Periostin C-Terminal Is Intrinsically Disordered and Interacts with 143 Proteins in an In Vitro Epidermal Model of Atopic Dermatitis.

Human periostin is a 78-91 kDa matricellular protein implicated in extracellular matrix remodeling, tumor development, metastasis, and inflammatory diseases like atopic dermatitis, psoriasis, and asthma. The protein consists of six domains, including an N-terminal Cys-rich CROPT domain, four fasciclin-1 domains, and a C-terminal domain. The exons encoding the C-terminal domain may be alternatively spliced by shuffling four exons, generating ten variants of unknown function. Here, we investigate the structure and interactome of the full-length variant of the C-terminal domain with no exons spliced out. The structural analysis showed that the C-terminal domain lacked a tertiary structure and was intrinsically disordered. In addition, we show that the motif responsible for heparin-binding is in the conserved very C-terminal part of periostin. Pull-down confirmed three known interaction partners and identified an additional 140 proteins, among which nine previously have been implicated in atopic dermatitis. Based on our findings, we suggest that the C-terminal domain of periostin facilitates interactions between connective tissue components in concert with the four fasciclin domains.

Cost-effectiveness of an antibacterial envelope for infection prevention in patients undergoing cardiac resynchronization therapy reoperations in Denmark.

AIMS: Use of an absorbable antibacterial envelope during implantation prevents cardiac implantable electronic device infections in patients with a moderate-to-high infection risk. Previous studies demonstrated that an envelope is cost-effective in high-risk patients within German, Italian, and English healthcare systems, but these analyses were based on limited data and may not be generalizable to other healthcare settings. METHODS AND RESULTS: A previously published decision-tree-based cost-effectiveness model was used to compare the costs per quality-adjusted life year (QALY) associated with adjunctive use of an antibacterial envelope for infection prevention compared to standard-of-care intravenous antibiotics. The model was adapted using data from a Danish observational two-centre cohort study that investigated infection-risk patients undergoing cardiac resynchronization therapy (CRT) reoperations with and without an antibacterial envelope (n = 1943). We assumed a cost-effectiveness threshold of €34 125/QALY gained, based on the upper threshold used by the National Institute for Health and Care Excellence (£30 000). An antibacterial envelope was associated with an incremental cost-effectiveness ratio (ICER) of €12 022 per QALY in patients undergoing CRT reoperations, thus indicating that the envelope is cost-effective when compared with standard of care. A separate analysis stratified by device type showed ICERS of €6227 (CRT defibrillator) and €29 177 (CRT pacemaker) per QALY gained. CONCLUSIONS: Cost-effectiveness ratios were favourable for patients undergoing CRT reoperations in the Danish healthcare system, and thus are in line with previous studies. Results from this study can contribute to making the technology available to Danish patients and align preventive efforts in the pacemaker and ICD area.

Cerebral Palsy - Early Diagnosis and Intervention Trial: protocol for the prospective multicentre CP-EDIT study with focus on diagnosis, prognostic factors, and intervention.

