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Oculocutaneous albinism is an autosomal recessive inherited disorder associated with mutations in the TYR gene. A single missense change in the tyrosinase (Tyr) could result in partial or complete loss of catalytic activity. The effect of two genetic mutations in the same Tyr as the molecule is less studied. Here, we study single mutation variants, R217Q, R402Q, and a double mutant variant, R217Q/R402Q, to establish a link between alterations at the level of the atomic model of the protein and the disease phenotype. Human recombinant intra-melanosomal Tyr domains of Tyr and three mutant variants were expressed in T. ni. Larvae were purified using the combination of IMAC and SEC, and diphenolase activities were measured. The Tyr homology model was equilibrated using 100 ns molecular dynamics and analyzed using computational methods. The purified R217Q and R217Q/R402Q variants show decreased catalytic activities compared to those of the Tyr and R402Q variants. The R217Q/R402Q variant has the lowest protein activity and is significantly reduced., (© 2025 The Protein Society.)

Background: Pathogenic variants in KIF11 , a kinesin family gene, cause MCLMR and FEVR. In MCLMR, chorioretinal atrophy is present in the majority of cases and can be a helpful diagnostic sign., Cases: We present the cases of two patients with chorioretinal atrophy and microcephaly who carry novel KIF11 mutations. Both patients have relatively good central vision similar inferior lacunae of retinal atrophy with relative sparing of the foveal center with., Conclusion: Two cases with classic features of MCLMR have foveal sparing that expands the associated spectrum of ocular findings.

Sarcopenic obesity (SO) is a body composition phenotype derived from the simultaneous presence in the same individual of an increase in fat mass and a decrease in skeletal muscle mass and/or function. Several protocols for the diagnosis of SO have been proposed in the last two decades making prevalence and disease risk estimates of SO heterogeneous and challenging to interpret. Dementia is a complex neurological disorder that significantly impacts patients, carers and healthcare systems. The identification of risk factors for early cognitive impairment and dementia is key to mitigating the forecasted trends of a 2-fold increase in dementia case numbers over the next two decades worldwide. Excess adiposity and sarcopenia have both been independently associated with risk of cognitive impairment and dementia. Whether SO is associated with a greater risk of cognitive impairment and dementia is currently uncertain. This review critically appraises the current evidence on the association between SO with cognitive outcomes and dementia risk. It also discusses some of the putative biological mechanisms that may link the SO phenotype with alteration of brain functions., (© 2025 British Nutrition Foundation.)

Background and Aims: This systematic review and meta-analysis aimed to examine the effect of Ramadan intermittent fasting on appetite-regulating hormones including leptin, ghrelin, insulin, gastrin, glucagon-like peptide-1, peptide YY, and cholecystokinin., Methods: We searched the MEDLINE, Embase, Cochrane Library, CINAHL, Google Scholar, and Web of Science databases to identify relevant research on appetite-regulating hormones during Ramadan intermittent fasting, published until the end of March 2024., Results: Data from 16 eligible studies comprising 664 participants (341, 51.4 % male) with a mean ± standard deviation age of 33.9 ± 10.8 years were included. The meta-analysis included 12 studies with complete leptin data, showing no significant effect of Ramadan intermittent fasting on leptin concentrations (standardised mean difference - SMD = -0.11 μg/mL, 95 % CI: -0.36 to 0.14). Analysis of three studies with complete ghrelin data demonstrated a significant increase in ghrelin concentrations following Ramadan intermittent fasting (SMD = 0.31 pg/mL, 95 % CI: 0.03 to 0.60). Six studies examining insulin concentrations pre- and post-fasting revealed no significant effect on insulin concentrations (SMD = -0.24 μU/mL, 95 % CI: -0.54 to 0.02). Similarly, analysis of three studies with complete gastrin data showed no significant effect of intermittent fasting on gastrin concentrations (SMD = 0.23 pg/mL, 95 % CI: -0.71 to 0.99)., Conclusion: Ramadan intermittent fasting significantly increases ghrelin concentrations while showing no significant effects on leptin, insulin, and gastrin. While ghrelin findings were consistent across studies, the high heterogeneity in leptin studies suggests further research to better understand the effects of Ramadan intermittent fasting on appetite-regulating hormones., Competing Interests: Conflict of interest The authors do not have a direct conflict of interest to report. DNL has received an unrestricted educational grant from B. Braun for unrelated work. He has also received speaker's honoraria for unrelated work from Abbott, Nestlé and Corza., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Image-defined risk factors (IDRFs) were introduced to provide a consensus approach for pre-treatment risk stratification on computed tomography (CT) and magnetic resonance imaging (MRI) in patients with neuroblastoma., Objective: To assess the intra- and inter-reader agreement of radiologists in identifying IDRFs on CT., Materials and Methods: Approval for this retrospective study was granted by our institutional research ethics board with a waiver of consent. CT studies of pediatric patients with neuroblastoma were assessed by seven radiologists in two rounds. Each CT was accompanied by a standard form to indicate presence or absence of IDRFs for each patient. At least a 4-week period between rounds, randomization, and relabeling of the CT studies was required to minimize recall bias. Finally, three of the seven radiologists conducted a subsequent consensus reading to determine true positive IDRFs in the cohort. Fleiss' kappa statistic was used to evaluate readers' agreements and Pearson's correlation assessed the correlation between years of experiences of radiologists and their performance in accurately (intra-reader agreement) detecting IDRFs., Results: A total of 31 children with a median age of 2.1 years (interquartile range (IQR) 1.1, 3.0; range 0-18; male=21 (67.7%)) were included and 251 total positive IDRFs were identified on their CT scans. The location of the primary tumor was in the neck in 1 patient (3.2%), within the chest in 2 patients (6.5%), within the abdomen in 27 patients (87.1%), and in the pelvis in 1 patient (3.2%). In determining IDRFs, the inter-reader agreement among radiologists was substantial: 0.65 (95% CI 0.60, 0.69) and the intra-reader agreement for each radiologist was substantial to near perfect, ranging from 0.67 (0.60, 0.70) to 0.86 (0.82, 0.90). The correlation between the number of years of experience of radiologists and their performances in accurately detecting IDRFs (their intra-reader agreements) was respectively low (r=45, P=0.30) for abdomino-pelvic IDRFs and high for organs' infiltration IDRFs (r=0.74, P=0.05)., Conclusion: The determination of IDRFs on CT is reproducible with significant agreement among radiologists. The two IDRF items with the lowest overall inter-reader agreements were "diaphragm infiltration" and "mesenteric infiltration.", Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Glucose homeostasis may be dependent on liver conditions and influence health-related markers and quality of life (QoL) objective measurements. This study aimed to analyze the interactions of glycemia with liver and health status in a prediabetic population., Subjects and Methods: This study included 2220 overweight/obese prediabetics from the multinational PREVIEW project. Anthropometrics; clinical, metabolic and other health-related markers; and QoL variables were analyzed. Univariate and multilinear-adjusted regression models were run to explain the interrelationships and effect modification between glycemia, health-related QoL (applying SF-12) and metabolic/liver health (using the HSI, a putative marker of fatty liver)., Results: Relevant age/sex interactions were found concerning the levels of insulin, HOMA-IR, C peptide and transaminases in this prediabetic population. Multivariate models identified age, sex, glucose, WC and QoL as important predictors of HSI variability (adj. R value = 0.1393, p < 0.001), whereas the QoL status was statistically related to age, sex, HOMA-IR and HSI (adj. R value = 0.1130, p < 0.001) in this glycemia-impaired group. Furthermore, the QoL values declined with increased HSI scores, where a significant interaction was found ( p = 0.011) when the data were analyzed when comparing lower glycemia vs. higher glycemia in prediabetics. Indeed, an effect modification was featured depending on the glycemia levels concerning the QoL and HSI worsening., Conclusion: Glycemia associations with the QoL status and liver metabolism markers were evidenced, with clinical implications for diabetes and liver disease precision management given the modification of the QoL outcomes depending on the liver status and glycemia concentrations. Notably, independent associations of circulating glucose with age, sex, adiposity, inflammation and C peptide levels were found.

Many studies have identified disease-causing variants of PIKFYVE in ocular tissues; however, a comprehensive review of these variants and their ocular phenotypes is lacking. The phosphoinositide kinase PIKFYVE plays crucial roles in the endolysosomal pathway in autophagy and phagocytosis, both essential for cellular homeostasis. In this review, we evaluate the reported disease-causing PIKFYVE variants and their associated phenotypes in humans to identify potential genotype-phenotype correlations. Variants in PIKFYVE have been associated with corneal fleck dystrophy, congenital cataracts and possibly keratoconus. There are unvalidated associations of variants in PIKFYVE with autism spectrum disorder and congenital heart disease. We show that variants causing corneal fleck dystrophy exist in the chaperonin-like domain of PIKFYVE as well as the region between the chaperonin-like and the kinase domains. Similarly, congenital cataract variants appear to be specific to the kinase domain of the protein. This review consolidates existing knowledge on PIKFYVE variants in ocular disease and bridges fundamental science and clinical manifestations, potentially informing future diagnostic and treatment strategies for PIKFYVE-associated ocular disorders., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The spleen constantly clears altered red blood cells (RBCs) from the circulation, tuning the balance between RBC formation (erythropoiesis) and removal. The retention and elimination of RBCs occur predominantly in the open circulation of the spleen, where RBCs must cross submicron-wide inter-endothelial slits (IES). Several experimental and computational studies have illustrated the role of IES in filtrating the biomechanically and morphologically altered RBCs based on a rigid wall assumption. However, these studies also reported that when the size of IES is close to the lower end of clinically observed sizes (less than 0.5 μm), an unphysiologically large pressure difference across the IES is required to drive the passage of normal RBCs, sparking debates on the feasibility of the rigid wall assumption. In this work, We propose two deformable IES models, namely the passive model and the active model, aiming to explore the impact of the deformability of IES on the filtration function of the spleen. In the passive model, we implement the worm-like string model to depict the IES's deformation as it interacts with blood plasma and allows RBC to traverse. In contrast, the active model involved regulating the IES deformation based on the local pressure surrounding the slit. To demonstrate the validity of the deformable model, we simulate the filtration of RBCs with varied size and stiffness by IES under three scenarios: (1) a single RBC traversing a single slit; (2) a suspension of RBCs traversing an array of slits, mimicking in vitro spleen-on-a-chip experiments; (3) RBC suspension passing through the 3D spleen filtration unit known as'the splenon'. Our simulation results of RBC passing through a single slit show that the deformable IES model offers more accurate predictions of the critical cell surface area to volume ratio that dictate the removal of aged RBCs from circulation compared to prior rigid-wall models. Our biophysical models of the spleen-on-a-chip indicate a hierarchy of filtration function stringency: rigid model > passive model > active model, providing a possible explanation of the filtration function of IES. We also illustrate that the biophysical model of 'the splenon' enables us to replicate the ex vivo experiments involving spleen filtration of malaria-infected RBCs. Taken together, our simulation findings indicate that the deformable IES model could serve as a mesoscopic representation of spleen filtration function closer to physiological reality, addressing questions beyond the scope of current experimental and computational models and enhancing our understanding of the fundamental flow dynamics and mechanical clearance processes within in the human spleen., 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., (Published by Elsevier Ltd.)

