashing. While maintaining an optimal oncological control, the retroperitoneal approach, which has been difficult to replicate and adopt using the MP approach, may become standard practice. However, more studies are needed to confirm the benefit of this approach and ultimately determine the impact of the daVinci SP on the management of UTUC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-23-48/coif). The series “Upper Tract Urothelial Cancer” was commissioned by the editorial office without any funding or sponsorship. SC is a consultant for Intuitive Surgical, Inc. The authors have no other conflicts of interest to declare., (2023 Translational Andrology and Urology. All rights reserved.) more...

Objective: Eating disorders are associated with significant illness burden and costs, yet access to evidence-based care is limited. Greater use of programme-led and focused interventions that are less resource-intensive might be part of the solution to this demand-capacity mismatch., Method: In October 2022, a group of predominantly UK-based clinical and academic researchers, charity representatives and people with lived experience convened to consider ways to improve access to, and efficacy of, programme-led and focused interventions for eating disorders in an attempt to bridge the demand-capacity gap., Results: Several key recommendations were made across areas of research, policy, and practice. Of particular importance is the view that programme-led and focused interventions are suitable for a range of different eating disorder presentations across all ages, providing medical and psychiatric risk are closely monitored. The terminology used for these interventions should be carefully considered, so as not to imply that the treatment is suboptimal., Conclusions: Programme-led and focused interventions are a viable option to close the demand-capacity gap for eating disorder treatment and are particularly needed for children and young people. Work is urgently needed across sectors to evaluate and implement such interventions as a clinical and research priority., (© 2023 The Authors. European Eating Disorders Review published by Eating Disorders Association and John Wiley & Sons Ltd.) more...

Background: High-grade squamous intraepithelial lesion (HSIL) is a disease that is closely related to the development of cervical cancer. In clinical work, cold knife conization and a loop electrosurgical excision procedure (LEEP) are often selected for diagnosis and treatment., Objective: In this paper, we aimed to discuss additional cuts, a common practice in cervical conization, and determine whether the doctor's choice to use additional cuts in conization can reduce the occurrence of a positive cone margin., Methods: From January 2018 to October 2019, 965 patients underwent cervical conization at the First Affiliated Hospital of Dalian Medical University (Dalian, China). Of these, 174 were in the positive cone margin group, and 791 were in the negative cone margin group. Age, preoperative pathology, pathological results of conization, additional cuts, cone depth, and cone volume were studied. Additionally, the additional cut rate and the efficiency of doctors with a habit of additional cuts were analyzed., Results: Of the 965 patients included in the study, the median age was 41 years (range 35-50). Multivariable logistic regression analysis suggested that additional cuts (OR, 2.480; 95% CI 1.608 to 3.826; p = 0.01) and smaller cone depth (OR, 0.591; 95% CI, 0.362 to 0.965, p = 0.036) were independent risk factors for positive margins. Six of the 64 doctors who performed conizations had a habit of making additional cuts, and there was no positive correlation between their additional cut rate and their effective additional cut rate., Conclusion: This study showed that a certain proportion of additional cuts can be effectively excised from the positive margin that cannot be removed in the initial conization. The practice of additional cuts in conization tends to be the personal habit of a small number of doctors., (© 2023. BioMed Central Ltd., part of Springer Nature.) more...

Background: There is limited information regarding adaptation of HIIT in female athletes which is important since the adaptation to HIIT may be different compared to male athletes. Therefore, the aim of this systematic review was to summarize the effects of HIIT on physical performance in female team sports athletes., Methods: The following databases Google Scholar, PubMed, Web of Science, Cochrane Library, ProQuest and Science Direct were searched prior to September 2nd, 2022. The inclusion criteria were longitudinal studies written in English, elite, sub-elite or college female team sports participants, and HIIT intensity had to be at 80-100% maximal heart rate. There were no exclusion criteria regarding the age of the participants or their training experience. The primary outcome measures were maximal oxygen uptake (VO 2 max), repeated sprint ability (RSA), change of direction speed, speed, explosive strength and body composition., Results: A total of 13 studies met the inclusion criteria, with a total of 230 participants. HIIT improved VO 2 max in five studies (ES from 0.19 to 1.08), while three studies showed improvement in their RSA (ES from 0.32 to 0.64). In addition, change of direction speed was improved in five studies (ES from 0.34 to 0.88), while speed improved in four studies (ES from 0.12 to 0.88). Explosive strength results varied (ES from 0.39 to 1.05), while in terms of body composition, the results were inconsistent through observed team sports., Conclusion: HIIT has significant effects on VO 2 max, RSA, change of direction speed, speed and explosive strength in female team sports, regardless of the competition level., (© 2023. Springer Nature Switzerland AG.) more...

