Citations

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 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.

Abstract Purpose: Neurocognitive and endocrine dysfunction are potential complications of cranial irradiation. However, risk factors are poorly understood, impeding accurate prognostication and exploration of potential preventive interventions. The objective of this study was to evaluate the prognostic value of various vascular and genotypic risk factors for the development of radiation-related toxicities. Methods: This single-institution retrospective cohort study included patients with metastatic and malignant primary brain tumors who received cranial irradiation as part of their initial tumor-directed therapy. Demographic and treatment characteristics were collected, as well as putative vascular and genotypic risk factors. Univariate, multivariate, and machine-learning analyses were performed using five pre-specified measures of radiation-related toxicity. The primary outcome was change in mini-mental status exam (MMSE). Results: Eighty patients (53% male, mean age 55.7, 53% primary and 44% metastatic brain tumors) were included. Elevated homocysteine and ApOE4genotype were the strongest predictors of MMSE decline in the multivariate model (OR 3.96 [6.5-200, p<0.001 and 2.85 [1.92-27.6], p=0.004). Elevated homocysteine was associated white matter change on MRI and both physician and patient assessment. ApoE4allele was associated with new endocrine deficiency, and physician assessment. An online nomogram provides risk predictions for each of the five late toxicity outcomes: (https://afranklin22.shinyapps.io/PRMMSERadiationRiskFactors/) Conclusion: Two pre-treatment laboratory values (elevated homocysteine and ApOE genotype) were strongly associated with post-radiation neurocognitive and endocrine dysfunction using a variety of simple but clinically meaningful definitions of dysfunction. Our predictive algorithm can aid clinicians in stratifying baseline risk and should be validated in prospective trials.

Abstract Solitary bone plasmacytoma (SBP) and SBP with minimal marrow involvement (SBPmm) are treated similarly with definitive radiation therapy (RT) followed by observation. However, differences in the natural disease course after RT between the two, are not well described. We performed a multicenter study assessing outcomes after RT in 141 patients with SBP and 102 with SBPmm diagnosed between January 2010 and December 2024. About 92% of patients with SBPmm progressed to multiple myeloma (MM) vs 76% of those with SBP (P = .01). Among patients with SBP, 21% progressed with a second solitary bone lesion vs 4% with SBPmm (P&lt; .01). Patients with longer time to progression (TTP) after initial RT could achieve durable responses with RT to a second solitary plasmacytoma in the absence of other myeloma-defining events (MDE). Multifocal lytic bone lesions were the most common MDE, occurring in 89% and 81% of patients with SBPmm and SBP, respectively. Patients with SBPmm had a median TTP of 15 months (95% confidence interval [CI], 14-21) compared to 43 months (95% CI, 34-55) for those with SBP (P&lt; .0001); 67% with SBPmm progressed within 2 years of diagnosis. Del(17p) and 1q+ (gain or amplification) were associated with shorter TTP to MM in SBPmm, with 2-year progression rates of 100% and 82%, respectively. We report significant differences in risk and modes of progression between SBP and SBPmm. Patients with SBPmm are at particularly high risk for early progression to MM, with most developing bone disease as the MDE. These findings support prospective studies incorporating frontline systemic therapy for SBPmm.

BACKGROUND AND OBJECTIVES: Perioperative protocols facilitate earlier discharge without compromising safety in nonfunctioning pituitary adenomas, but no large multicenter studies in the United States have investigated protocols regarding Cushing disease (CD). We sought to characterize perioperative protocols and how their implementation influences clinical outcomes in patients with CD. METHODS: A retrospective analysis was conducted using data from the Registry of Adenomas of the Pituitary and Related Disorders consortium comprising 13 US academic pituitary centers. Institutions were surveyed regarding perioperative procedures for patients undergoing transsphenoidal tumor resection for CD. The impacts of institutional procedures and approaches to implementation on length of stay (LOS) and unplanned 90-day readmission were evaluated. RESULTS: Thirteen institutions contributed survey responses and clinical data for a total of 832 patients meeting inclusion criteria. Ten (76.9%) institutions reported having a postoperative protocol, 9 (69.2%) used a formal document to outline their protocol, and 3 (23.1%) had protocols implemented into hospital policy. Mean LOS was significantly reduced in centers with an established protocol (3.14 vs 3.42 days, P = .032), and more so with a formal document (3.10 vs 3.48 days, P = .001) or hospital policy (2.72 vs 3.36 days, P < .001). Patients treated after protocol implementation experienced shorter LOS ( P < .001). Other factors associated with reduced LOS were presence of a separate CD pathway, intraoperative checklist specific to pituitary surgery, non-narcotic pain regimen, Foley removal order, dedicated outpatient advanced practice provider follow-up, and target discharge date ≤2 days. Intraoperative checklist ( P = .045), non-narcotic pain regimen ( P = .048), nasal packing ( P = .005), and 1-day target discharge date ( P = .032) were important factors against readmission. Compared with microscopic surgery, endoscopic surgery was associated with shorter LOS but increased readmission odds. CONCLUSION: This is the first multicenter study to illustrate that implementation of perioperative protocols is associated with a reduction in LOS and readmission risk in patients with CD.

In a large, multicenter cohort of HIV and non–HIV immunocompromised patients with Pneumocystis jirovecii pneumonia, chest CT most commonly demonstrated diffusely distributed ground-glass opacity, with no imaging features distinguishing between immunocompromise etiology.