BACKGROUND: Early diagnosis of cerebral palsy (CP) is important to enable intervention at a time when neuroplasticity is at its highest. Current mean age at diagnosis is 13 months in Denmark. Recent research has documented that an early-diagnosis set-up can lower diagnostic age in high-risk infants. The aim of the current study is to lower diagnostic age of CP regardless of neonatal risk factors. Additionally, we want to investigate if an early intervention program added to standard care is superior to standard care alone. METHODS: The current multicentre study CP-EDIT (Early Diagnosis and Intervention Trial) with the GO-PLAY intervention included (Goal Oriented ParentaL supported home ActivitY program), aims at testing the feasibility of an early diagnosis set-up and the GO-PLAY early intervention. CP-EDIT is a prospective cohort study, consecutively assessing approximately 500 infants at risk of CP. We will systematically collect data at inclusion (age 3-11 months) and follow a subset of participants (n = 300) with CP or at high risk of CP until the age of two years. The GO-PLAY early intervention will be tested in 80 infants with CP or high risk of CP. Focus is on eight areas related to implementation and perspectives of the families: early cerebral magnetic resonance imaging (MRI), early genetic testing, implementation of the General Movements Assessment method, analysis of the GO-PLAY early intervention, parental perspective of early intervention and early diagnosis, early prediction of CP, and comparative analysis of the Hand Assessment for Infants, Hammersmith Infant Neurological Examination, MRI, and the General Movements method. DISCUSSION: Early screening for CP is increasingly possible and an interim diagnosis of "high risk of CP" is recommended but not currently used in clinical care in Denmark. Additionally, there is a need to accelerate identification in mild or ambiguous cases to facilitate appropriate therapy early. Most studies on early diagnosis focus on identifying CP in infants below five months corrected age. Little is known about early diagnosis in the 50% of all CP cases that are discernible later in infancy. The current study aims at improving care of patients with CP even before they have an established diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov ID 22013292 (reg. date 31/MAR/2023) for the CP-EDIT cohort and ID 22041835 (reg. date 31/MAR/2023) for the GO-PLAY trial.

175 W average power from a single-core rod fiber-based chirped-pulse-amplification system.

We report on a fiber-based chirped-pulse-amplification laser system with bulk transmission grating compression to a pulse duration of 357 fs, average power of 175 W, and pulse energy of 233µ J. The compressed pulse train has a beam quality factor M2 of 1.21. The power amplifier is based on a state-of-the-art single-mode photonic crystal rod-type ytterbium-doped fiber operating at 248 W of average power and a repetition rate of 750 kHz. The long-term stability of the laser system has been tested continuously for more than 4000 hours and shows no sign of transverse mode instability.

Consensus on communication curriculum content in Danish undergraduate medical education: A Delphi study.

BACKGROUND: The acquisition of skills in patient-centered communication is a critical aspect of medical education which demands both resource-intensive instruction and longitudinal opportunities for learning. Significant variation currently exists in the content and timing of communication education. The aim of this study was to establish consensus regarding communication curriculum content for undergraduate medical education (UME) within the country of Denmark. METHODS: This study employed a Delphi process which is a widely accepted method for establishing consensus among experts and can be utilized to guide planning and decision-making in education. For this study, consensus was based on greater than 60% agreement between participants. Diverse stakeholders, representing all four universities with medical schools in Denmark, participated in an iterative three-round Delphi process which involved: (1) identifying key curricular elements for medical student education, (2) rating the importance of each item, and (3) prioritizing items relative to one another and rating each item based on the level of mastery that was expected for each skill (i.e. knowledge, performance with supervision, or performance independently). RESULTS: A national sample of 149 stakeholders participated with a 70% response rate for round 1, 81% for round 2, and 86% for round 3. The completed Delphi process yielded 56 content items which were prioritized in rank order lists within five categories: (1) establishing rapport, engaging patient perspectives and responding to needs; (2) basic communication skills and techniques; (3) phases and structure of the encounter; (4) personal characteristics and skills of the student; (5) specific challenging patient groups and context-dependent situations. DISCUSSION: Using a Delphi process, it was possible to achieve consensus regarding communication curriculum content for UME. These findings provide an important foundation for ensuring greater uniformity in UME, as well as supporting the important longitudinal goals of communication skill development across medical training.

Observation of dynamical eigenmodes induced by the moving refractive index grating of TMI in a rod amplifier.

We report a novel, to the best of our knowledge, analysis of high power rod fiber amplifiers by monitoring the cross-polarization of the output. Spatially and temporally resolved imaging of co- and cross-polarizations at high power amplification reveals dynamic eigenmode behavior of the rod fiber. The dynamic of the eigenmodes is caused by the moving refractive index grating written by the modal interference pattern of transverse mode instability and is the first direct observation of this refractive index grating, to our knowledge.

Challenging 'colour time': A practice and narrative approach to organising waiting time in hospitals.