Anorexia nervosa-focussed family therapy (FT-AN) is the first-line treatment for adolescent anorexia nervosa (AN), but the predictors of poor treatment response are not well understood. The main aim of this study was to investigate the role of attachment and mentalization in predicting treatment outcome. The secondary aims of the study were to investigate therapeutic alliance at 1 month as a predictor of outcome, and to test the associations between alliance and baseline attachment and mentalization. 192 adolescents with AN and their parents were recruited as they began family therapy in out-patient specialist eating disorder services. Self-report measures of attachment, mentalization, and emotion regulation were completed at the start of treatment by adolescent patients and one of their parents. Self-reported alliance scores were collected at one month. Higher scores on the Certainty Scale of the Reflective Functioning Questionnaire, completed by parents, which indicate over-certainty about mental states, were the strongest predictor of poor outcome (Odds Ratio: 0.42, CI: 0.20-0.87). Similarly, for adolescents, higher Lack of Clarity scores on the Difficulties in Emotion Regulation Scale, representing being unclear about one's feelings, were predictive of positive treatment outcome (OR: 1.10, CI: 1.00-1.21). Higher alliance scores at 1 month predicted positive outcome, and were associated with attachment security and mentalization. These novel findings suggest that, particularly in parents, a tendency towards excessive certainty about mental states in others may predict poor outcome in FT-AN. Further research is warranted to replicate the finding and characterise families at risk of poor outcome., (© 2021. The Author(s).) more...

Human papillomavirus (HPV) is causally involved in the development of head and neck squamous cell carcinoma (HNSCC). The integration of HPV drives tumorigenesis through expression of oncogenic viral genes as well as genomic alterations in surrounding regions. To elucidate involvement of epigenetic dysregulation in tumorigenesis, we here performed integrated analyses of the epigenome, transcriptome and interactome using ChIP-seq, RNA-seq and Hi-C and 4C-seq for HPV(+) HNSCCs. We analyzed clinical HNSCC using The Cancer Genome Atlas data and found that genes neighboring HPV integration sites were significantly upregulated and were correlated with oncogenic phenotypes in HPV(+) HNSCCs. While we found four HPV integration sites in HPV(+) HNSCC cell line UPCI-SCC-090 through target enrichment sequencing, 4C-seq revealed 0.5 to 40 Mb of HPV-interacting regions (HPVIRs) where host genomic regions interacted with integrated HPV genomes. While 9% of the HPVIRs were amplified and activated epigenetically forming super-enhancers, the remaining non-amplified regions were found to show a significant increase in H3K27ac levels and an upregulation of genes associated with GO terms, for example, Signaling by WNT and Cell Cycle. Among those genes, ITPR3 was significantly upregulated, involving UPCI-SCC-090-specific super-enhancer formation around the ITPR3 promoter and in the 80-kb-downstream region. The knockdown of ITPR3 by siRNA or CRISPR deletions of the distant enhancer region led to a significant suppression of cell proliferation. The epigenetic activation of HPVIRs was also confirmed in other cell lines, UM-SCC-47 and UM-SCC-104. These data indicate that epigenetic activation in HPVIRs contributes, at least partially, to genesis of HPV(+) HNSCC., (© 2023 UICC.) more...

