Citations

Introduction: Diabetes, a modifiable risk factor for dementia, is thought to impart increased risk of dementia through cerebral small vessel disease. While the importance of diabetes in midlife is well-documented, the influence of different glycemic levels, duration of diabetes, and Alzheimer’s disease genetic risk (apolipoprotein [ APOE ] ε4 genotype) in late-life on dementia risk remains uncertain. This could have implications for individualized prevention strategies. In this study, we investigated whether a higher glycemic level and longer duration of diabetes in late-life is associated with a higher risk of dementia, and whether associations vary by APOE ε4 genotype. Methods: We performed a prospective cohort analysis with the Atherosclerosis Risk in Communities Study using up to 11 years of follow-up (baseline, 2011-2013). We defined diabetes as glycated hemoglobin A1c (HbA 1c ) ≥6.5%, self-reported physician diagnosis, or use of any diabetes medication. Among those with diabetes, we categorized participants as having a lower glycemic level (HbA 1c <7%) or higher level (HbA 1c ≥7%), and duration as short (<5 years) or long (≥5 years). We estimated hazard ratios (HR) for incident dementia by HbA 1c levels and by diabetes duration in separate multivariable-adjusted Cox regression models. We tested for statistical multiplicative interaction on the relative risk of dementia by fitting interaction terms between diabetes measures and APOE ε4 genotype in separate regression models. Results: In 5030 participants without dementia (mean age, 75.4 years; 58.6% female; 21% Black; 28% with diabetes), there were 1167 (23.2%) incident dementia cases over a median follow-up of 9.0 years. Compared to no diabetes, a lower glycemic level and higher level were both associated with elevated dementia risk ( P -trend <.0001; Table). A higher glycemic level was associated with an elevated risk of dementia relative to a lower level (HR=1.47 [95% CI: 1.22-1.77]; Table). Compared to no diabetes, both shorter duration and longer duration were associated with an increase in dementia risk ( P -trend <.0001; Table). Longer duration was associated with an increased risk of dementia relative to shorter duration (HR=1.57 [95% CI: 1.24-1.98]; Table). Associations for glycemic level and diabetes duration did not significantly differ by APOE ε4 genotype (all P >.05). Conclusions: Diabetes management in older adults that includes lower glycemic goals may help reduce dementia risk.

Abstract Additive manufacturing (AM), commonly referred to as 3D printing, has been broadly used in the field of medical imaging and radiotherapy. In medical imaging applications, patient‐specific anatomic models have been used to aid in preoperative planning, patient communication, imaging technique assessment and optimization, and medical education. Within the field of radiation therapy, 3D printing finds significance in fabricating patient‐specific immobilization devices, custom bolus devices, anthropomorphic phantoms, brachytherapy devices, and electron therapy devices. Consistent with standard medical physics practices there is a need to establish quality assurance and quality control (QA/QC) protocols, tolerances, and testing frequencies. The diversity of 3D printing technologies and products poses challenges for medical adoption and thus requires guidelines in workflow standardization and establishment of testing procedures. This report is centered around providing comprehensive vendor‐neutral implementation guidelines and recommendations for QC and QA processes. The scope of this report encompasses diverse requirements within medical imaging and radiation therapy settings, serving both clinical and research purposes. Brief overview of 3D printing technology, common materials, and potential clinical applications is provided. QA team, infrastructure, measurement techniques and challenges are discussed. QA processes for each step in 3D printing are discussed in great detail and baseline and action limits are recommended. This report also touched on regulatory considerations. Key recommendations are summarized at the end of the report.