Objective: To design and implement a formal skills workshop for ophthalmology residents to practice breaking bad news., Methods: A 2-session workshop was developed for 7 ophthalmology residents at the University of Alberta based on a workshop published by Ohio State University. Residents discussed the SPIKES protocol for breaking bad news, practiced mock cases with standardized patients, and listened to shared experiences from patients who had received ocular diagnoses., Results: All the residents (n = 6; p = 0.03) at the University of Alberta reported an increase in confidence in 3 measures of an encounter in which they had to break bad news, one of which shared the significant improvement reported by the Ohio State group (n = 9; p = 0.01): setting realistic expectations without destroying hope. Standardized patients discussed their satisfaction with their case training and suggested the provision of eye models or printouts to enhance the realism in the examination rooms. The University of Alberta workshop results replicated those from Ohio State in that the SPIKES lecture and standardized patient session were ranked highly in efficacy (median, 4 of 5). The University of Alberta panel discussion was ranked lower than at Ohio State University, which may have resulted from 1 of 2 patient guest speakers being unexpectedly unable to attend., Conclusion: The pilot Breaking Bad News Workshop was well received overall and may serve to inform future incorporation of soft skills development in a formal residency curriculum., (Copyright © 2023 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Background & Aims: The role of sarcopenic obesity (SO) in impaired cognitive function has been investigated in several observational studies, but results have been mixed. This study applied the proposed European Society for Clinical Nutrition and Metabolism (ESPEN)-European Association for the Study of Obesity (EASO) definition of SO to a representative population aged ≥50 years to identify the association between SO and cognitive function., Methods: Data from the National Health and Nutrition Examination Survey 1999-2002 waves were used. At the screening phase, body mass index or waist circumference were used to evaluate obesity; sarcopenia was identified using the SARC-F questionnaire. At the diagnostic phase I and II, sarcopenia was assessed using knee extensor isometric strength and appendicular lean mass, and fat mass percent was used to assess obesity. Cognitive function in older participants (60-85 years) was assessed using the Digit Symbol Substitution Test. A self-reported memory question was used in middle-aged individuals (50-59 years)., Results: The sample included 2356 participants (men, 44.7%). The prevalence of SO was 32.3%, 21.2% and 15.0% at the screening, diagnosis I, and diagnosis II, respectively. Significant associations between SO and cognitive impairment were observed in individuals aged 60-85 at diagnosis I (OR: 2.3, 95%CI 1.4-3.8, P = 0.007) and diagnosis II (OR: 2.7, 95%CI 1.5-4.9, P = 0.004)., Conclusion: The new ESPEN-EASO definition of SO identified a high prevalence of SO cases. A significant association between SO and poor cognitive function in older individuals was observed., Competing Interests: Declaration of competing interest I.A.M. was a member of the UK Government Scientific Advisory Committee on Nutrition, the Mars Scientific Advisory Council, the Mars Europe Nutrition Advisory Board, the Nestle Research Scientific Advisory Board, the Novozymes Scientific Advisory Board, and was a Scientific Adviser to the Waltham Centre for Pet Nutrition until 2020. On 1 August 2020 he became Professor Emeritus at the University of Nottingham and took up the post of Scientific Director of the Nestle Institute of Health Sciences in Lausanne, Switzerland, which terminated in August 2022. Other authors No conflicts to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Alterations to cilia are responsible for a wide range of severe disease; however, understanding of the transcriptional control of ciliogenesis remains incomplete. In this study we investigated whether altered cilia-mediated signaling contributes to the pleiotropic phenotypes caused by the Forkhead transcription factor FOXC1. Here, we show that patients with FOXC1-attributable Axenfeld-Rieger Syndrome (ARS) have a prevalence of ciliopathy-associated phenotypes comparable to syndromic ciliopathies. We demonstrate that altering the level of Foxc1 protein, via shRNA mediated inhibition, CRISPR/Cas9 mutagenesis and overexpression, modifies cilia length in vitro. These structural changes were associated with substantially perturbed cilia-dependent signaling [Hedgehog (Hh) and PDGFRα], and altered ciliary compartmentalization of the Hh pathway transcription factor, Gli2. Consistent with these data, in primary cultures of murine embryonic meninges, cilia length was significantly reduced in heterozygous and homozygous Foxc1 mutants compared to controls. Meningeal expression of the core Hh signaling components Gli1, Gli3 and Sufu was dysregulated, with comparable dysregulation of Pdgfrα signaling evident from significantly altered Pdgfrα and phosphorylated Pdgfrα expression. On the basis of these clinical and experimental findings, we propose a model that altered cilia-mediated signaling contributes to some FOXC1-induced phenotypes., (© 2024. The Author(s).)

Objective: Sarcopenic-obesity (SO) is characterized by the concomitant presence of low muscle mass and high adiposity. This study explores the association of body composition and SO phenotypes with cognitive function in older adults., Methods: Cross-sectional data in older adults (≥60 years) from NHANES 1999-2002 and 2011-2014 were used. In the 1999-2002 cohort, phenotypes were derived from body mass index (BMI) and dual-X-ray-absorptiometry, and cognition was assessed the by Digit-Symbol-Substitution-Test (DSST). In the 2011-2014 cohort, phenotypes were derived from BMI, waist-circumference (WC), and hand-grip-strength (HGS). Cognition was assessed using four tests: DSST, Animal Fluency, the Consortium-to-Establish-a-Registry-for-Alzheimer's-Disease-Delayed-Recall, and Word Learning. Mediation analysis was conducted to evaluate the contribution of inflammation (C-reactive-protein, CRP) and insulin resistance (Homeostatic-Model-Assessment-for-Insulin-Resistance, HOMA-IR) to the association between body composition and cognitive outcomes., Results: The SO phenotype had the lowest DSST mean scores ( p  < 0.05) and was associated with a significant risk of cognitive impairment [Odds Ratio (OR) = 1.9; 95%CI 1.0-3.7, p  = 0.027] in the 1999-2002 cohort. A higher ratio of fat mass and fat free mass (FM/FFM) also showed a greater risk of cognitive impairment (OR = 2.0; 95%CI 1.3-3.1, p  = 0.004). In the 2011-2014 cohort, the high WC-Low HGS group showed significantly lower scores on all four cognitive tests ( p  < 0.05) and a higher risk of cognitive impairment. CRP and HOMA-IR were significant partial mediators of the association between FM/FFM and DSST in the 1999-2002 cohort., Conclusions: The SO phenotype was associated with a higher risk of cognitive impairment in older adults. Insulin resistance and inflammation may represent key mechanisms linking SO to the development of cognitive impairment.

Background: Radial arterial access has gained interest for neurovascular procedures in recent years. Although there are no randomized control trials for neurointervention procedures using radial access, there is growing literature demonstrating its feasibility and favorable outcomes. Equipment technical improvements, like the recently introduced BENCHMARK™ BMX®81 System, have made radial navigation safer, with improved maneuverability and support for a variety of procedures. We present a multicenter case series highlighting our institutional radial access experience comparing the BMX®81 with alternative catheters., Methods: Multicenter retrospective cohort study of 80 patients who underwent neurovascular procedures through a radial approach. In half of the cases a BENCHMARK™ BMX®81 System was used. The comparison group consisted of the BENCHMARK™071 and 96, Neuron MAX®088 and BALLAST™ systems. Procedures included endovascular thrombectomy, carotid and brachiocephalic artery stenting, middle meningeal artery embolization, flow diverter stenting, vertebral artery sacrifice, aneurysm coiling, and WEB™ device deployment., Results: In our series, the BMX®81 was successful in the navigation of the anatomy to the target location in 95% of cases. No radial access or BMX®81 related complications were identified. There was no significant difference in fluoroscopy time between the BMX81 and the comparison group. Four patients in the comparison group had catheter-related complications due to vasospasm. Eighty-six percent of BMX®81 cases had satisfactory outcomes and no technical difficulties. The remainder presented technical difficulties, but none of these were considered secondary to the puncture site or support structure., Conclusions: The BENCHMARK™ BMX®81 System is a recently developed guiding catheter which has design and size features supporting radial access for a variety of neurovascular interventions. Early multicenter experience highlights the ease of use and versatility of this new catheter as an alternative to transfemoral access as well as other catheters used for radial access., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DV is a consultant for Penumbra.