Objective: Individuals with eating disorders are known to have higher rates of insecure attachment compared to community controls, but the factors underlying this finding are poorly understood. We conducted the first meta-analysis comparing attachment in eating disorder samples compared to community controls that included quality assessment, publication bias and moderation analysis., Method: We pre-registered our meta-analysis (CRD42019146799) and followed PRISMA guidelines. We searched PsychINFO, Embase, Medline, CINAHL, and Scopus for publications. Attachment scores were extracted, and Cohen's d calculated for each study using a random effects model., Results: In total, 35 studies were included in the meta-analysis and six studies were summarized in a narrative review. Eating disorder samples showed higher rates of insecure attachment compared to community controls, with a large effect size, across measurement methods and different attachment dimensions. Blinding of assessors moderated effect sizes for attachment interview studies, but no other moderators were significant., Discussion: Risk of insecure attachment is elevated in individuals with eating disorders, albeit heterogeneity is high and largely unexplained. Clinicians may need to take this into account in their work, particularly given the association between attachment insecurity and challenges to therapeutic alliance. Future studies comparing eating disorder samples with community samples should control for general psychopathology., Public Significance: Attachment is a broad concept referring to a person's thoughts, feelings and behaviors in relation to close others. This systematic review and meta-analysis found that individuals with eating disorders are lower in attachment security than community controls, regardless of attachment construct or measurement approach. Attachment may be relevant in influencing eating disorder recovery, the development of therapeutic alliance, and potentially clinical outcomes, although more research is needed., (© 2023 The Authors. International Journal of Eating Disorders published by Wiley Periodicals LLC.) more...

Purpose: This study compared craniospinal irradiation using proton beam therapy (PBT) according to irradiation method and investigated the initial effects., Methods and Materials: Twenty-four pediatric patients (1-24 years old) who received proton craniospinal irradiation were examined. Passive scattered PBT (PSPT) and intensity modulated PBT (IMPT) were used in 8 and 16 patients, respectively. The whole vertebral body technique was used for 13 patients <10 years old, and the vertebral body sparing (VBS) technique was used for the remaining 11 patients aged ≥10 years. The follow-up period was 17 to 44 (median, 27) months. Organ-at-risk and planning target volume (PTV) doses and other clinical data were examined., Results: The maximum lens dose using IMPT was lower than that using PSPT ( P  = .008). The mean thyroid, lung, esophagus, and kidney doses were lower in patients treated using the VBS technique compared with the whole vertebral body technique (all P < .001). The minimum PTV dose of IMPT was higher than that of PSPT ( P  = .01). The inhomogeneity index of IMPT was lower than that of PSPT ( P  = .004)., Conclusions: IMPT is better than PSPT at reducing the dose to the lens. The VBS technique can decrease the doses to neck-chest-abdomen organs. The PTV coverage of IMPT is superior to that of PSPT., (© 2023 Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.) more...

Biologics have become an important component of treatment strategies for a variety of diseases, but the immunogenicity of large immune complexes (ICs) and aggregates of biologics may increase risk of adverse events is a concern for biologics and it remains unclear whether large ICs consisting of intrinsic antigen and therapeutic antibodies are actually involved in acute local inflammation such as injection site reaction (ISR). Ozoralizumab is a trivalent, bispecific NANOBODY ® compound that differs structurally from IgGs. Treatment with ozoralizumab has been shown to provide beneficial effects in the treatment of rheumatoid arthritis (RA) comparable to those obtained with other TNFα inhibitors. Very few ISRs (2%) have been reported after ozoralizumab administration, and the drug has been shown to have acceptable safety and tolerability. In this study, in order to elucidate the mechanism underlying the reduced incidence of ISRs associated with ozoralizumab administration, we investigated the stoichiometry of two TNFα inhibitors (ozoralizumab and adalimumab, an anti-TNFα IgG) ICs and the induction by these drugs of Fcγ receptor (FcγR)-mediated immune responses on neutrophils. Ozoralizumab-TNFα ICs are smaller than adalimumab-TNFα ICs and lack an Fc portion, thus mitigating FcγR-mediated immune responses on neutrophils. We also developed a model of anti-TNFα antibody-TNFα IC-induced subcutaneous inflammation and found that ozoralizumab-TNFα ICs do not induce any significant inflammation at injection sites. The results of our studies suggest that ozoralizumab is a promising candidate for the treatment of RA that entails a lower risk of the IC-mediated immune cell activation that leads to unwanted immune responses., Competing Interests: All author are employed by Taisho Pharmaceutical Co., Ltd. This study received funding from Taisho Pharmaceutical Co., Ltd. The funder had the following involvement with the study: the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication., (Copyright © 2023 Kyuuma, Kaku, Mishima-Tsumagari, Ogawa, Endo, Tamura, Ishikura, Mima, Nakanishi and Fujii.) more...