Background: Given the faster onset and shorter duration of action of ultra-rapid insulin lispro-aabc (URLi, Lyumjev™ insulin), compared with insulin lispro (a rapid-acting insulin [RAI]), the present study investigated the safety and glycemic outcomes of MiniMed™ 780G advanced hybrid closed-loop (AHCL) use with URLi in youths and adults with T1D. Methods: This 19-site, single-arm, clinical trial enrolled children and adolescents (aged 7–17 years) and adults (aged 18–80 years) with T1D who underwent a run-in period (∼2 weeks) using open loop or automated basal only with an RAI (aspart or lispro), followed by a 3-month study period using URLi with AHCL (AHCL + URLi). End-of-study glycemic metrics and A1c were compared to predefined thresholds and to data from baseline/run-in. Use of recommended optimal settings (ROS, 100 mg/dL glucose target with an active insulin time [AIT] of 2 h) was also assessed. Results: In an intention-to-treat population ( N = 101 pediatric and N = 110 adult participants), percentage of time in range (%TIR) during the last ∼6 weeks of the study period was significantly greater than the predefined thresholds for both the pediatric and adult participants. A1c was unchanged in the pediatric cohort but significantly reduced in the adult cohort (from 7.4 ± 0.9% to 6.9 ± 0.6% [ P < 0.001]). Compared with run-in, study period %TIR and percentage of time in tight target range (%TITR) were significantly increased (pediatric mean %TIRΔ [17.4%] and %TITRΔ [16.0%], respectively, and adult mean %TIRΔ [10.6%] and %TITRΔ [11.6%], respectively; P < 0.001 for all). Additionally, % time above range for both groups was significantly reduced. Use of ROS allowed more participants to achieve recommended glycemic targets. There were no severe hypoglycemia or diabetic ketoacidosis events. Most caregivers agreed that mealtime versus premeal URLi delivery simplified pediatric meal management. Conclusions: Similar to previous studies investigating automated URLi delivery, URLi use in the MiniMed™ 780G system was safe, and glycemic outcomes were favorable for pediatric and adult participants.

Abstract Pain treatments have modest effects. Health outcomes might be improved if treatments are matched to mechanisms underlying the persistence and biopsychosocial impact of an individual's pain. The International Association for the Study of Pain (IASP) defines 3 mechanistic pain descriptors presumed to involve different mechanisms—nociceptive, neuropathic, and nociplastic. Although treatments to address each descriptor have been proposed, there is no consensus on how to assign descriptors to clinical presentations. A recent consensus identified candidate clinical features to discriminate between descriptors in clinical practice and research. These need refinement to progress towards a tool. This study aimed to determine the rank and relative weight of identified clinical features to aid discrimination between mechanistic pain descriptors. Candidate clinical features (n = 196) were refined by the IASP Terminology Task Force to converge similar and remove redundant features. The Task Force (n = 24) and an expert panel (n = 39) ranked features using 1000minds conjoint analysis software and assigned weights based on discrete pairwise choices. Participants nominated from pairs of scenarios, which most likely indicated that pain aligned predominantly to a descriptor. Highest ranked features for neuropathic and nociplastic pain were aligned with IASP Clinical Criteria. Criteria for nociceptive pain have not been established. A ranked list of features shared by 2 mechanisms (indicating mixed mechanisms) was also identified. This study identified expert consensus on the highest ranked clinical features with potential to discriminate between pain descriptors, reflective of different underlying mechanisms. This study extends current frameworks by identifying and refining key discriminators for future operationalisation and validation.

Abstract Purpose: Familial adenomatous polyposis (FAP) confers a significant risk of colorectal/duodenal cancer. Encapsulated rapamycin (eRapa) has demonstrated promise as FAP chemoprevention in early clinical studies. Patients and Methods: Thirty patients with FAP enrolled to three dosing regimens of eRapa (0.5 mg): cohort 1—every other day, cohort 2—daily every other week, or cohort 3—daily. The primary endpoints were safety/tolerability, pharmacokinetics, and percentage change from baseline (PCFB) in colorectal polyp burden (CPB) at 6 months. Secondary endpoints included PCFB total (TPB) and duodenal (DPB) polyp burden and change in International Society for Gastrointestinal Hereditary Tumors stage and Spigelman score at 6 and 12 months. Results: Twenty nine of thirty patients (97%) completed the 12-month study with predictable bioavailability. Low-grade adverse events were frequent but most pronounced in daily dosing. Two patients discontinued treatment related to toxicity. Cohort 1 had the largest decrease median PCFB CPB, DPB, and TPB at 6 months: −39.4 % (IQR, 108.9; P = 0.28), −33.33 % (IQR, 90; P = 0.04), and −38.6 % (IQR, 88.5; P = 0.26), respectively. At 12 months, cohort 2 had the largest decrease median PCFB CPB and TPB: −29.3 % (IQR, 67.6; P = 0.37) and −26.3 % (IQR, 49.5; P = 0.29), respectively. Intermittent dosing cohorts (1 and 2) reduced DPB at 6 months (P = 0.04) and improved TPB at 12 months (P = 0.05) compared with daily dosing. Conclusions: eRapa was safe, tolerable, and showed preliminary efficacy for FAP chemoprevention. The 0.5 mg daily every-other-week schedule will be evaluated in an upcoming phase III trial.

