Investigating Intra-Individual Networks of Response Inhibition and Interference Resolution using 7T MRI.

Response inhibition and interference resolution are often considered subcomponents of an overarching inhibition system that utilizes the so-called cortico-basal-ganglia loop. Up until now, most previous functional magnetic resonance imaging (fMRI) literature has compared the two using between-subject designs, pooling data in the form of a meta-analysis or comparing different groups. Here, we investigate the overlap of activation patterns underlying response inhibition and interference resolution on a within-subject level, using ultra-high field MRI. In this model-based study, we furthered the functional analysis with cognitive modelling techniques to provide a more in-depth understanding of behaviour. We applied the stop-signal task and multi-source interference task to measure response inhibition and interference resolution, respectively. Our results lead us to conclude that these constructs are rooted in anatomically distinct brain areas and provide little evidence for spatial overlap. Across the two tasks, common BOLD responses were observed in the inferior frontal gyrus and anterior insula. Interference resolution relied more heavily on subcortical components, specifically nodes of the commonly referred to indirect and hyperdirect pathways, as well as the anterior cingulate cortex, and pre-supplementary motor area. Our data indicated that orbitofrontal cortex activation is specific to response inhibition. Our model-based approach provided evidence for the dissimilarity in behavioural dynamics between the two tasks. The current work exemplifies the importance of reducing inter-individual variance when comparing network patterns and the value of UHF-MRI for high resolution functional mapping.

Psilocybin induces acute and persisting alterations in immune status in healthy volunteers: An experimental, placebo-controlled study.

Patients characterized by stress-related disorders such as depression display elevated circulating concentrations of pro-inflammatory cytokines and a hyperactive HPA axis. Psychedelics are demonstrating promising results in treatment of such disorders, however the mechanisms of their therapeutic effects are still unknown. To date the evidence of acute and persisting effects of psychedelics on immune functioning, HPA axis activity in response to stress, and associated psychological outcomes is preliminary. To address this, we conducted a placebo-controlled, parallel group design comprising of 60 healthy participants who received either placebo (n = 30) or 0.17 mg/kg psilocybin (n = 30). Blood samples were taken to assess acute and persisting (7 day) changes in immune status. Seven days' post-administration, participants in each treatment group were further subdivided: 15 underwent a stress induction protocol, and 15 underwent a control protocol. Ultra-high field (7-Tesla) magnetic resonance spectroscopy was used to assess whether acute changes in glutamate or glial activity were associated with changes in immune functioning. Finally, questionnaires assessed persisting self-report changes in mood and social behavior. Psilocybin immediately reduced concentrations of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α), while other inflammatory markers (interleukin (IL)- 1ß, IL-6, and C-reactive protein (CRP)) remained unchanged. Seven days later, TNF-α concentrations returned to baseline, while IL-6 and CRP concentrations were persistently reduced in the psilocybin group. Changes in the immune profile were related to acute neurometabolic activity as acute reductions in TNF-α were linked to lower concentrations of glutamate in the hippocampus. Additionally, the more of a reduction in IL-6 and CRP seven days after psilocybin, the more persisting positive mood and social effects participants reported. Regarding the stress response, after a psychosocial stressor, psilocybin did not significantly alter the stress response. Results are discussed in regards to the psychological and therapeutic effects of psilocybin demonstrated in ongoing patient trials.

Preoperative considerations and benefits of neoadjuvant chemotherapy: insights from a 12-year review of the Hong Kong Breast Cancer Registry.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) was initially used for locally advanced or inoperable breast cancers. Its extension to early disease has facilitated breast-conserving surgery (BCS). This study investigated the use of NAC in patients registered with the Hong Kong Breast Cancer Registry (HKBCR); it also assessed NAC effectiveness according to rates of pathological complete response (pCR) and BCS. METHODS: Records were retrieved from the HKBCR regarding 13 435 women who had been diagnosed with invasive breast cancer during the period of 2006 to 2017, including 1084 patients who received NAC. RESULTS: The proportion of patients treated with NAC nearly doubled from 5.6% in 2006-2011 to 10.3% in 2012-2017. The increase was most pronounced among patients with stage II or III disease. In terms of biological subtype, substantial increases in the receipt of NAC were evident among patients with triple-negative and human epidermal growth factor receptor 2 (HER2)-positive (non-luminal) tumours. The best rates of pCR were observed in patients with HER2-positive (non-luminal) [46.0%] tumours, followed by patients with luminal B (HER2-positive) [29.4%] and triple-negative (29.3%) tumours. After NAC, the rate of BCS was 53.9% in patients with clinical stage IIA disease, compared with 38.2% in patients with pathological stage IIA disease who did not receive NAC. CONCLUSION: The use of NAC in Hong Kong increased from 2006 to 2017. The findings regarding rates of pCR and BCS indicate that NAC is an effective treatment; it should be considered in patients with stage ≥II disease, as well as patients with HER2- positive (non-luminal) or triple-negative breast cancers.