Waiting time in hospitals is often studied from one of two perspectives: a distributed resource in hospitals or a potential steering and measuring factor. In this article, waiting time in an emergency department is examined from a practice and a narrative perspective, placing time at the core of our analysis. Our article explores patient waiting time as a local practice that builds on the temporal structuring that affects how waiting time is regulated by both normal clock time and event time-as interpretative time. We also consider how individual narratives in situated spaces allow for negotiations, but we also present isolated time experiences. The empirical data derive from an organisational ethnographic study of a newly introduced triage system for incoming patients at an emergency department in Denmark. The analysis shows how waiting time is organised in the formal visitation system as 'colour time' based on the negotiations of the health-care professional as at the 'right time' and as the patient's individual illness experiences with 'wasting time'. The findings indicate the importance of the unequal relationship between clock time and event time and the different contextual situations affecting the possibilities of organising.

Ultrasound-Based Molecular Imaging of Tumors with PTPmu Biomarker-Targeted Nanobubble Contrast Agents.

Ultrasound imaging is a widely used, readily accessible and safe imaging modality. Molecularly-targeted microbubble- and nanobubble-based contrast agents used in conjunction with ultrasound imaging expand the utility of this modality by specifically targeting and detecting biomarkers associated with different pathologies including cancer. In this study, nanobubbles directed to a cancer biomarker derived from the Receptor Protein Tyrosine Phosphatase mu, PTPmu, were evaluated alongside non-targeted nanobubbles using contrast enhanced ultrasound both in vitro and in vivo in mice. In vitro resonant mass and clinical ultrasound measurements showed gas-core, lipid-shelled nanobubbles conjugated to either a PTPmu-directed peptide or a Scrambled control peptide were equivalent. Mice with heterotopic human tumors expressing the PTPmu-biomarker were injected with PTPmu-targeted or control nanobubbles and dynamic contrast-enhanced ultrasound was performed. Tumor enhancement was more rapid and greater with PTPmu-targeted nanobubbles compared to the non-targeted control nanobubbles. Peak tumor enhancement by the PTPmu-targeted nanobubbles occurred within five minutes of contrast injection and was more than 35% higher than the Scrambled nanobubble signal for the subsequent two minutes. At later time points, the signal in tumors remained higher with PTPmu-targeted nanobubbles demonstrating that PTPmu-targeted nanobubbles recognize tumors using molecular ultrasound imaging and may be useful for diagnostic and therapeutic purposes.

Effects of an intensive lifestyle intervention on the underlying mechanisms of improved glycaemic control in individuals with type 2 diabetes: a secondary analysis of a randomised clinical trial.

AIMS/HYPOTHESIS: The aim was to investigate whether an intensive lifestyle intervention, with high volumes of exercise, improves beta cell function and to explore the role of low-grade inflammation and body weight. METHODS: This was a randomised, assessor-blinded, controlled trial. Ninety-eight individuals with type 2 diabetes (duration <10 years), BMI of 25-40 kg/m2, no use of insulin and taking fewer than three glucose-lowering medications were randomised (2:1) to either the standard care plus intensive lifestyle group or the standard care alone group. Standard care consisted of individual guidance on disease management, lifestyle advice and blinded regulation of medication following a pre-specified algorithm. The intensive lifestyle intervention consisted of aerobic exercise sessions that took place 5-6 times per week, combined with resistance exercise sessions 2-3 times per week, with a concomitant dietary intervention aiming for a BMI of 25 kg/m2. In this secondary analysis beta cell function was assessed from the 2 h OGTT-derived disposition index, which is defined as the product of the Matsuda and the insulinogenic indices. RESULTS: At baseline, individuals were 54.8 years (SD 8.9), 47% women, type 2 diabetes duration 5 years (IQR 3-8) and HbA1c was 49.3 mmol/mol (SD 9.2); 6.7% (SD 0.8). The intensive lifestyle group showed 40% greater improvement in the disposition index compared with the standard care group (ratio of geometric mean change [RGM] 1.40 [95% CI 1.01, 1.94]) from baseline to 12 months' follow-up. Plasma concentration of IL-1 receptor antagonist (IL-1ra) decreased 30% more in the intensive lifestyle group compared with the standard care group (RGM 0.70 [95% CI 0.58, 0.85]). Statistical single mediation analysis estimated that the intervention effect on the change in IL-1ra and the change in body weight explained to a similar extent (59%) the variance in the intervention effect on the disposition index. CONCLUSIONS/INTERPRETATION: Our findings show that incorporating an intensive lifestyle intervention, with high volumes of exercise, in individuals with type 2 diabetes has the potential to improve beta cell function, associated with a decrease in low-grade inflammation and/or body weight. TRIAL REGISTRATION: ClinicalTrials.gov NCT02417012 Graphical abstract.