Background: Pre-treatment stratification and outcomes of neuroblastoma patients often depend on the assessment of image-defined risk factors (IDRFs) on MR Imaging, usually using Gadolinium-contrast materials which are cautioned in pediatrics. We aimed to address whether gadolinium contrast-enhanced sequences are necessary to identify the presence/absence of IDRFs. Methods: Patients with neuroblastoma with MR imaging were retrospectively identified from 2005 to 2021. Ninety confirmed IDRFs were evaluated in 23 patients. Corresponding MR studies were anonymized, randomized, and independently evaluated by 3 fellowship-trained pediatric radiologists. Each radiologist assessed the studies twice. At the first reading, all enhanced sequences were omitted, while in the second reading, the full study with enhanced sequences were included. Consensus reading was obtained among readers. Inter- and intra-rater agreements using Kappa statistics (κ) as well as the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of non-enhanced MR in assessing IDRFs with respect to enhanced MR were calculated. Results: There were substantial (ĸ: 0.64-0.73) intra-reader agreements, and moderate to substantial (ĸ: 0.57-0.62) inter-reader agreements among radiologists in identifying IDRFs using non-enhanced MR. Non-enhanced MR had a sensitivity of 87.8% (95% CI [79-94]), specificity of 93% (89-96), PPV of 82.3 (73-89), NPV of 95.4 (92-98), and accuracy of 91.6 (88-94) in identifying IDRFs. However, 5/23 patients (21.7%) had a change in staging with the inclusion of contrast sequences. Conclusion: Although contrast sequences have a role in IDRF assessment, the majority can be adequately assessed on MR without gadolinium-contrast enhancement. Validation in a larger cohort is an important next step., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Bed-rest (BR) of only a few days duration reduces muscle protein synthesis and induces skeletal muscle atrophy and insulin resistance, but the scale and juxtaposition of these events have not been investigated concurrently in the same individuals. Moreover, the impact of short-term exercise-supplemented remobilization (ESR) on muscle volume, protein turnover and leg glucose uptake (LGU) in humans is unknown., Methods: Ten healthy males (24 ± 1 years, body mass index 22.7 ± 0.6 kg/m 2 ) underwent 3 days of BR, followed immediately by 3 days of ESR consisting of 5 × 30 maximal voluntary single-leg isokinetic knee extensions at 90°/s each day. An isoenergetic diet was maintained throughout the study (30% fat, 15% protein and 55% carbohydrate). Resting LGU was calculated from arterialized-venous versus venous difference across the leg and leg blood flow during the steady-state of a 3-h hyperinsulinaemic-euglycaemic clamp (60 mU/m 2 /min) measured before BR, after BR and after remobilization. Glycogen content was measured in vastus lateralis muscle biopsy samples obtained before and after each clamp. Leg muscle volume (LMV) was measured using magnetic resonance imaging before BR, after BR and after remobilization. Cumulative myofibrillar protein fractional synthetic rate (FSR) and whole-body muscle protein breakdown (MPB) were measured over the course of BR and remobilization using deuterium oxide and 3-methylhistidine stable isotope tracers that were administered orally., Results: Compared with before BR, there was a 45% decline in insulin-stimulated LGU (P < 0.05) after BR, which was paralleled by a reduction in insulin-stimulated leg blood flow (P < 0.01) and removal of insulin-stimulated muscle glycogen storage. These events were accompanied by a 43% reduction in myofibrillar protein FSR (P < 0.05) and a 2.5% decrease in LMV (P < 0.01) during BR, along with a 30% decline in whole-body MPB after 2 days of BR (P < 0.05). Myofibrillar protein FSR and LMV were restored by 3 days of ESR (P < 0.01 and P < 0.01, respectively) but not by ambulation alone. However, insulin-stimulated LGU and muscle glycogen storage were not restored by ESR., Conclusions: Three days of BR caused concurrent reductions in LMV, myofibrillar protein FSR, myofibrillar protein breakdown and insulin-stimulated LGU, leg blood flow and muscle glycogen storage in healthy, young volunteers. Resistance ESR restored LMV and myofibrillar protein FSR, but LGU and muscle glycogen storage remained depressed, highlighting divergences in muscle fuel and protein metabolism. Furthermore, ambulation alone did not restore LMV and myofibrillar protein FSR in the non-exercised contralateral limb, emphasizing the importance of exercise rehabilitation following even short-term BR., (© 2024 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Self-report and device-based measures of physical activity (PA) both have unique strengths and limitations; combining these measures should provide complementary and comprehensive insights to PA behaviours. Therefore, we aim to 1) identify PA clusters and clusters of change in PA based on self-reported daily activities and 2) assess differences in device-based PA between clusters in a lifestyle intervention, the PREVIEW diabetes prevention study. In total, 232 participants with overweight and prediabetes (147 women; 55.9 ± 9.5yrs; BMI ≥25 kg·m-2; impaired fasting glucose and/or impaired glucose tolerance) were clustered using a partitioning around medoids algorithm based on self-reported daily activities before a lifestyle intervention and their changes after 6 and 12 months. Device-assessed PA levels (PAL), sedentary time (SED), light PA (LPA), and moderate-to-vigorous PA (MVPA) were assessed using ActiSleep+ accelerometers and compared between clusters using (multivariate) analyses of covariance. At baseline, the self-reported "walking and housework" cluster had significantly higher PAL, MVPA and LPA, and less SED than the "inactive" cluster. LPA was higher only among the "cycling" cluster. There was no difference in the device-based measures between the "social-sports" and "inactive" clusters. Looking at the changes after 6 months, the "increased walking" cluster showed the greatest increase in PAL while the "increased cycling" cluster accumulated the highest amount of LPA. The "increased housework" and "increased supervised sports" reported least favourable changes in device-based PA. After 12 months, there was only minor change in activities between the "increased walking and cycling", "no change" and "increased supervised sports" clusters, with no significant differences in device-based measures. Combining self-report and device-based measures provides better insights into the behaviours that change during an intervention. Walking and cycling may be suitable activities to increase PA in adults with prediabetes., Competing Interests: Ian MacDonald: Principle investigator of the Nottingham site, conception of the study, editing of the manuscript. International Life Sciences Institute (ILSI) Europe: Member of Dietary Carbohydrates Task Force, Member of expert group on ’Efficacy Markers of Diabetes Risk’. Travel and subsistence paid but no attendance fees. Nature Publishing Group (Springer Nature) - Editor International Journal of Obesity. Travel and accommodation re-imbursed and honorarium paid (Amount received per annum over £5,000: yes). Nestle Research - Scientific Advisory Board. Travel and accommodation reimbursed, and honorarium paid (Amount received per annum over £5,000: yes) Mars Incorporated-Waltham Centre for Pet Nutrition Peer-review of pet nutrition research projects honorarium received (Amount received per annum over £5,000: no); Mars UK/Europe - Member of Nutrition Advisory Board, and Health and Wellbeing Committee travel and subsistence costs reimbursed. Honorarium paid to the University of Nottingham. Mars Incorporated - Member of Mars Scientific Advisory Committee. Honorarium paid to the University of Nottingham. Novozymes - Member of Science Advisory Board. Travel and subsistence costs reimbursed. Honorarium paid to the University of Nottingham. Public Health England - Member of Scientific Advisory Committee on Nutrition. Travel and accommodation re-imbursed and honorarium paid (Amount received per annum over £5,000: no) Jennie Brand-Miller: Principle investigator of the Sydney site and participated in editing of the manuscript. Jennie Brand-Miller is President and Director of the Glycemic Index Foundation and oversees a glycemic index testing service at the University of Sydney. She receives royalties for books about carbohydrates, obesity and diabetes. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Klos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Meal pattern is a potential health determinant. Previously, mean values for properties of meal pattern, such as daily meal frequency, have been considered. Means, however, obscure variability between-day (irregular or chaotic eating). This systematic review aimed to identify and critique published methods used to characterise between-day variability in meal pattern, and to explore relationships between this and obesity, as well as associated health outcomes., Methods: Using relevant databases, a systematic search was undertaken for studies with adults and children in which between-day variability in meal pattern was measured, and related to body weight, metabolic syndrome components and cognitive function., Results: In 34 papers identified (28 observational and six intervention studies), between-day variability in meal pattern was characterised by a variety of methods. These ranged from single questions about intake regularity to more complex methods quantifying the degree of variability. Assumptions were made, such as there being three main meals, resulting in dissociation from the "clock time" of eating. In 24 of the papers, between-day variability in meal pattern was associated with negative weight and health outcomes including higher weight, reduced thermogenic response to meals and poorer academic achievement., Conclusions: Between-day variability in meal pattern is a promising research area that might inform low-cost public health interventions. However, current methods of characterising between-day variability tend to make assumptions and be inconsistent in the meal pattern properties considered. Well controlled dietary intervention studies are required to confirm causation., (© 2023 The Authors. Journal of Human Nutrition and Dietetics published by John Wiley & Sons Ltd on behalf of British Dietetic Association.)

Background: Pseudoxanthoma elasticum (PXE) is an autosomal recessive condition caused by mutations in the ABCC6 gene. Ocular features include angioid streaks, peau d'orange fundus, and drusen. We report a novel ABCC6 mutation causing PXE in a patient with a mixed phenotype of PXE and retinitis pigmentosa (RP)., Case: A 37-year-old female presented with decreased peripheral vision and nyctalopia. Ocular imaging revealed angioid streaks emanating from the optic nerve as well as peripheral pigmentary changes and bone spicules. Genetic testing revealed two mutations in ABCC6 in trans. No other mutation was identified., Conclusion: We present a rare case with ocular findings of PXE and RP in a patient with a novel ABCC6 mutation. The patient presented both with peripheral pigmentary changes and angioid streaks. Further investigation into this novel mutation would be beneficial to determine if the mutation is involved in the RP phenotype.