Oxygen-Sensing Paramagnetic Probes for Clinical Oximetry.

Electron paramagnetic resonance (EPR) oximetry based on lithium naphthalocyanine paramagnetic crystals as oxygen sensors enables direct measurement of the partial pressure of oxygen (pO2) in tissues. The method uses topical or implantable forms of these oxygen-sensing crystals embedded in a biocompatible siloxane elastomer. This article presents a summary of these sensors for EPR oximetry and their applicability for tissue oxygen measurement in the clinic.

Ultra-high resolution and multi-shell diffusion MRI of intact ex vivo human brains using kT-dSTEAM at 9.4T.

Diffusion MRI (dMRI) in ex vivo human brain specimens is an important research tool for neuroanatomical investigations and the validation of dMRI techniques. Many ex vivo dMRI applications have benefited from very high dMRI resolutions achievable on small-bore preclinical or animal MRI scanners for small tissue samples. However, the investigation of entire human brains post mortem provides the important context of entire white matter (WM) network systems and entire gray matter (GM) areas connected through these systems. The investigation of intact ex vivo human brains in large bore systems creates challenges due to the limited gradient performance and transmit radio-frequency (B1+) inhomogeneities, specially at ultra-high field (UHF, 7T and higher). To overcome these issues, it is necessary to tailor ex vivo diffusion-weighted sequences specifically for high resolution and high diffusion-weighting. Here, we present kT-dSTEAM, which achieves B1+ homogenization across whole human brain specimens using parallel transmit (pTx) on a 9.4T MR system. We use kT-dSTEAM to obtain multi-shell high b-value and high resolution diffusion-weighted data in ex vivo whole human brains. Isotropic whole brain data can be acquired at high b-value (6000-8000 s/mm2) at high resolution (1000 µm) and at moderate b-value (3000 s/mm2) at ultra-high isotropic resolution (400 µm). As an illustration of the advantages of the ultra-high resolution, tractography across the WM/GM border shows less of the unwanted gyral crown bias, and more high-curvature paths connecting the sulcal wall than at lower resolution. The kT-dSTEAM also allows for acquisition of T1 and T2 weighted images suitable for estimating quantitative T1 and T2 maps. Finally, multi-shell analysis of kT-dSTEAM data at variable mixing time (TM) is shown as an approach for ex vivo data analysis which is adapted to the strengths of STEAM diffusion-weighting. Here, we use this gain for multi-orientation modelling and crossing-fiber tractography. We show that multi-shell data allows superior multiple orientation tractography of known crossing fiber structures in the brain stem.

High resolution anatomical and quantitative MRI of the entire human occipital lobe ex vivo at 9.4T.

Several magnetic resonance imaging (MRI) contrasts are sensitive to myelin content in gray matter in vivo which has ignited ambitions of MRI-based in vivo cortical histology. Ultra-high field (UHF) MRI, at fields of 7T and beyond, is crucial to provide the resolution and contrast needed to sample contrasts over the depth of the cortex and get closer to layer resolved imaging. Ex vivo MRI of human post mortem samples is an important stepping stone to investigate MRI contrast in the cortex, validate it against histology techniques applied in situ to the same tissue, and investigate the resolutions needed to translate ex vivo findings to in vivo UHF MRI. Here, we investigate key technology to extend such UHF studies to large human brain samples while maintaining high resolution, which allows investigation of the layered architecture of several cortical areas over their entire 3D extent and their complete borders where architecture changes. A 16 channel cylindrical phased array radiofrequency (RF) receive coil was constructed to image a large post mortem occipital lobe sample (~80×80×80mm3) in a wide-bore 9.4T human scanner with the aim of achieving high-resolution anatomical and quantitative MR images. Compared with a human head coil at 9.4T, the maximum Signal-to-Noise ratio (SNR) was increased by a factor of about five in the peripheral cortex. Although the transmit profile with a circularly polarized transmit mode at 9.4T is relatively inhomogeneous over the large sample, this challenge was successfully resolved with parallel transmit using the kT-points method. Using this setup, we achieved 60µm anatomical images for the entire occipital lobe showing increased spatial definition of cortical details compared to lower resolutions. In addition, we were able to achieve sufficient control over SNR, B0 and B1 homogeneity and multi-contrast sampling to perform quantitative T2* mapping over the same volume at 200µm. Markov Chain Monte Carlo sampling provided maximum posterior estimates of quantitative T2* and their uncertainty, allowing delineation of the stria of Gennari over the entire length and width of the calcarine sulcus. We discuss how custom RF receive coil arrays built to specific large post mortem sample sizes can provide a platform for UHF cortical layer-specific quantitative MRI over large fields of view.