Experimental investigations of seeding mechanisms of TMI in rod fiber amplifier using spatially and temporally resolved imaging.

In this work we investigate transverse mode instability (TMI) in the presence of pump intensity noise and a controlled perturbation of the input coupling for a rod-type fiber amplifier using spatially and temporally resolved imaging (ST). We show that inherent pump intensity noise from the power supply can define significant peaks in the resulting TMI spectrum. ST measurements show that the TMI in the transition region consists of different orientations of LP11. This finding indicates that the simple picture of TMI being seeded by the combination of a static initial fraction of LP11 and pump or signal intensity noise is not valid for our measurements. Furthermore we present seeding of TMI by perturbing the input coupling dynamically. ST measurements of the resulting TMI as a function of perturbation frequency provides quantitative information regarding the frequency response of the non-linear coupling coefficient. Finally, ST measurements of the resulting TMI as a function of signal power shows that the TMI experiences an exponential gain long before visible beam fluctuations appear.

PTPmu-targeted nanoparticles label invasive pediatric and adult glioblastoma.

Poor prognosis for glioblastoma (GBM) is a consequence of the aggressive and infiltrative nature of gliomas where individual cells migrate away from the main tumor to distant sites, making complete surgical resection and treatment difficult. In this manuscript, we characterize an invasive pediatric glioma model and determine if nanoparticles linked to a peptide recognizing the GBM tumor biomarker PTPmu can specifically target both the main tumor and invasive cancer cells in adult and pediatric glioma models. Using both iron and lipid-based nanoparticles, we demonstrate by magnetic resonance imaging, optical imaging, histology, and iron quantification that PTPmu-targeted nanoparticles effectively label adult gliomas. Using PTPmu-targeted nanoparticles in a newly characterized orthotopic pediatric SJ-GBM2 model, we demonstrate individual tumor cell labeling both within the solid tumor margins and at invasive and dispersive sites.

Photo-Based Range-of-Motion Measurement: Reliability and Concurrent Validity in Children With Cerebral Palsy.

PURPOSE: To investigate intrarater and interrater reliability, agreement, and concurrent validity of a smartphone photography-based application compared with a universal goniometer in children with cerebral palsy. METHODS: Range of motion of hip abduction, popliteal angle, and ankle dorsiflexion was measured with a universal goniometer and a photography-based application in children with cerebral palsy, Gross Motor Function Classification System levels I to V.A 2-way random-effects intraclass correlation coefficients and Bland-Altman plots, standard error of measurement, and smallest detectable change were used for analyses. RESULTS: The application had good to excellent reliability and concurrent validity compared with a universal goniometer, while the large measurement error of both methods suggests that changes of 10° to 23° are needed to be certain that changes over time are not results of measurement error. CONCLUSIONS: A photography-based goniometer can be a reliable and valid tool when measuring range of motion in children with cerebral palsy.

Type 2 diabetes remission 1 year after an intensive lifestyle intervention: A secondary analysis of a randomized clinical trial.