Background: The Identifying Child Anxiety Through Schools-identification to intervention (iCATS-i2i) trial is being conducted to establish whether 'screening and intervention', consisting of usual school practice plus a pathway comprising screening, feedback and a brief parent-led online intervention (OSI: Online Support and Intervention for child anxiety), bring clinical and health economic benefits compared to usual school practice and assessment only - 'usual school practice', for children aged 8-9 years in the following: (1) the 'target population', who initially screen positive for anxiety problems according to a two-item parent-report child anxiety questionnaire - iCATS-2, and (2) the 'total population', comprising all children in participating classes. This article describes the detailed statistical analysis plan for the trial., Methods and Design: iCATS-i2i is a definitive, superiority, pragmatic, school-based cluster randomised controlled trial (with internal pilot), with two parallel groups. Schools are randomised 1:1 to receive either screening and intervention or usual school practice. This article describes the following: trial objectives and outcomes; statistical analysis principles, including detailed estimand information necessary for aligning trial objectives, conduct, analyses and interpretation when there are different analysis populations and outcome measures to be considered; and planned main analyses, sensitivity and additional analyses., Trial Registration: ClinicalTrials.gov ISRCTN76119074. Registered on 4 January 2022., (© 2024. The Author(s).)

Background: Lifestyle interventions can prevent type 2 diabetes (T2D) by successfully inducing behavioral changes (eg, avoiding physical inactivity and sedentariness, increasing physical activity and/or healthy eating) that reduce body weight and normalize metabolic levels (eg, HbA1c). For interventions to be successful, it is important to influence "behavioral mechanisms" such as self-efficacy, which motivate behavioral changes. Theory-based expectations of how self-efficacy, chronic stress, and mood changed over time were investigated through a group-based behavior change intervention (PREMIT). At 8 intervention sites, PREMIT was offered by trained primary care providers in 18 group-sessions over a period of 36 months, divided into 4 intervention phases. Adherence to the intervention protocol was assessed., Method: Participants (n = 962) with overweight and prediabetes who had achieved ≥8% weight loss during a diet reduction period and completed the intervention were categorized into 3 groups: infrequent, frequent, or very frequent group sessions attendance. The interactions between participation in the group sessions and changes in self-efficacy, stress, and mood were multivariate tested. Intervention sites were regularly asked where and how they deviated from the intervention protocol., Results: There was no increase in the participants' self-efficacy in any group. However, the level of self-efficacy was maintained among those who attended the group sessions frequently, while it decreased in the other groups. For all participants, chronic stress and the frequency of attending group sessions were inversely related. Significant differences in mood were found for all groups. All intervention centers reported specific activities, additional to intervention protocol, to promote participation in the group sessions., Conclusions: The results suggest that the behavioral changes sought by trained primary care providers are related to attendance frequency and follow complex trajectories. The findings also suggest that group-based interventions in naturalistic primary care settings aimed at preventing T2D require formats and strategies that encourage participants to attend group sessions regularly., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Anne Raben has received honorariums from Nestlé, the International Sweeteners Association and Unilever. Pia Siig Vestentoft has received travel grants from the Cambridge Weight Plan, UK. Ian Macdonald was a member of the UK Government Scientific Advisory Committee on Nutrition, Treasurer of the Federation of European Nutrition Societies, Treasurer of the World Obesity Federation, member of the Mars Scientific Advisory Council, member of the Mars Europe Nutrition Advisory Board and Scientific Adviser to the Waltham Centre for Pet Nutrition. He was also a member of the Nestle Research Scientific Advisory Board and of the Novozymes Scientific Advisory Board. Jennie Brand-Miller is President and Director of the Glycemic Index Foundation, oversees a glycaemic index testing service at the University of Sydney and is a co-author of books about diet and diabetes. Sally Poppitt was the Fonterra Chair in Human Nutrition and Principle Investigator for NZ National Science Challenge High Value Nutrition during the PREVIEW intervention. Thomas Meinert Larsen is advisor for the “Sense” diet program. J. Alfredo Martinez is President of IUNS. All other authors have no conflicts of interest to declare.

Malnutrition is present in most countries of the world. This ranges from general undernutrition due to insufficient food, or poor-quality diets low in some essential nutrients, to overnutrition and obesity with energy-rich but nutrient-poor diets. The fundamental aim of dietary recommendations is to prevent deficiency diseases, and the assumptions which underpin these recommendations need to be understood when considering what advice to give to the general public or individual patients. This is particularly relevant in early life as the nutritional state and dietary intake of the mother are of major importance for both her and her baby's health. There is a particular concern with pregnancy in teenage women, as they are still likely to be growing and have different nutrient requirements compared to older women. There is now evidence of beneficial effects for both the mother and baby of supplementation of the mother's diet in those with a low nutritional status. For infants, early gut microbiome development is supported by human milk components (including oligosaccharides) and the reported health benefits are of growing interest and offer potential areas for future developments. Yet, the increasing overweight and obesity in children are a serious concern, in both developed and developing economies. Considerations of the achievements, challenges, and future directions of early life nutrition need to be addressed in a global environment in which every country in the world is experiencing some form of malnutrition. The term malnutrition encompasses a number of different scenarios ranging from undernutrition, which encompasses an inadequate nutrient intake in a diet with a low level of diversity, up to overnutrition where there is an excess of energy intake in a diet which is predominantly composed of nutrient-poor foods. The major feature of malnutrition is that there is micronutrient inadequacy, and even deficiency, which is particularly concerning in early life. The present chapter will consider the major achievements and future challenges in relation to achieving optimal nutrition in early life as well as in older children. Clearly, when considering nutrition in children, it is important to also consider the nutritional state of women before, during, and after pregnancy, as this can have a major impact on the fetus and young child. Before considering these issues in detail, this chapter will begin by addressing the basis on which nutritional recommendations are founded and the challenges that have to be met in getting novel recommendations approved by the appropriate authorities., (© 2024 S. Karger AG, Basel.)

Inclusion in nasogastric tube feeds (NGTF) of acid-sensitive, seaweed-derived alginate, expected to form a reversible gel in the stomach, may create a more normal intragastric state and modified gastrointestinal responses. This may ameliorate NGTF-associated risk of diarrhoea, upper gastrointestinal symptoms and appetite suppression. In a randomised, crossover, comparison study, undertaken in twelve healthy males, an alginate-containing feed (F + ALG) or one that was alginate-free (F-ALG) (300 ml) was given over 1 h with a 7-14-d washout period between treatments. Baseline and for 4-h post-feed initiation, MRI measurements were made to establish small bowel water content (SBWC), gastric contents volume (GCV) and appearance, and superior mesenteric artery blood flux. Blood glucose and gut peptides were measured. Subjective appetite and upper gastrointestinal symptoms scores were obtained. Ad libitum pasta consumption 3-h post-feeding was measured. F + ALG exhibited a gastric appearance consistent with gelling surrounded by a freely mobile water halo. Significant main effects of feed were seen for SBWC ( P = 0·03) and peptide YY (PYY) ( P = 0·004) which were attributed to generally higher values for SBWC with F + ALG (max difference between adjusted means 72 ml at 210 min) and generally lower values for PYY with F + ALG. GCV showed a faster reduction with F + ALG, less between-participant variation and a feed-by-time interaction ( P = 0·04). Feed-by-time interactions were also seen with glucagon-like-peptide 1 (GLP-1) ( P = 0·02) and glucose-dependent insulinotropic polypeptide (GIP) ( P = 0·002), both showing a blunted response with F + ALG. Apparent intragastric gelling with F + ALG and subsequent differences in gastrointestinal and endocrine responses have been demonstrated between an alginate-containing and alginate-free feed.

Background: Sedentary lifestyle and unhealthy diet combined with overweight are risk factors for type 2 diabetes (T2D). Lifestyle interventions with weight-loss are effective in T2D-prevention, but unsuccessful completion and chronic stress may hinder efficacy. Determinants of chronic stress and premature cessation at the start of the 3-year PREVIEW study were examined., Methods: Baseline Quality of Life (QoL), social support, primary care utilization, and mood were examined as predictors of intervention cessation and chronic stress for participants aged 25 to 70 with prediabetes (n = 2,220). Moderating effects of sex and socio-economic status (SES) and independence of predictor variables of BMI were tested., Results: Participants with children, women, and higher SES quitted intervention earlier than those without children, lower SES, and men. Lower QoL, lack of family support, and primary care utilization were associated with cessation. Lower QoL and higher mood disturbances were associated with chronic stress. Predictor variables were independent (p ≤ .001) from BMI, but moderated by sex and SES., Conclusions: Policy-based strategy in public health should consider how preventive interventions may better accommodate different individual states and life situations, which could influence intervention completion. Intervention designs should enable in-built flexibility in delivery enabling response to individual needs., Trial Registration: ClinicalTrials.gov Identifier: NCT01777893., (© 2023. BioMed Central Ltd., part of Springer Nature.)

X-linked retinitis pigmentosa (XLRP) is a rare inherited retinal disease manifesting as impaired night vision and peripheral vision loss that progresses to legal blindness. Although several trials of ocular gene therapy for XLRP have been conducted or are in progress, there is currently no approved treatment. In July 2022, the Foundation Fighting Blindness convened an expert panel to examine relevant research and make recommendations for overcoming the challenges and capitalizing on the opportunities in conducting clinical trials of RPGR-targeted therapy for XLRP. Data presented concerned RPGR structure and mutation types known to cause XLRP, RPGR mutation-associated retinal phenotype diversity, patterns in genotype/phenotype relationships, disease onset and progression from natural history studies, and the various functional and structural tests used to monitor disease progression. Panel recommendations include considerations, such as genetic screening and other factors that can impact clinical trial inclusion criteria, the influence of age on defining and stratifying participant cohorts, the importance of conducting natural history studies early in clinical development programs, and the merits and drawbacks of available tests for measuring treatment outcomes. We recognize the need to work with regulators to adopt clinically meaningful end points that would best determine the efficacy of a trial. Given the promise of RPGR-targeted gene therapy for XLRP and the difficulties encountered in phase III clinical trials to date, we hope these recommendations will help speed progress to finding a cure., Translational Relevance: Examination of relevant data and recommendations for the successful clinical development of gene therapies for RPGR-associated XLRP.