Transmembrane proteins are internalized by clathrin- and caveolin-dependent endocytosis. Both pathways converge on early endosomes and are thought to share the small GTPase Rab5 as common regulator. In contrast to this notion, we show here that the clathrin- and caveolin-mediated endocytic pathways are differentially regulated. Rab5 and Rab21 localize to distinct populations of early endosomes in cortical neurons and preferentially regulate clathrin- and caveolin-mediated pathways, respectively, suggesting heterogeneity in the early endosomes, rather than a converging point. Suppression of Rab21, but not Rab5, results in decreased plasma membrane localization and total protein levels of caveolin-1, which perturbs immature neurite pruning of cortical neurons, an in vivo-specific step of neuronal maturation. Taken together, our data indicate that clathrin- and caveolin-mediated endocytic pathways run in parallel in early endosomes, which show different molecular regulation and physiological function., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.) more...

The aim of this research was to determine the influence of a 12-week program of aerobics mix on the parameters of body composition in healthy adult women. The research has been performed in a sample of 64 women participants, and it is divided into two groups, an experimental group (E), made of 34 women participants (age 32 ± 1.8 years), and a control one (C), made of 30 women participants (age 33 ± 0.5 years). Their anthropometric and body composition were evaluated using the following respective parameters: body height, body weight, body fat percentage, muscle mass percentage, skinfold-back (KNL), skinfold-upper arm (KNN), skinfold-stomach (KNT), and skinfold-thigh (KNNK). After mix aerobics realization, among the women of the E group, there is a reduction of body mass by -2.5% and waist size by -3.39%, while muscle mass increased by 2.26%. With all skinfolds within the participants of the E group, there is a statistically important gained reduction of p < 0.05 at the final measuring, compared with the initial one (upper arm -21.10%, stomach -14.36%, back -20.58%, and upper leg -13.98%). The reduction of body mass percentage was -10.59%, and that of body mass index was -2.5%. Based on the gained results, it can be concluded that the mix program was efficient in the reduction of the subcutaneous fat tissue and visceral fat and also influential on the increase of muscle mass., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor BM declared a past co-authorship with the author BK., (Copyright © 2023 Špirtović, Čaprić, Stanković, Đorđević, Murić, Kahrović, Mujanović, Mekić, Katanić, Jelaska and Sporiš.) more...

Nasopharyngeal carcinoma (NPC) is Epstein-Barr virus (EBV)-associated invasive malignancy. Increasing evidence indicates that epigenetic abnormalities, including DNA methylation, play important roles in the development of NPC. In particular, the EBV principal oncogene, latent membrane protein 1 (LMP1), is considered a key factor in inducing aberrant DNA methylation of several tumour suppressor genes in NPC, although the mechanism remains unclear. Herein, we comprehensively analysed the methylome data of Infinium BeadArray from 51 NPC and 52 normal nasopharyngeal tissues to identify LMP1-inducible methylation genes. Using hierarchical clustering analysis, we classified NPC into the high-methylation, low-methylation, and normal-like subgroups. We defined high-methylation genes as those that were methylated in the high-methylation subgroup only and common methylation genes as those that were methylated in both high- and low-methylation subgroups. Subsequently, we identified 715 LMP1-inducible methylation genes by observing the methylome data of the nasopharyngeal epithelial cell line with or without LMP1 expression. Because high-methylation genes were enriched with LMP1-inducible methylation genes, we extracted 95 high-methylation genes that overlapped with the LMP1-inducible methylation genes. Among them, we identified DERL3 as the most significantly methylated gene affected by LMP1 expression. DERL3 knockdown in cell lines resulted in significantly increased cell proliferation, migration, and invasion. Lower DERL3 expression was more frequently detected in the advanced T-stage NPC than in early T-stage NPC. These results indicate that DERL3 repression by DNA methylation contributes to NPC tumour progression., 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 © 2022 Elsevier B.V. All rights reserved.) more...

Matrix metalloproteinase-2 (MMP2) is a zinc-dependent endopeptidase and a promising target for various diseases, including cancer and fibrosis. Herein, we report the discovery of a novel MMP2-selective inhibitor with high chemical stability and slow tight-binding features. Based on the degradation mechanism of our small-molecule-peptide hybrid 1 , the tripeptide linker {5-aminopentanoic acid [Ape(5)]-Glu-Asp} of 1 was replaced by a shorter linker (γ-D-Glu). Phenylbenzamide was suitable for the new generation of MMP2 inhibitors as an S1' pocket-binding group. The introduction of (4 S )-aminoproline dramatically increased the chemical stability while maintaining high subtype selectivity because of its interaction with Glu130. TP0597850 ( 18 ) exhibited high stability over a wide range of pH values as well as potent MMP2 inhibition ( K i = 0.034 nM) and ≥2000-fold selectivity determined using the inhibition constants. A kinetic analysis revealed that it possesses slow tight-binding nature with a long MMP2 dissociative half-life ( t 1/2 = 265 min). more...