AIM: To investigate whether an intensive lifestyle intervention induces partial or complete type 2 diabetes (T2D) remission. MATERIALS AND METHODS: In a secondary analysis of a randomized, assessor-blinded, single-centre trial, people with non-insulin-dependent T2D (duration <10 years), were randomly assigned (2:1, stratified by sex, from April 2015 to August 2016) to a lifestyle intervention group (n = 64) or a standard care group (n = 34). The primary outcome was partial or complete T2D remission, defined as non-diabetic glycaemia with no glucose-lowering medication at the outcome assessments at both 12 and 24 months from baseline. All participants received standard care, with standardized, blinded, target-driven medical therapy during the initial 12 months. The lifestyle intervention included 5- to 6-weekly aerobic and combined aerobic and strength training sessions (30-60 minutes) and individual dietary plans aiming for body mass index ≤25 kg/m2 . No intervention was provided during the 12-month follow-up period. RESULTS: Of the 98 randomized participants, 93 completed follow-up (mean [SD] age 54.6 [8.9] years; 46 women [43%], mean [SD] baseline glycated haemoglobin 49.3 [9.3] mmol/mol). At follow-up, 23% of participants (n = 14) in the intervention and 7% (n = 2) in the standard care group met the criteria for any T2D remission (odds ratio [OR] 4.4, 95% confidence interval [CI] 0.8-21.4]; P = 0.08). Assuming participants lost to follow-up (n = 5) had relapsed, the OR for T2D remission was 4.4 (95% CI 1.0-19.8; P = 0.048). CONCLUSIONS: The statistically nonsignificant threefold increased remission rate of T2D in the lifestyle intervention group calls for further large-scale studies to understand how to implement sustainable lifestyle interventions among people with T2D.

A PTPmu Biomarker is Associated with Increased Survival in Gliomas.

An integrated approach has been adopted by the World Health Organization (WHO) for diagnosing brain tumors. This approach relies on the molecular characterization of biopsied tissue in conjunction with standard histology. Diffuse gliomas (grade II to grade IV malignant brain tumors) have a wide range in overall survival, from months for the worst cases of glioblastoma (GBM) to years for lower grade astrocytic and oligodendroglial tumors. We previously identified a change in the cell adhesion molecule PTPmu in brain tumors that results in the generation of proteolytic fragments. We developed agents to detect this cell surface-associated biomarker of the tumor microenvironment. In the current study, we evaluated the PTPmu biomarker in tissue microarrays and individual tumor samples of adolescent and young adult (n = 25) and adult (n = 69) glioma populations using a fluorescent histochemical reagent, SBK4-TR, that recognizes the PTPmu biomarker. We correlated staining with clinical data and found that high levels of the PTPmu biomarker correlate with increased survival of glioma patients, including those with GBM. Patients with high PTPmu live for 48 months on average, whereas PTPmu low patients live only 22 months. PTPmu high staining indicates a doubling of patient survival. Use of the agent to detect the PTPmu biomarker would allow differentiation of glioma patients with distinct survival outcomes and would complement current molecular approaches used in glioma prognosis.

Fast magnetic resonance fingerprinting for dynamic contrast-enhanced studies in mice.

PURPOSE: The goal of this study was to develop a fast MR fingerprinting (MRF) method for simultaneous T1 and T2 mapping in DCE-MRI studies in mice. METHODS: The MRF sequences based on balanced SSFP and fast imaging with steady-state precession were implemented and evaluated on a 7T preclinical scanner. The readout used a zeroth-moment-compensated variable-density spiral trajectory that fully sampled the entire k-space and the inner 10 × 10 k-space with 48 and 4 interleaves, respectively. In vitro and in vivo studies of mouse brain were performed to evaluate the accuracy of MRF measurements with both fully sampled and undersampled data. The application of MRF to dynamic T1 and T2 mapping in DCE-MRI studies were demonstrated in a mouse model of heterotopic glioblastoma using gadolinium-based and dysprosium-based contrast agents. RESULTS: The T1 and T2 measurements in phantom showed strong agreement between the MRF and the conventional methods. The MRF with spiral encoding allowed up to 8-fold undersampling without loss of measurement accuracy. This enabled simultaneous T1 and T2 mapping with 2-minute temporal resolution in DCE-MRI studies. CONCLUSION: Magnetic resonance fingerprinting provides the opportunity for dynamic quantification of contrast agent distribution in preclinical tumor models on high-field MRI scanners.