Radial artery access has experienced increasing adoption and rapid expansion of indications for neurointerventional procedures. This access is an attractive neurointervention route to be considered, with many advantages over the traditional femoral access in terms of ease of vasculature navigation and decreased risk of complications such as significant bleeding. Although a promising technique for neurointerventional procedures, there are inherent and unique considerations as well as potential complications involved. The following case report highlights some of these vital concepts associated with radial artery access, including appropriate patient selection as well as assessment of arterial size in the context of neurointerventional techniques. Early identification of complications such as arterial injury and compartment syndrome, with an emphasis on appropriate draping and inter-procedure monitoring, is discussed as well as approaches for subsequent management. Finally, the issue of radiation safety in this emerging technique is considered. These concepts are critical for the successful use and the continued growth of radial artery access for neurointervention procedures.

Aims: To examine the differences between HbA 1c and glucose related variables in predicting weight loss and glycaemic changes following 8 weeks of low energy diet (LED) in individuals with overweight and hyperglycaemia., Research Design and Methods: 2178 individuals with ADA-defined pre-diabetes - impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) - who started an 8 week LED weight loss diet, were included in this analysis. Participants were enrolled in the PREVIEW (PREVention of diabetes through lifestyle interventions and population studies In Europe and around the World) clinical trial. Multivariable linear mixed effects regression models and generalised additive mixed effect logistic models were used., Results: Only 1 in 3 participants (33%) had HbA 1c levels defined as pre-diabetes. Neither baseline HbA 1c , IFG or IGT were associated with body weight change at 8 weeks. Higher baseline body weight, baseline fasting insulin and weight loss predicted normalisation of fasting plasma glucose (FPG), whilst higher baseline fasting insulin, C-reactive protein (hsCRP) and older age predicted normalisation of HbA 1c . Additionally, male sex and higher baseline BMI, body fat and energy intake were positively associated with weight loss, whereas greater age and higher HDL-cholesterol predicted less weight loss., Conclusions: Whilst neither HbA 1c nor fasting glucose predicts short-term weight loss success, both may impact the metabolic response to rapid weight loss. We propose a role of inflammation versus total body adiposity since these variables are independent predictors of the normalisation of HbA 1c and fasting glucose, respectively., Competing Interests: Declaration of competing interests AR has received honorariums from the International Sweeteners Association and Unilever. IAM was a member of the UK Government Scientific Advisory Committee on Nutrition, Treasurer of the Federation of European Nutrition Societies, Treasurer of the World Obesity Federation, member of the Mars Scientific Advisory Council, member of the Mars Europe Nutrition Advisory Board, and Scientific Adviser to the Waltham Centre for Pet Nutrition. He was also a member of the Nestle Research Scientific Advisory Board, and of the Novozymes Scientific Advisory Board. He withdrew from all of these roles in 2020 and on August 1 2020 became Professor Emeritus at the University of Nottingham and took up the post of Scientific Director of the Nestle Institute of Health Sciences in Lausanne, Switzerland. JB-M is President and Director of the Glycemic Index Foundation, oversees of a glycemic index testing service at the University of Sydney and is a co-author of books about diet and diabetes. She is also a member of the Scientific Advisory Board of the Novo Foundation and of ZOE Global. SDP was the Fonterra Chair in Human Nutrition during the PREVIEW intervention. TL is employed by NetUnion sarl, who contributed to the data collection process in the absence of commercial or financial conflict of interest with the study analysis., (Copyright © 2023 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Dietary sugars are often linked to the development of overweight and type 2 diabetes (T2D) but inconsistencies remain., Objective: We investigated associations of added, free, and total sugars, and glycaemic index (GI) with indices of glucose metabolism (IGM) and indices of body fatness (IBF) during a 3-year weight loss maintenance intervention., Design: The PREVIEW (PREVention of diabetes through lifestyle Intervention and population studies in Europe and around the World) study was a randomised controlled trial designed to test the effects of four diet and physical activity interventions, after an 8-week weight-loss period, on the incidence of T2D. This secondary observational analysis included pooled data assessed at baseline (8), 26, 52, 104 and 156 weeks from 514 participants with overweight/obesity (age 25-70 year; BMI ≥ 25 kg⋅m -2 ) and with/without prediabetes in centres that provided data on added sugars (Sydney and Helsinki) or free sugars (Nottingham). Linear mixed models with repeated measures were applied for IBF (total body fat, BMI, waist circumference) and for IGM (fasting insulin, HbA1c, fasting glucose, C-peptide). Model A was adjusted for age and intervention centre and Model B additionally adjusted for energy, protein, fibre, and saturated fat., Results: Total sugars were inversely associated with fasting insulin and C-peptide in all centres, and free sugars were inversely associated with fasting glucose and HbA1c (Model B: all p < 0.05). Positive associations were observed between GI and IGM (Model B: fasting insulin, HbA1c, and C-peptide: (all p < 0.01), but not for added sugars. Added sugar was positively associated with body fat percentage and BMI, and GI was associated with waist circumference (Model B: all p < 0.01), while free sugars showed no associations (Model B: p > 0.05)., Conclusions: Our findings suggest that added sugars and GI were independently associated with 3-y weight regain, but only GI was associated with 3-y changes in glucose metabolism in individuals at high risk of T2D.

Background: Owing to its role in glucose homeostasis, liver glycogen concentration ([LGly]) can be a marker of altered metabolism seen in disorders that impact the health of children. However, there is a paucity of normative data for this measure in children to allow comparison with patients, and time-course assessment of [LGly] in response to feeding has not been reported. In addition, carbon-13 magnetic resonance spectroscopy ( 13 C-MRS) is used extensively in research to assess liver metabolites in adult health and disease noninvasively, but similar measurements in children are lacking., Objectives: The main objectives were to quantify the depletion of [LGly] after overnight fasting and the subsequent response to feeding., Methods: In a randomly assigned, open-label, incomplete block design study, healthy, normal-weight children (8-12 y) attended 2 evening visits, each separated by ≥5 d and directly followed by a morning visit. An individually tailored, standardized meal was consumed 3-h prior to evening assessments. Participants then remained fasted until the morning visit. [LGly] was assessed once in the fed (20:00) and fasted state (08:00) using 13 C-MRS. After the 8:00 assessment, 200 ml of a mixed-macronutrient drink containing 15.5 g (402 kJ) or 31 g carbohydrates (804 kJ), or water only, was consumed, with 13 C-MRS measurements then performed hourly for 4 h. Each child was randomly assigned to 2 of 3 drink options across the 2 mornings. Data are expressed as mean (SD)., Results: Twenty-four children including females and males (13F:11M) completed the study [9.9 (1.1) y, BMI percentile 45.7 (25.9)]. [LGly] decreased from 377.9 (141.3) to 277.3 (107.4) mmol/L overnight; depletion rate 0.14 (0.15) mmol/L min. Incremental responses of [LGly] to test drinks differed (P < 0.001), with incremental net area under the curve of [LGly] over 4 h being higher for 15.5 g [-67.1 (205.8) mmol/L·240 min; P < 0.01] and 31 g carbohydrates [101.6 (180.9) mmol/L·240 min; P < 0.005] compared with water [-253.1 (231.2) mmol/L·240 min]., Conclusions: After overnight fasting, [LGly] decreased by 22.9 (25.1)%, and [LGly] incremental net area under the curve over 4 h was higher after subsequent consumption of 15.5 g and 31 g carbohydrates, compared to water. Am J Clin Nutr 20XX;xx:xx-xx., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the long-term safety and efficacy of AAV2-REP1 in choroideremia (CHM) patients, and to test a potential antisense oligonucleotide therapy for CHM., Design: Extended, prospective phase 1/2 clinical trial and laboratory investigation., Methods: Five patients who received a single subfoveal injection of AAV2-REP1 were studied. The long-term safety was evaluated by ophthalmic examination, spectral domain optical coherence tomography, and fundus autofluorescence (FAF) for up to 5 years. Functional and structural changes were determined by different test modalities. Four antisense oligonucleotides (ASOs) were designed to treat the CHM c.1245-521A>G mutation, which was present in 2 patients within this trial., Results: Subject P3 experienced a localized intraretinal immune response that resulted in a significant loss of preserved retinal pigment epithelium (RPE). P4 experienced an exacerbation of peripheral retinoschisis. P2 had a constant ≥15-letter best-corrected visual acuity (BCVA) gain in the treated eye, whereas P5 had ≥15-letter BCVA improvement once in the untreated eye. The preserved FAF areas declined more rapidly in the treated eyes compared to the untreated eyes (P = .043). A customized 25-mer ASO recovered 83.2% to 95.0% of the normal RNA and 57.5% of the normal protein in fibroblasts from 2 trial patients., Conclusions: Intraretinal inflammation triggered by AAV2-REP1 subretinal injection stabilized after 2 years but resulted in permanent damage to the retinal structure. Long-term progression of the disease was seen in both treated and untreated eyes, casting doubt as to the effectiveness of this approach in late-stage CHM. Alternative approaches such as ASO may have a therapeutic effect in a subgroup of CHM patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background & Aims: It is unclear if dietary adjustments to maintain energy balance during reduced physical activity can offset inactivity-induced reductions in insulin sensitivity and glucose disposal to produce normal daily glucose concentrations and meal responses. Therefore, the aim of the present study was to examine the impact of long-term physical inactivity (60 days of bed rest) on daily glycemia when in energy balance., Methods: Interstitial glucose concentrations were measured using Continuous Glucose Monitoring Systems (CGMS) for 5 days before and towards the end of bed rest in 20 healthy, young males (Age: 34 ± 8 years; BMI: 23.5 ± 1.8 kg/m 2 ). Energy intake was reduced during bed rest to match energy expenditure, but the types of foods and timing of meals was maintained. Fasting venous glucose and insulin concentrations were determined, as well as the change in whole-body glucose disposal using a hyperinsulinemic-euglycemic clamp (HIEC)., Results: Following long-term bed rest, fasting plasma insulin concentration increased 40% (p = 0.004) and glucose disposal during the HIEC decreased 24% (p < 0.001). Interstitial daily glucose total area under the curve (tAUC) from pre-to post-bed rest increased on average by 6% (p = 0.041), despite a 20 and 25% reduction in total caloric and carbohydrate intake, respectively. The nocturnal period (00:00-06:00) showed the greatest change to glycemia with glucose tAUC for this period increasing by 9% (p = 0.005). CGMS measures of daily glycemic variability (SD, J-Index, M-value and MAG) were not changed during bed rest., Conclusions: Reduced physical activity (bed rest) increases glycemia even when daily energy intake is reduced to maintain energy balance. However, the disturbance to daily glucose homeostasis was much more modest than the reduced capacity to dispose of glucose, and glycemic variability was not negatively affected by bed rest, likely due to positive mitigating effects from the contemporaneous reduction in dietary energy and carbohydrate intake., Clinical Trials Record: NCT03594799 (registered July 20, 2018) (https://clinicaltrials.gov/ct2/show/NCT03594799)., Competing Interests: Conflicts of interest I.A.M. was a member of the Mars Scientific Advisory Council, member of the Mars Europe Nutrition Advisory Board, and Scientific Adviser to the Waltham Centre for Pet Nutrition, and was also a member of the Nestle Research Scientific Advisory Board, and of the Novozymes Scientific Advisory Board. He withdrew from all of these roles in 2020 and on 1 August 2020 became Professor Emeritus at the University of Nottingham and took up the post of Scientific Director of the Nestle Institute of Health Sciences in Lausanne, Switzerland, which terminated in August 2022. D. T is an investigator on research grants funded by BBSRC, British Heart Foundation, Diabetes UK, Evolution Education Trust, GlaxoSmithKline R&D, MRC, NIHR, Nutricia Research Foundation, UK Sport, Unilever, and Versus Arthritis; and has completed paid consultancy for Gemina Labs, International Consumer Research & Testing (ICRT), Unilever, and Sugar Nutrition UK. The remaining authors have no conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We describe the case of a 9-month-old boy presenting with isolated intermittent vertical eye movements most in keeping with upward saccadic pulses, a form of saccadic intrusions. Full-field electroretinogram was consistent with a generalized retinal dystrophy, and genetic testing revealed a hemizygous pathogenic mutation in the CACNA1F gene, confirming the diagnosis of incomplete congenital stationary night blindness (iCSNB). This case describes vertical saccadic pulses as the sole presenting sign of a retinal dystrophy., (Copyright © 2022 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Aims: N 6 -methyladenosine modification of RNA (m 6 A) regulates translational control, which may influence neuronal dysfunction underlying neurodegenerative diseases., Methods: Using microscopy and a machine learning approach, we performed cellular profiling of m 6 A-RNA abundance and YTHDF1/YTHDF3 m 6 A reader expression within four regions of the human brain from non-affected individuals and individuals with Parkinson's disease, dementia with Lewy bodies or mild cognitive impairment (MCI)., Results: In non-diseased tissue, we found that m 6 A-modified RNAs showed cell-type and sub-compartment-specific variation. YTHDF1 and YTHDF3 showed opposing expression patterns in the cerebellum and the frontal and cingulate cortices. Machine learning quantitative image analysis revealed that m 6 A-modified transcripts were significantly altered in localisation and abundance in disease tissue with significant decreases in m 6 A-RNAs in Parkinson's disease, and significant increases in m 6 A-RNA abundance in dementia with Lewy bodies. MCI tissue showed variability across regions but similar to DLB; in brain areas with an overall significant increase in m 6 A-RNAs, modified RNAs within dendritic processes were reduced. Using mass spectrometry proteomic datasets to corroborate our findings, we found significant changes in YTHDF3 and m 6 A anti-reader protein abundance in Alzheimer's disease (AD) and asymptomatic AD/MCI tissue and correlation with cognitive resilience., Conclusions: These results provide evidence for disrupted m 6 A regulation in Lewy body diseases and a plausible mechanism through which RNA processing could contribute to the formation of Lewy bodies and other dementia-associated pathological aggregates. The findings suggest that manipulation of epitranscriptomic processes influencing translational control may lead to new therapeutic approaches for neurodegenerative diseases., (© 2023 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