Contemporary top-division soccer is characterized by high-intensity activity throughout the entire match, which also requires high levels of a wide range of the players' functional and motor abilities. Furthermore, motor and functional requirements vary in relation to the players' position on the pitch. In view of the above, the objective of this study was to determine any differences in body composition and specific motor abilities in relation to position. Twenty elite female soccer players (age: 20.90 ± 3.70 years; height: 166.95 ± 5.83 cm; weight: 58.97 ± 7.50 kg; training experience: 9.50 ± 4.11 years) were recruited for the purpose of this study. Based on their position within the team, the players were divided into three groups: defenders (N-7), midfielders (N-6), and forwards (N-7). The instruments used included the InBody770 (for body composition assessment), Optojump and Polar for the assessment of specific motor abilities. The results obtained indicate a strong link between the parameters body composition and specific motor abilities; however, the level of significance varies, as do the variables concerning specific motor abilities and body composition in relation to the players' position on the pitch. In accordance with these results, coaches and others working in the soccer industry should be apprised of the necessity of a tailored approach when it comes to planning the development of specific motor abilities, as well of with the importance of balanced body composition as prerequisites for achieving top results. more...

The aims of this study were to determine the relationship between vertical jumping performance, linear speed, change of direction speed (CODs) time and the COD deficit (CODD) in adolescent basketball players and to analyze the CODD between faster and slower players based on linear speed performance. Thirty-eight male basketball players (age: 15.47 ± 0.51 years; body height: 185.19 ± 5.67 cm; body mass: 71.87 ± 7.29 kg) completed countermovement jumps (CMJ) with and without an arm swing, squat jumps (SJs), linear sprints at 20 m with split times at 5 and 10 m, the pro-agility test and the zig-zag tests. Furthermore, the CODD was calculated as the difference between the 20 m linear speed result and CODs time in both COD tests. Pearson and Spearman analyses were used to determine the correlations between power-speed-related variables and the CODD. Moreover, independent t-tests and Cohen's d effect size (ES) were used to analyze the differences between the faster and slower players in the CODD. Moderate to strong significant negative correlations were observed between the CODD in the pro-agility test and linear speed at 5 m, 10 m, and 20 m (r = -0.55 to -0.46), while moderate negative significant correlation was found between the zig-zag CODD and SJs (r = -0.37) as well as small positive significant correlation between the CODD in the zig-zag test and the eccentric utilization ratio (EUR) (r = 0.23). Additionally, faster basketball players displayed significantly higher CODD values performing the pro-agility test. In summary, these findings underline the complexity of COD performance and the importance of remodeling traditional training programs in basketball players., (© 2022 Anja Lazić, Slobodan Andrašić, Mima Stanković, Zoran Milanović, Nebojša Trajković, published by Sciendo.) more...

Heparanase-1 (HPSE1) is an endo-β-d-glucuronidase that cleaves heparan sulfate proteoglycans into short-chain heparan sulfates (HS). The inhibition of HPSE1 has therapeutic potential for proteinuric diseases such as nephrotic syndrome because increased HPSE1 expression is associated with the loss of HS in the glomerular basement membrane, leading to the development of proteinuria. The present study examined the generation of a lead compound focusing on chemical structures with a sugar moiety, such as glycosides and sugar analogs, taking their physical properties into consideration. Compound 10, an exo-β-d-glucuronidase (GUSβ) inhibitor, was found to have a weak inhibitory activity against endo-β-d-glucuronidase HPSE1. A structure-activity relationship study using the X-ray co-crystal structure of 10 and HPSE1 resulted in 12a, which showed a more than 14-fold increase in HPSE1 inhibitory activity compared with that of 10. Compound 12a could be a novel lead compound for the development of a potent HPSE1 inhibitor., 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 © 2022 Elsevier Ltd. All rights reserved.) more...