Abstract Gastrointestinal (GI) involvement is a clinically relevant but undercharacterized manifestation of systemic light chain amyloidosis (AL). We aimed to define the clinical spectrum, histologic patterns, and outcomes of symptomatic GI involvement in AL. We retrospectively analyzed 4396 patients with AL from 2010 to 2024, of whom 521 (11.9%) had provider-attributed symptomatic GI involvement; 66% had biopsy-proven GI AL. Symptoms most commonly included early satiety (61%), bowel irregularities (58%), nausea (35%), abdominal pain (28%), and dysphagia (23%). Autonomic neuropathy was frequent (43% clinician attributed; 23% via autonomic reflex testing) and contributed to dysmotility-related symptoms, often without GI biopsy positivity. Among 747 GI biopsies, mucosal infiltration predominated (71%) and was associated with bleeding (22% vs 9%), cachexia, and inferior survival, whereas vascular involvement was associated with lower bleeding risk. Combined involvement of mucosa, submucosa, and vessels conferred the worst prognosis (median overall survival [mOS], 2.4 vs 5.1 vs 7.8 years for 3 vs 2 vs 1 layer); mOS was 6.8 years and was primarily driven by cardiac stage and hematologic response (very good partial response [VGPR] or better: hazard ratio, 0.20; 95% CI 0.13-0.32), with more favorable outcomes in patients with isolated GI involvement. Cachexia and persistent diarrhea were the main drivers of morbidity, need for nutritional support, and GI-related mortality (odds ratio, 2.7 for the combined end point). GI bleeding rarely recurred after achieving VGPR or better. Overall, mucosal involvement, cachexia, and dysmotility define clinically meaningful GI AL and support systematic assessment of autonomic dysfunction as well as evaluation of the need for nutritional support as a GI-specific end point for AL trials.

This article describes the typical and atypical chest imaging appearances of Pneumocystis jirovecii pneumonia.

Abstract Systemic light chain amyloidosis (AL) arises from monoclonal immunoglobulin light chains, but determinants of progression from precursor states remain poorly defined. In a cross-sectional cohort comprising 1950 systemic AL patients diagnosed 2010-2024, 258 (13.2%) patients with a previously diagnosed plasma cell disorder (PCD) were compared to patients with no prior PCD diagnosis. Patients with monoclonal gammopathy of undetermined signficance (MGUS) and smoldering multiple myeloma (SMM) in the former group had lower difference between involved and uninvolved FLCs (dFLC), higher M-protein, and lower rates of t(11;14) at AL diagnosis. Patients developing AL from SMM had a shorter time to AL (median 34.2 versus 61.3 months) and higher dFLC (median 28.9 versus 11.0 mg/dl) compared to those from MGUS. Patients developing AL after known multiple myeloma (MM) or lymphoplasmacytic lymphoma (LPL) commonly lacked deep hematologic response before AL (≤ very good partial response in 78% of MM, 100% of LPL patients). We additionally studied longitudinally followed cohorts of 3,966 MGUS and 426 (SMM) patients with longitudinal FLC measurements and matched follow-up, in which 1.8% of MGUS and 7.2% of SMM patients developed AL. Those patients who developed AL showed markedly higher dFLC at MGUS/SMM diagnosis and more frequent λ restriction and rates of t(11;14). Higher dFLC was associated with progressively earlier AL development; a 10% cumulative risk occurred at 20 months for patients with a dFLC >80 mg/dL but was not reached if dFLC <10 mg/dL at an estimated median follow-up of 86 months. In multivariable analysis, dFLC >6.4 mg/dL (HR 11.3) and λ isotype (HR 3.6) independently predicted AL, whereas heavy chain secretion was associated with lower risk (HR 0.2 for IgG). These findings indicate that AL risk is primarily driven by cumulative light chain exposure, refining our knowledge of AL pathophysiology and providing guidance for follow-up of patients with elevated dFLC.

Abstract Purpose: This multicenter, multi-surgeon retrospective study aimed to identify risk factors for postoperative cerebrospinal fluid (CSF) leak following endonasal resection of craniopharyngioma, while evaluating the "perception gap" through a surgeon survey. Methods: A retrospective review was conducted on 416 patients who underwent endoscopic transsphenoidal surgery (ETS) for craniopharyngioma from 20 institutions. Factors were compared between patients with and without postoperative CSF leak, and between Early (2007-2015) and Late (2016-2025) Epochs. Complementing the clinical data, a survey of 19 neurosurgeons captured expert perspectives on risk stratification and management strategies. Results: Overall postoperative CSF leak rate was 13.5% (56/416 patients). Univariate analysis identified predominantly cystic tumors (34% vs. 21%, p = 0.034)and intraoperative lumbar drain (LD) use ( p < 0.028) as associated with postoperative CSF leak. BMI ( p = 0.587), prior surgery ( p = 0.576), and tumor size ( p = 0.363) were not significant. In the multivariable analysis, LD use was associated with a higher postoperative CSF leak rate (OR 1.91, 95% CI 1.06–3.46; p = 0.030). Between Epochs, nasoseptal flap (NSF) utilization increased from 70.7% to 87.6% ( p <0.001). NSF was protective (OR 0.28, 95% CI 0.07–0.92; p = 0.037) in the Early Epoch; no factors were significant in the Late Epoch. The surgeons’ survey identified prior surgery and intraoperative high flow leaks as primary risks; however, their LD protocols diverged from clinical data. Conclusion: Despite increased use of NSF, CSF leak persists. The study highlights a significant divergence between expert perception and clinical data regarding lumbar drains.