Abstract Background Presacral tumours are rare and heterogeneous lesions arising within a complex anatomical space, resulting in variability in diagnosis and management. Increasing incidental detection and evolving surgical and oncological strategies have highlighted the need for contemporary guidance. The aim of this study was to establish an international expert consensus on the optimal diagnosis and management of presacral tumours. Methods An international panel of colorectal surgeons from high-volume units was convened. Evidence- and practice-based statements were developed after domain-based literature reviews and refined through five online and two in-person meetings. Consensus was achieved using a modified Delphi process with anonymous voting. Results In total, 16 colorectal surgeons participated in the study. Ten domains were identified resulting in the development of 22 statements based on expert opinion and retrospective studies. After two rounds, unanimous (100%) agreement was achieved for all statements. High-resolution MRI with structured synoptic reporting is endorsed as central to risk stratification. Selective image-guided transperineal or parasacral biopsy is recommended for high-risk lesions where histology would alter management. Complete surgical resection is defined as the operative goal, with approach tailored to tumour biology and anatomy; minimally invasive surgery is considered appropriate in selected cases. Non-operative surveillance is supported for carefully selected asymptomatic, low-risk cystic lesions. Postoperative surveillance is recommended in a risk-adapted manner according to histopathology and margin status. Conclusion This international consensus provides a pragmatic, risk-stratified framework for the multidisciplinary diagnosis and management of presacral tumours. These recommendations aim to reduce practice variation, support decision-making in specialized centres, and inform future prospective collaborative research.

Abstract Background/Aims Sleep disturbance is a defining feature of fibromyalgia (FM), contributing to pain, fatigue, cognitive dysfunction, and reduced quality of life. Effective management options remain limited. Cognitive behavioural therapy for insomnia (CBT-I) is effective in primary insomnia, but evidence in FM is sparse and access to face-to-face therapy is limited. Digital CBT-I (dCBT-I) offers a scalable, self-directed solution that may overcome these barriers. We conducted the first randomised controlled trial of dCBT-I in FM to evaluate its impact on quality of life and associated symptoms. Methods This single-blind randomised controlled trial evaluated Sleepio, a validated dCBT-I programme of six self-directed 20-minute sessions delivered over 12 weeks. Participants with a clinical diagnosis of FM, self-reported sleep disturbance, and cognitive complaints were recruited in Oxford, UK. After baseline assessment, participants were randomized to dCBT-I or a control group. All participants also received standardised sleep hygiene advice. The primary outcome was disease-specific quality of life measured by the revised Fibromyalgia Impact Questionnaire (FIQR). Secondary outcomes included insomnia severity (Insomnia Severity Index), actigraphy-derived sleep parameters, pain (SF36 Bodily Pain Scale), cognitive complaints (British Columbia Cognitive Complaints Inventory), sustained attention, and fear of movement (Tampa Scale of Kinesiophobia). Outcomes were collected online at baseline, 3 months, and 6 months. Analyses followed the intention-to-treat principle using constrained longitudinal data analysis. Ethical approval was obtained from South Central - Oxford B Research Ethics Committee (19/SC/0168). The study was pre-registered with clinicaltrials.gov (NCT05962138). Results Of 514 individuals contacted, 241 were screened, 132 were eligible, and 80 were randomised (42 dCBT-I, 38 control). The mean age was 46.6 (SD 14.5) years; 93.8% were female. Retention was high: 97.5% of participants provided outcomes at 3 months, and 83.8% at 6 months. In the dCBT-I group, 90.5% initiated the programme, and 54.8% reached the core session on sleep restriction therapy. At 3 months, there was no significant difference between groups in FIQR (mean difference −2.79; p = 0.3). At 6 months, however, dCBT-I participants demonstrated greater improvement in FIQR compared with controls (mean difference −5.45; 95% CI − 10.5 to − 0.4; p = 0.035), corresponding to a small-to-moderate effect size (Cohen’s d = −0.31). No significant between-group differences were observed for secondary outcomes. Conclusion In adults with FM, dCBT-I produced a sustained, clinically meaningful improvement in disease-related quality of life at 6 months compared with a sleep hygiene control. Although benefits were not observed across secondary outcomes, this trial provides the first controlled evidence that dCBT-I can address an important unmet need in FM. Digital behavioural therapies represent scalable, accessible, non-pharmacological interventions with potential for rapid integration into clinical care. Disclosure E. Kelleher: Grants/research support; National Institute for Health Research (NIHR) Pfizer Doctoral Fellowship (NIHR301808). A.J. Wall: Grants/research support; Grant is funded by UKRI and Versus Arthritis as part of the UKRI Strategic Priorities Fund (SPF) Advanced Pain Discovery Platform (APDP), a co-funded initiative by UKRI (MRC, BBSRC, ESRC), VA. V. Wanigasekera: None. R. Sharman: None. S. Kyle: None. I. Tracey: None. B. Seymour: Grants/research support; Grant is funded by UKRI and Versus Arthritis as part of the UKRI Strategic Priorities Fund (SPF) Advanced Pain Discovery Platform (APDP), a co-funded initiative by UKRI (MRC, BBSRC, ESRC), VA. A. Irani: Grants/research support; Grant is funded by UKRI and Versus Arthritis as part of the UKRI Strategic Priorities Fund (SPF) Advanced Pain Discovery Platform (APDP), a co-funded initiative by UKRI (MRC, BBSRC, ESRC), VA.