Static and dynamic mode coupling in a double-pass rod-type fiber amplifier.

This Letter describes an experimental realization of a double-pass amplifier using rod-type fiber. In this device, the gain reaches 26 dB amplifying a 300 mW, 20 ps, 20 MHz seed up to 120 W, with an optical-to-optical efficiency of 50% and excellent beam quality. In addition, by design the output of the amplifier has a polarization extinction ratio of 33 dB. Besides these good performances, we report a marginal degradation of mode quality and degree of polarization followed by the so-called transverse mode instability which occurs at 120 W signal power. The first degradation is static, and by analyzing its two polarizations, we conclude it is caused by a coupling between modes due to the formation of a static thermal long-period grating, which in turn initiates the dynamic instability.

Why prescribe exercise as therapy in type 2 diabetes? We have a pill for that!

The majority of T2D cases are preventable through a healthy lifestyle, leaving little room for questions that lifestyle should be the first line of defence in the fight against the development of T2D. However, when it comes to the clinical care of T2D, the potential efficacy of lifestyle is much less clear-cut, both in terms of impacting the pathological metabolic biomarkers of the disease, and long-term complications. A healthy diet, high leisure-time physical activity, and exercise are considered to be cornerstones albeit adjunct to drug therapy in the management of T2D. The prescription and effective implementation of structured exercise and other lifestyle interventions in the treatment of T2D have not been routinely used. In this article, we critically appraise and debate our reflections as to why exercise and physical activity may not have reached the status of a viable and effective treatment in the clinical care of T2D to the same extent as pharmaceutical drugs. We argue that the reason why exercise therapy is not utilized to a satisfactory degree is multifaceted and primarily relates to a "vicious cycle" with lack of proven efficacy on T2D complications and a lack of proven effectiveness on risk factors in the primary care of T2D. Furthermore, there is a lack of experimental research establishing the optimal dose of exercise. This precludes widespread and sustained implementation of physical activity and exercise in the clinical treatment of T2D will not succeed.

Quantitative Molecular Imaging with a Single Gd-Based Contrast Agent Reveals Specific Tumor Binding and Retention in Vivo.

Magnetic resonance imaging (MRI) has become an indispensable tool in the diagnosis and treatment of many diseases, especially cancer. However, the poor sensitivity of MRI relative to other imaging modalities, such as PET, has hindered the development and clinical use of molecular MRI contrast agents that could provide vital diagnostic information by specifically locating a molecular target altered in the disease process. This work describes the specific and sustained in vivo binding and retention of a protein tyrosine phosphatase mu (PTPµ)-targeted, molecular magnetic resonance (MR) contrast agent with a single gadolinium (Gd) chelate using a quantitative MRI T1 mapping technique in glioma xenografts. Quantitative T1 mapping is an imaging method used to measure the longitudinal relaxation time, the T1 relaxation time, of protons in a magnetic field after excitation by a radiofrequency pulse. T1 relaxation times can in turn be used to calculate the concentration of a gadolinium-containing contrast agent in a region of interest, thereby allowing the retention or clearance of an agent to be quantified. In this context, retention is a measure of molecular contrast agent binding. Using conventional peptide chemistry, a PTPµ-targeted peptide was linked to a chelator that had been conjugated to a lysine residue. Following complexation with Gd, this PTPµ-targeted molecular contrast agent containing a single Gd ion showed significant tumor enhancement and a sustained increase in Gd concentration in both heterotopic and orthotopic tumors using dynamic quantitative MRI. This single Gd-containing PTPµ agent was more effective than our previous version with three Gd ions. Differences between nonspecific and specific agents, due to specific tumor binding, can be determined within the first 30 min after agent administration by examining clearance rates. This more facile chemistry, when combined with quantitative MR techniques, allows for widespread adoption by academic and commercial entities in the field of molecular MRI ultimately leading to improved detection of disease.

Effect of an Intensive Lifestyle Intervention on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial.