There is interest in the impact that dietary interventions can have on preventing the transition from insulin resistance to type 2 diabetes, including a suggestion that the bioactive components of cocoa may enhance fasting insulin sensitivity. However, a role for cocoa flavanols (CF) in reducing insulin resistance in the insulin-stimulated state, an important risk factor for cardiovascular disease, is unresolved. This study investigated whether CF consumption improved whole-body insulin-mediated glucose uptake ('M') in females with overweight/obesity, using a randomized, double-blinded, placebo-controlled, parallel-group design. Thirty-two premenopausal females (19-49 years; 27-35 kg·m -2 ) with elevated HOMA-IR (HOMA-IR >1.5) supplemented their habitual diet with two servings/day of a high-flavanol cocoa drink (HFC; 609 mg CF/serving; n = 16) or low-flavanol cocoa drink (LFC; 13 mg CF/serving; n = 16) for 4 weeks. Assessment of HOMA-IR and 'M' during a 3-h, 60 mIU insulin·m -2 ·min -1 euglycemic clamp was performed before and after the intervention. Data are the mean (SD). Changes to HOMA-IR (HFC -0.003 (0.57); LFC -0.0402 (0.86)) and 'M' (HFC 0.99 (7.62); LFC -1.32 (4.88) µmol·kg -1 ·min -1 ) after the intervention were not different between groups. Four weeks' consumption of ~1.2 g CF/day did not improve indices of fasting insulin sensitivity or insulin-mediated glucose uptake. A recommendation for dietary supplementation with cocoa flavanols to improve glycemic control is therefore not established.

The expression of genetic information is tightly controlled by chromatin regulatory proteins, including those in the heterochromatin gene repression family. Many of these regulatory proteins work together on the chromatin substrate to precisely regulate gene expression during mammalian development, giving rise to many different tissues in higher organisms from a fixed genomic template. Here we identify and characterize the interactions of two related heterochromatin regulatory proteins, heterochromatin protein 1 alpha (HP1α) and M-phase phosphoprotein 8 (MPP8), with hepatoma-derived growth factor-related protein 2 (HRP2). We find in biochemical experiments that HRP2 copurifies and co-sediments with heterochromatin-associated proteins, including HP1α and MPP8. Using the Chromatin in vivo Assay in multiple cell types, we demonstrate that HP1α-mediated gene repression dynamics are altered by the presence of HRP2. Furthermore, the knockout of HRP2 in MDA-MB-231 cells results in significant changes to chromatin structure and stability, which alter gene expression patterns. Here, we detail a mechanism by which HRP2 contributes to epigenetic transcriptional regulation through engagement with heterochromatin-associated proteins to stabilize the chromatin landscape and influence gene expression.

Overnutrition, expressed as overweight and obesity, sometimes combined with inadequate micronutrient intake, coexists together with undernutrition as the major threats of malnutrition in children. Appropriate growth and metabolism of children have been extensively studied as to their association with future metabolic diseases. It is appreciated that early growth is controlled via the biochemical pathways that support organ and tissue growth and development, energy release from dietary intake, and production and release of hormones and growth factors regulating the biochemical processes. Anthropometric measurements, body composition, and their trajectories have been the metrics to evaluate both age-appropriate growth and link to future metabolic disease risk. As factors associated with risk of metabolic disease like childhood obesity are fairly well known, a strategic framework that includes appropriate nutrition and healthy dietary habits, adoption of the right behavior, and healthy food choices from early infancy to childhood is necessary to decrease this risk. The role of industry in this is to provide foods rich in nutrients developmentally appropriate and to promote responsible consumption and age-adapted portion sizes., (© 2023 S. Karger AG, Basel.)