A man with non-small-cell lung cancer who was negative for anti-nuclear antibodies was admitted for dyspnea after immune checkpoint inhibitor (ICI) administration. Computed tomography (CT) showed complexed radiologic features, including subpleural and basal predominant reticular shadow with cystic structures and peribronchovascular consolidation. Although we treated him with high-dose steroid under a diagnosis of ICI-related pneumonitis, he developed acute exacerbation of pneumonitis with progressive fibrosis and volume loss. A re-evaluation identified anti-aminoacyl-tRNA synthetase antibody in the serum collected before ICI administration. This case highlights the importance of re-evaluating pre-existing autoimmune disorders in patients who develop ICI-related pneumonitis with atypical radiologic features., Competing Interests: The authors declare that all authors have no conflict of interests., (© 2022 The Authors. Published by Elsevier Ltd.) more...

Objective: This study aimed to investigate whether a computerized cognitive bias modification training delivered remotely would reduce expectations of rejection in adolescents with eating disorders., Method: Sixty-seven adolescents aged 12-18 (99.5% female) with an eating disorder diagnosis (94% anorexia nervosa) and receiving specialist treatment were recruited. Participants were randomized to an intervention condition (n = 37) which included treatment as usual (TAU) supplemented by nine sessions of online cognitive bias modification training for social stimuli (CBMT + TAU), or a control condition (n = 30), which included TAU only. Participants were invited to complete assessments at baseline and post-intervention., Results: In the intervention condition, 22/37 participants completed six or more training sessions and post-intervention measures, the pre-defined criteria to be considered "completers." In the control condition, 28/30 participants completed the post-intervention measures. Participants who completed the intervention displayed a significantly greater reduction in negative interpretations of ambiguous social scenarios, with a medium effect size (p = .048, ηp2 = .090), and eating disorder psychopathology, with a medium effect size (p = .027, ηp2 = .105), compared to participants in the control condition. No significant between-group differences were found on emotional response to criticism, and anxiety and depression symptoms post-intervention (ps > .05; small effect sizes)., Discussion: Enhancing treatment as usual with CBMT targeting expectations of social rejection might be feasible and effective to reduce expectations of social rejection and eating disorder psychopathology in adolescents with eating disorders. Training adaptations might be necessary to impact on emotional processing and comorbid psychological distress., Public Significance: Adolescents with eating disorders who completed a brief (4-week) online cognitive training intervention, alongside their usual treatment, reported greater reductions in expectations of social rejection and eating disorder psychopathology after the intervention, compared to a separate group of patients who received their usual treatment only. This brief and accessible intervention may be a helpful treatment adjunct for adolescents with eating disorders., (© 2022 The Authors. International Journal of Eating Disorders published by Wiley Periodicals LLC.) more...

Background: We investigated the neurocognitive profiles of Early-Onset Schizophrenia (EOS; onset before age 18) and paired unaffected siblings and the little-studied effect of age-of-onset and duration of illness on cognitive performance., Methods: 31 EOS probands, and 31 of their siblings, had four cognitive domains assessed: (a) Memory: California Verbal Learning Test, and the Wechsler Memory Scale-Revised; (b) Working memory: Digit Span; (c) Attention: Degraded-Stimulus Continuous Performance Test, Span of Apprehension (SPAN), and Trail Making Test (TMT) part A; (d) Executive function: Wisconsin card sorting task, and TMT part B. Diagnosis was confirmed using the structured clinical interview for DSM-IV., Results: While EOS showed a generalised neurocognitive deficit (0.25-0.50 effect size) compared with siblings, across all cognitive domains, significantly greater patient deficits were observed with, working memory, attention, and executive function and minimal differences for digit span forward, block design and false alarms on the SPAN-12 confirmed by repeated measures MANOVA. Patients with earlier onset (12-15) showed greater deficits on false alarm and digits backward scores. Siblings showed individual cognitive task profiles similar to patients, confirming familial effects. EOS showed much more variable scores than siblings with more individual tasks showing 2 SD deficits than siblings. Long duration patients had greater z-score variability across tasks., Conclusions: Duration of illness was a more important characteristic in patients with onset 16 and over than in younger onset patients with comparable durations. Both the similarity of sibling pair profiles and greater patient variability across task provide further support for neurobiological heterogeneity in schizophrenia. more...