Importance: It is unclear whether a lifestyle intervention can maintain glycemic control in patients with type 2 diabetes. Objective: To test whether an intensive lifestyle intervention results in equivalent glycemic control compared with standard care and, secondarily, leads to a reduction in glucose-lowering medication in participants with type 2 diabetes. Design, Setting, and Participants: Randomized, assessor-blinded, single-center study within Region Zealand and the Capital Region of Denmark (April 2015-August 2016). Ninety-eight adult participants with non-insulin-dependent type 2 diabetes who were diagnosed for less than 10 years were included. Participants were randomly assigned (2:1; stratified by sex) to the lifestyle group (n = 64) or the standard care group (n = 34). Interventions: All participants received standard care with individual counseling and standardized, blinded, target-driven medical therapy. Additionally, the lifestyle intervention included 5 to 6 weekly aerobic training sessions (duration 30-60 minutes), of which 2 to 3 sessions were combined with resistance training. The lifestyle participants received dietary plans aiming for a body mass index of 25 or less. Participants were followed up for 12 months. Main Outcomes and Measures: Primary outcome was change in hemoglobin A1c (HbA1c) from baseline to 12-month follow-up, and equivalence was prespecified by a CI margin of ±0.4% based on the intention-to-treat population. Superiority analysis was performed on the secondary outcome reductions in glucose-lowering medication. Results: Among 98 randomized participants (mean age, 54.6 years [SD, 8.9]; women, 47 [48%]; mean baseline HbA1c, 6.7%), 93 participants completed the trial. From baseline to 12-month follow-up, the mean HbA1c level changed from 6.65% to 6.34% in the lifestyle group and from 6.74% to 6.66% in the standard care group (mean between-group difference in change of -0.26% [95% CI, -0.52% to -0.01%]), not meeting the criteria for equivalence (P = .15). Reduction in glucose-lowering medications occurred in 47 participants (73.5%) in the lifestyle group and 9 participants (26.4%) in the standard care group (difference, 47.1 percentage points [95% CI, 28.6-65.3]). There were 32 adverse events (most commonly musculoskeletal pain or discomfort and mild hypoglycemia) in the lifestyle group and 5 in the standard care group. Conclusions and Relevance: Among adults with type 2 diabetes diagnosed for less than 10 years, a lifestyle intervention compared with standard care resulted in a change in glycemic control that did not reach the criterion for equivalence, but was in a direction consistent with benefit. Further research is needed to assess superiority, as well as generalizability and durability of findings. Trial Registration: clinicaltrials.gov Identifier: NCT02417012.

Cancer stem cell-specific scavenger receptor CD36 drives glioblastoma progression.

Glioblastoma (GBM) contains a self-renewing, tumorigenic cancer stem cell (CSC) population which contributes to tumor propagation and therapeutic resistance. While the tumor microenvironment is essential to CSC self-renewal, the mechanisms by which CSCs sense and respond to microenvironmental conditions are poorly understood. Scavenger receptors are a broad class of membrane receptors well characterized on immune cells and instrumental in sensing apoptotic cellular debris and modified lipids. Here, we provide evidence that CSCs selectively use the scavenger receptor CD36 to promote their maintenance using patient-derived CSCs and in vivo xenograft models. CD36 expression was observed in GBM cells in addition to previously described cell types including endothelial cells, macrophages, and microglia. CD36 was enriched in CSCs and was able to functionally distinguish self-renewing cells. CD36 was coexpressed with integrin alpha 6 and CD133, previously described CSC markers, and CD36 reduction resulted in concomitant loss of integrin alpha 6 expression, self-renewal, and tumor initiation capacity. We confirmed oxidized phospholipids, ligands of CD36, were present in GBM and found that the proliferation of CSCs, but not non-CSCs, increased with exposure to oxidized low-density lipoprotein. CD36 was an informative biomarker of malignancy and negatively correlated to patient prognosis. These results provide a paradigm for CSCs to thrive by the selective enhanced expression of scavenger receptors, providing survival, and metabolic advantages.