Background: Bed rest (BR) reduces whole-body insulin-stimulated glucose disposal (GD) and alters muscle fuel metabolism, but little is known about metabolic adaptation from acute to chronic BR nor the mechanisms involved, particularly when volunteers are maintained in energy balance., Methods: Healthy males (n = 10, 24.0 ± 1.3 years), maintained in energy balance, underwent 3-day BR (acute BR). A second cohort matched for sex and body mass index (n = 20, 34.2 ± 1.8 years) underwent 56-day BR (chronic BR). A hyperinsulinaemic euglycaemic clamp (60 mU/m 2 /min) was performed to determine rates of whole-body insulin-stimulated GD before and after BR (normalized to lean body mass). Indirect calorimetry was performed before and during steady state of each clamp to calculate rates of whole-body fuel oxidation. Muscle biopsies were taken to determine muscle glycogen, metabolite and intramyocellular lipid (IMCL) contents, and the expression of 191 mRNA targets before and after BR. Two-way repeated measures analysis of variance was used to detect differences in endpoint measures., Results: Acute BR reduced insulin-mediated GD (Pre 11.5 ± 0.7 vs. Post 9.3 ± 0.6 mg/kg/min, P < 0.001), which was unchanged in magnitude following chronic BR (Pre 10.2 ± 0.4 vs. Post 7.9 ± 0.3 mg/kg/min, P < 0.05). This reduction in GD was paralleled by the elimination of the 35% increase in insulin-stimulated muscle glycogen storage following both acute and chronic BR. Acute BR had no impact on insulin-stimulated carbohydrate (CHO; Pre 3.69 ± 0.39 vs. Post 4.34 ± 0.22 mg/kg/min) and lipid (Pre 1.13 ± 0.14 vs. Post 0.59 ± 0.11 mg/kg/min) oxidation, but chronic BR reduced CHO oxidation (Pre 3.34 ± 0.18 vs. Post 2.72 ± 0.13 mg/kg/min, P < 0.05) and blunted the magnitude of insulin-mediated inhibition of lipid oxidation (Pre 0.60 ± 0.07 vs. Post 0.85 ± 0.06 mg/kg/min, P < 0.05). Neither acute nor chronic BR increased muscle IMCL content. Plentiful mRNA abundance changes were detected following acute BR, which waned following chronic BR and reflected changes in fuel oxidation and muscle glycogen storage at this time point., Conclusions: Acute BR suppressed insulin-stimulated GD and storage, but the extent of this suppression increased no further in chronic BR. However, insulin-mediated inhibition of fat oxidation after chronic BR was less than acute BR and was accompanied by blunted CHO oxidation. The juxtaposition of these responses shows that the regulation of GD and storage can be dissociated from substrate oxidation. Additionally, the shift in substrate oxidation after chronic BR was not explained by IMCL accumulation but reflected by muscle mRNA and pyruvate dehydrogenase kinase 4 protein abundance changes, pointing to lack of muscle contraction per se as the primary signal for muscle adaptation., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: To better support participants to achieve long-lasting results within interventions aiming for weight loss and maintenance, more information is needed about the maintenance of behavioral changes. Therefore, we examined whether perceived stress predicts the maintenance of changes in eating behavior (flexible and rigid restraint of eating, disinhibition, and hunger)., Methods: The present study was a secondary analysis of the PREVIEW intervention including participants with overweight (BMI ≥ 25 kg/m 2 ) at baseline and high risk of type 2 diabetes (n = 1311). Intervention included a 2-month low-energy diet phase and a 34-month subsequent weight maintenance phase. The first 6 months were considered an active behavior change stage and the remaining 2.5 years were considered a behavior maintenance stage. Eating behavior was measured using the Three Factor Eating Questionnaire and stress using the Perceived Stress Scale. The associations between stress and eating behavior were analyzed using linear mixed effects models for repeated measurements., Results: Perceived stress measured after the active behavior change stage (at 6 months) did not predict changes in eating behavior during the behavior maintenance stage. However, frequent high stress during this period was associated with greater lapse of improved flexible restraint (p = 0.026). The mean (SD) change in flexible restraint from 6 to 36 months was -1.1 (2.1) in participants with frequent stress and -0.7 (1.8) in participants without frequent stress (Cohen's d s (95% CI) = 0.24 (0.04-0.43)). Higher perceived stress at 6 months was associated with less flexible restraint and more disinhibition and hunger throughout the behavior maintenance stage (all p < 0.001)., Conclusions: Perceived stress was associated with features of eating behavior that may impair successful weight loss maintenance. Future interventions should investigate, whether incorporating stress reduction techniques results in more effective treatment, particularly for participants experiencing a high stress level., (© 2022. The Author(s).)

Motile and non-motile cilia are associated with mutually-exclusive genetic disorders. Motile cilia propel sperm or extracellular fluids, and their dysfunction causes primary ciliary dyskinesia. Non-motile cilia serve as sensory/signalling antennae on most cell types, and their disruption causes single-organ ciliopathies such as retinopathies or multi-system syndromes. CFAP20 is a ciliopathy candidate known to modulate motile cilia in unicellular eukaryotes. We demonstrate that in zebrafish, cfap20 is required for motile cilia function, and in C. elegans, CFAP-20 maintains the structural integrity of non-motile cilia inner junctions, influencing sensory-dependent signalling and development. Human patients and zebrafish with CFAP20 mutations both exhibit retinal dystrophy. Hence, CFAP20 functions within a structural/functional hub centered on the inner junction that is shared between motile and non-motile cilia, and is distinct from other ciliopathy-associated domains or macromolecular complexes. Our findings suggest an uncharacterised pathomechanism for retinal dystrophy, and potentially for motile and non-motile ciliopathies in general., (© 2022. The Author(s).)

Objective: To examine whether the effect of a 3-year lifestyle intervention on body weight and cardiometabolic risk factors differs by prediabetes metabolic phenotype., Research Design and Methods: This post hoc analysis of the multicenter, randomized trial, PREVention of diabetes through lifestyle interventions and population studies In Europe and around the World (PREVIEW), included 1,510 participants with prediabetes (BMI ≥25 kg ⋅ m-2; defined using oral glucose tolerance tests). Of these, 58% had isolated impaired fasting glucose (iIFG), 6% had isolated impaired glucose tolerance (iIGT), and 36% had IFG+IGT; 73% had normal hemoglobin A1c (HbA1c; <39 mmol ⋅ mol-1) and 25% had intermediate HbA1c (39-47 mmol ⋅ mol-1). Participants underwent an 8-week diet-induced rapid weight loss, followed by a 148-week lifestyle-based weight maintenance intervention. Linear mixed models adjusted for intervention arm and other confounders were used., Results: In the available-case and complete-case analyses, participants with IFG+IGT had greater sustained weight loss after lifestyle intervention (adjusted mean at 156 weeks -3.5% [95% CI, -4.7%, -2.3%]) than those with iIFG (mean -2.5% [-3.6%, -1.3%]) relative to baseline (P = 0.011). Participants with IFG+IGT and iIFG had similar cardiometabolic benefits from the lifestyle intervention. The differences in cardiometabolic benefits between those with iIGT and IFG+IGT were minor or inconsistent in different analyses. Participants with normal versus intermediate HbA1c had similar weight loss over 3 years and minor differences in cardiometabolic benefits during weight loss, whereas those with normal HbA1c had greater improvements in fasting glucose, 2-h glucose (adjusted between-group difference at 156 weeks -0.54 mmol ⋅ L-1 [95% CI -0.70, -0.39], P < 0.001), and triglycerides (difference -0.07 mmol ⋅ L-1 [-0.11, -0.03], P < 0.001) during the lifestyle intervention., Conclusions: Individuals with iIFG and IFG+IGT had similar improvements in cardiometabolic health from a lifestyle intervention. Those with normal HbA1c had greater improvements than those with intermediate HbA1c., (© 2022 by the American Diabetes Association.)

Photoreceptor dysfunctions and degenerative diseases are significant causes of vision loss in patients, with few effective treatments available. Targeted interventions to prevent or reverse photoreceptor-related vision loss are not possible without a thorough understanding of the underlying mechanism leading to disease, which is exceedingly difficult to accomplish in the human system. Cone diseases are particularly challenging to model, as some popular genetically modifiable model animals are nocturnal with a rod-dominant visual system and cones that have dissimilarities to human cones. As a result, cone diseases, which affect visual acuity, colour perception, and central vision in patients, are generally poorly understood in terms of pathology and mechanism. Zebrafish (Danio rerio) provide the opportunity to model photoreceptor diseases in a diurnal vertebrate with a cone-rich retina which develops many macular degeneration-like pathologies. Zebrafish undergo external development, allowing early-onset retinal diseases to be detected and studied, and many ophthalmic tools are available for zebrafish visual assessment during development and adulthood. There are numerous zebrafish models of photoreceptor disease, spanning the various types of photoreceptor disease (developmental, rod, cone, and mixed photoreceptor diseases) and genetic/molecular cause. In this review, we explore the features of zebrafish that make them uniquely poised to model cone diseases, summarize the established zebrafish models of inherited photoreceptor disease, and discuss how disease in these models compares to the human presentation, where applicable. Further, we highlight the contributions of these zebrafish models to our understanding of photoreceptor biology and disease, and discuss future directions for utilising and investigating these diverse models., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Systematically screening for child anxiety problems, and offering and delivering a brief, evidence-based intervention for children who are identified as likely to benefit would minimise common barriers that families experience in accessing treatment. We have developed a short parent-report child anxiety screening questionnaire, and procedures for administering screening questionnaires, sharing screening outcomes with families, and offering and delivering a brief parent-led online intervention (OSI: Online Support and Intervention for child anxiety) through schools. This trial aims to evaluate clinical and health economic outcomes for (1) children (aged 8-9) who screen positive for anxiety problems at baseline (target population) and (2) the wider population of all children in participating classes (total population) in schools randomly allocated to receive identification-to-intervention procedures and usual school practice ('screening and intervention'), compared to assessment and usual school practice only ('usual school practice').  METHODS: The trial design is a parallel-group, superiority cluster randomised controlled trial, with schools (clusters) randomised to 'screening and intervention' or 'usual school practice' arms in a 1:1 ratio stratified according to the level of deprivation within the school. We will recruit schools and participants in two phases (a pilot phase (Phase 1) and Phase 2), with progression criteria assessed prior to progressing to Phase 2. In total, the trial will recruit 80 primary/junior schools in England, and 398 children (199 per arm) who screen positive for anxiety problems at baseline (target population). In schools allocated to 'screening and intervention': (1) parents/carers will complete a brief parent-report child anxiety screening questionnaire (at baseline) and receive feedback on their child's screening outcomes (after randomisation), (2) classes will receive a lesson on managing fears and worries and staff will be provided with information about the intervention and (3) parents/carers of children who screen positive for anxiety problems (target population) will be offered OSI. OSI will also be available for any other parents/carers of children in participating classes (total population) who request it. We will collect child-, parent- and teacher-report measures for the target population and total population at baseline (before randomisation), 4 months, 12 months and 24 months post-randomisation. The primary outcome will be the proportion of children who screen positive for anxiety problems at baseline (target population) who screen negative for anxiety problems 12 months post-randomisation., Discussion: This trial will establish if systematic screening for child anxiety problems, sharing screening outcomes with families and delivering a brief parent-led online intervention through schools is effective and cost-effective., Trial Registration: ISRCTN registry ISRCTN76119074. Prospectively registered on 4.1.2022., (© 2022. The Author(s).)