Abstract Aims Heart failure is prevalent; however, there is no cost-effective screening option. Against formal echocardiography, we assessed the diagnostic performance of focused cardiac ultrasound (FoCUS), performed by novice users guided and interpreted by artificial intelligence (AI) for the assessment of left ventricular ejection fraction (LVEF). Methods and results We prospectively enrolled 496 adults referred for diagnostic echocardiography. Novice operators (without clinical or imaging experience) underwent a 4-h imaging workshop, then performed FoCUS using a point-of-care device (Philips Lumify) utilizing real-time AI-image guidance (UltraSight). Images were assessed by AI-image interpretation software (Mayo Clinic), and two expert blinded echocardiologists. Median age was 67, 39% female, and body mass index range 17–56 kg/m2. Forty-one subjects (8.3%) exhibited moderate or greater LV dilatation and 28 (5.6%) had LVEF &lt;40%. The median scan time was 4 min (IQR 3–5). Adequate views were achieved in 95.0% and 97.4% of subjects for AI interpretation and expert analysis, respectively. A two-step diagnostic screening process for low EF in which only abnormal AI reads or uninterpretable scans were reviewed by experts (15.1%) had a sensitivity 96.2%, specificity 95.4%, PPV 54.3%, and NPV 99.8%. A subsequent prospective validation study of 344 subjects demonstrated similar results (sensitivity 100%, specificity 99.4%). Conclusion In this early feasibility investigation, AI-guidance technology embedded on a handheld device, enabled novice users without clinical or imaging experience to acquire sufficient quality images to accurately assess LVEF with minimal training. The technology evaluated in this study may hold promise for AI-guidance and interpretation to facilitate low-cost screening for cardiac dysfunction.

ABSTRACT Pancreatic islet transplantation can restore endogenous insulin production and offers a potential cure for diabetes, but its clinical impact has been limited by the inability to preserve large numbers of functional islets for timely use. Cryopreservation could provide an on-demand supply, yet conventional methods cause ice formation, cell injury, and loss of insulin secretion. We developed CryoMesh, a vitrification platform that combines a low-toxicity cryoprotectant with a thermally conductive, biocompatible mesh to enable ultra-rapid cooling and rewarming for ice-free cryopreservation. This approach supports long-term, clinical-scale preservation of both human pancreatic and stem cell–derived islets while maintaining viability, architecture, mitochondrial integrity, and glucose-responsive insulin secretion. Human islets preserved for up to one year restored normoglycemia in diabetic mice, with complete recovery of function and no increase in immunogenicity or loss of potency. The combination of high viability, recovery, and functional preservation at clinical scale has not been achieved previously. By decoupling islet isolation and manufacture from transplantation, CryoMesh enables extended quality, potency, and safety testing, cost-effective batch production, and global banking and distribution. These capabilities remove a major barrier to curative cell therapy for diabetes and establish a generalizable strategy for preserving complex multicellular therapeutics. One Sentence Summary A clinical scale vitrification platform enables long-term banking of human pancreatic and stem cell–derived islets for transplantation.