Background: Anxiety disorders are common among primary-school aged children, but few affected children receive evidence-based treatment. Identifying and supporting children who experience anxiety problems through schools would address substantial treatment access barriers that families and school staff often face. We have worked with families and school staff to co-design procedures that incorporate screening, feedback for parents, and the offer of a brief intervention in primary schools. This study sets out to assess the feasibility of a subsequent school-based cluster randomised controlled trial to evaluate these procedures. Our objectives are to ensure our procedures for identifying and supporting children with anxiety difficulties through primary schools are acceptable and there are no negative impacts, to estimate recruitment and retention rates, and to identify any changes needed to study procedures or measures., Methods: We will recruit six primary/junior schools in England (2 classes per school), and invite all children (aged 8-9) (n = 360) and their parent/carer and class teacher in participating classes to take part. Children, parents and class teachers will complete questionnaires at baseline and 12-week follow-up. Children who 'screen positive' on a 2-item parent-report child anxiety screen at baseline will be the target population (expected n = 43). Parents receive feedback on screening questionnaire responses, and where the child screens positive the family is offered support (OSI: Online Support and Intervention for child anxiety). OSI is a brief, parent-led online intervention, supported by short telephone sessions with a Children's Wellbeing Practitioner. Participants' experiences of study procedures will be assessed through qualitative interviews/discussion groups., Discussion: Evidence-based procedures for identifying and supporting children with anxiety difficulties through primary schools would improve children's access to timely, effective intervention for anxiety difficulties., Trial Registration: ISRCTN registry: ISRCTN30032471 . Retrospectively registered on 18 May 2021., (© 2022. The Author(s).)

Behavioural responses to hypoglycaemia require coordinated recruitment of broadly distributed networks of interacting brain regions. We investigated hypoglycaemia-related changes in brain connectivity in people without diabetes (ND) and with type 1 diabetes with normal (NAH) or impaired (IAH) hypoglycaemia awareness. Two-step hyperinsulinaemic hypoglycaemic clamps were performed in 14 ND, 15 NAH and 22 IAH participants. BOLD timeseries were acquired at euglycaemia (5.0 mmol/L) and hypoglycaemia (2.6 mmol/L), with symptom and counter-regulatory hormone measurements. We investigated hypoglycaemia-related connectivity changes using established seed regions for the default mode (DMN), salience (SN) and central executive (CEN) networks and regions whose activity is modulated by hypoglycaemia: the thalamus and right inferior frontal gyrus (RIFG). Hypoglycaemia-induced changes in the DMN, SN and CEN were evident in NAH (all p < 0.05), with no changes in ND or IAH. However, in IAH there was a reduction in connectivity between regions within the RIFG (p = 0.001), not evident in the ND or NAH groups. We conclude that hypoglycaemia induces coordinated recruitment of the DMN and SN in diabetes with preserved hypoglycaemia awareness which is absent in IAH and ND. Changes in connectivity in the RIFG, a region associated with attentional modulation, may be key in impaired hypoglycaemia awareness.

Aims/hypothesis: Lifestyle interventions are the first-line treatment option for body weight and cardiometabolic health management. However, whether age groups or women and men respond differently to lifestyle interventions is under debate. We aimed to examine age- and sex-specific effects of a low-energy diet (LED) followed by a long-term lifestyle intervention on body weight, body composition and cardiometabolic health markers in adults with prediabetes (i.e. impaired fasting glucose and/or impaired glucose tolerance)., Methods: This observational study used longitudinal data from 2223 overweight participants with prediabetes in the multicentre diabetes prevention study PREVIEW. The participants underwent a LED-induced rapid weight loss (WL) period followed by a 3 year lifestyle-based weight maintenance (WM) intervention. Changes in outcomes of interest in prespecified age (younger: 25-45 years; middle-aged: 46-54 years; older: 55-70 years) or sex (women and men) groups were compared., Results: In total, 783 younger, 319 middle-aged and 1121 older adults and 1503 women and 720 men were included in the analysis. In the available case and complete case analyses, multivariable-adjusted linear mixed models showed that younger and older adults had similar weight loss after the LED, whereas older adults had greater sustained weight loss after the WM intervention (adjusted difference for older vs younger adults -1.25% [95% CI -1.92, -0.58], p<0.001). After the WM intervention, older adults lost more fat-free mass and bone mass and had smaller improvements in 2 h plasma glucose (adjusted difference for older vs younger adults 0.65 mmol/l [95% CI 0.50, 0.80], p<0.001) and systolic blood pressure (adjusted difference for older vs younger adults 2.57 mmHg [95% CI 1.37, 3.77], p<0.001) than younger adults. Older adults had smaller decreases in fasting and 2 h glucose, HbA 1c and systolic blood pressure after the WM intervention than middle-aged adults. In the complete case analysis, the above-mentioned differences between middle-aged and older adults disappeared, but the direction of the effect size did not change. After the WL period, compared with men, women had less weight loss (adjusted difference for women vs men 1.78% [95% CI 1.12, 2.43], p<0.001) with greater fat-free mass and bone mass loss and smaller improvements in HbA 1c , LDL-cholesterol and diastolic blood pressure. After the WM intervention, women had greater fat-free mass and bone mass loss and smaller improvements in HbA 1c and LDL-cholesterol, while they had greater improvements in fasting glucose, triacylglycerol (adjusted difference for women vs men -0.08 mmol/l [-0.11, -0.04], p<0.001) and HDL-cholesterol., Conclusions/interpretation: Older adults benefited less from a lifestyle intervention in relation to body composition and cardiometabolic health markers than younger adults, despite greater sustained weight loss. Women benefited less from a LED followed by a lifestyle intervention in relation to body weight and body composition than men. Future interventions targeting older adults or women should take prevention of fat-free mass and bone mass loss into consideration., Clinical Trial Registration Number: ClinicalTrials.gov NCT01777893., (© 2022. The Author(s).)

Introduction: Changing lifestyle habits to achieve and maintain weight loss can be effective in prevention of Type II diabetes. Ability to resist temptations is considered one of the key factors in behavior change. This study examined how habit strength, motivation, and temptations for an energy-dense diet developed during the maintenance stage of a behavior modification intervention tool., Method: Participants with prediabetes and overweight/obesity were recruited in the two-phase trial PREVIEW with the aim to achieve ≥ 8% body weight loss over 2 months and maintain weight loss over a subsequent 34-month period. The four-stage intervention (PREVIEW Behavior Modification Intervention Toolbox, or PREMIT) supported participants in weight maintenance. Uni- and multivariate analyses were completed from the beginning of the PREMIT maintenance stage (Week 26 of the PREVIEW trial) with 962 individuals who completed the trial., Results: Habit strength and ability to resist temptations increased during the early PREMIT adherence stage (Weeks 26 to 52) before plateauing during middle (Weeks 52 to 104) and late (Weeks 104 to 156) PREMIT adherence stages. Higher habit strength for energy-dense diet was significantly associated with larger weight regain ( p ≤ .007). No changes in motivation or interactions with PREMIT attendance were observed., Discussion: Changing diet habits is a complex, multifactorial process, with participants struggling at least with some aspects of weight maintenance. Habits against consuming energy-dense, sweet, and fatty food appeared effective in protecting against weight regain. The observed effect sizes were small, reflecting the complexity of breaking old habits and forming new ones to support long-term maintenance of weight loss. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Ocean oil slicks can be attributed to natural seepages or to anthropogenic discharges. To date, the global picture of their distribution and relative natural and anthropogenic contributions remains unclear. Here, by analyzing 563,705 Sentinel-1 images from 2014-2019, we provide the first global map of oil slicks and a detailed inventory of static-and-persistent sources (natural seeps, platforms, and pipelines). About 90% of oil slicks were within 160 kilometers of shorelines, with 21 high-density slick belts coinciding well with shipping routes. Quantified by slick area, the proportion of anthropogenic discharges was an order of magnitude greater than natural seepages (94 versus 6%), in contrast to the previous estimate quantified by volume during 1990-1999 (54 versus 46%). Our findings reveal that the present-day anthropogenic contribution to marine oil pollution may have been substantially underestimated.

Background: The gold-standard techniques for measuring insulin sensitivity and secretion are well established. However, they may be perceived as invasive and expensive for use in dietary intervention studies. Thus, surrogate markers have been proposed as alternative markers for insulin sensitivity and secretion. This systematic review aimed to identify markers of insulin sensitivity and secretion in response to dietary intervention and assess their suitability as surrogates for the gold-standard methodology., Methods: Three databases, PubMed, Scopus, and Cochrane were searched, intervention studies and randomised controlled trials reporting data on dietary intake, a gold standard of analysis of insulin sensitivity (either euglycaemic-hyperinsulinaemic clamp or intravenous glucose tolerance test and secretion (acute insulin response to glucose), as well as surrogate markers for insulin sensitivity (either fasting insulin, area under the curve oral glucose tolerance tests and HOMA-IR) and insulin secretion (disposition index), were selected., Results: We identified thirty-five studies that were eligible for inclusion. We found insufficient evidence to predict insulin sensitivity and secretion with surrogate markers when compared to gold standards in nutritional intervention studies., Conclusions: Future research is needed to investigate if surrogate measures of insulin sensitivity and secretion can be repeatable and reproducible in the same way as gold standards.

Endovascular thrombectomy (EVT) is part of first-line intervention for acute ischemic stroke management. Recent technological advances have demonstrated that large-bore catheters are an attractive approach for EVT. A multitude of approaches such as A Direct Aspiration first Pass Technique (ADAPT) or in conjunction with stent retrieval (Solumbra technique) have been developed with increasingly large-bore catheters, demonstrating safety and efficacy. Furthermore, these techniques have demonstrated promise for the intervention of cerebral venous thrombosis as well as posterior circulation ischemic events. Recently, advances in neurointerventional catheters have focused on improved maneuverability to navigate the neurovasculature, as well as larger inner diameters for improved procedural versatility, including aspiration. We describe a case report highlighting our early institutional experience with the recently developed large-bore catheter, the BENCHMARK™ BMX™ 96. The case report entails near complete occlusion of the internal carotid artery from acute thrombus and the utility of the BMX™ 96 catheter for treatment of such extensive clot burden. The applicability of large-bore aspiration catheters, with an emphasis on recent advances, for mechanical thrombectomy in arterial as well as venous systems is discussed. To our knowledge, this is the first reported case of use of the BENCHMARK™ BMX™ 96 access system for EVT in acute ischemic stroke. Such new-generation large-bore catheters are a promising advance in neurointervention, and our early institution experience highlights the ease of use and versatility for neurointerventional procedures such as EVT.