The DizzyQuest: relation between self-reported hearing loss, tinnitus and objective hearing thresholds in patients with Meniere's disease.

BACKGROUND: Combining a mobile application-based vestibular diary called the DizzyQuest and an iPad-based hearing test enables evaluation of the relationship between experienced neuro-otological symptoms and hearing thresholds in daily life setting. The aim was to investigate the relationship between self-reported hearing symptoms and hearing thresholds in patients with Meniere's disease (MD), using the DizzyQuest and the iPad-based hearing test simultaneously. METHODS: The DizzyQuest was administered for 3 weeks in 21 patients. Using the experience-sampling-method (ESM), it assessed hearing loss and tinnitus severity for both ears separately. Each day after the DizzyQuest, an iPad-based hearing test was used to measure hearing thresholds. A mixed model regression analysis was performed to investigate relationships between hearing thresholds and self-reported hearing loss and tinnitus severity. RESULTS: Fifteen patients were included. Overall, pure-tone averages (PTAs) were not correlated with self-reported hearing loss severity and tinnitus. Individual differences in PTA results between both ears did not significantly influence the difference in self-reported hearing loss severity between both ears. Self-reported hearing loss and tinnitus scores were significantly higher in ears that corresponded with audiometric criteria of MD (p < 0.001). Self-reported tinnitus severity significantly increased with self-reported hearing loss severity in affected (p = 0.011) and unaffected ears (p < 0.001). CONCLUSION: Combining the DizzyQuest and iPad-based hearing test, facilitated assessment of self-reported hearing loss and tinnitus severity and their relationship with hearing thresholds, in a daily life setting. This study illustrated the importance of investigating neuro-otological symptoms at an individual level, using multiple measurements. ESM strategies like the DizzyQuest should therefore be considered in neuro-otological research.

Relative resistance to HIV-1 infection of CD4 lymphocytes from persons who remain uninfected despite multiple high-risk sexual exposure.

Some individuals remain uninfected with human immunodeficiency virus type-1 (HIV-1) despite multiple high-risk sexual exposures. We studied a cohort of 25 subjects with histories of multiple high-risk sexual exposures to HIV-1 and found that their CD8+ lymphocytes had greater anti-HIV-1 activity than did CD8+ lymphocytes from nonexposed controls. Further studies indicated that their purified CD4+ lymphocytes were less susceptible to infection with multiple primary isolates of HIV-1 than were CD4+ lymphocytes from the nonexposed controls. This relative resistance to HIV-1 infection did not extend to T-cell line-adapted strains, was restricted by the envelope glycoprotein, was not explained by the cell surface density of CD4 molecules, but was associated with the activity of the C-C chemokines RANTES, MIP-1alpha, and MIP-1beta. This relative resistance of CD4+ lymphocytes may contribute to protection from HIV-1 in multiply exposed persons.

Rapid microscopic fractional anisotropy imaging via an optimized linear regression formulation.

Water diffusion anisotropy in the human brain is affected by disease, trauma, and development. Microscopic fractional anisotropy (µFA) is a diffusion MRI (dMRI) metric that can quantify water diffusion anisotropy independent of neuron fiber orientation dispersion. However, there are several different techniques to estimate µFA and few have demonstrated full brain imaging capabilities within clinically viable scan times and resolutions. Here, we present an optimized spherical tensor encoding (STE) technique to acquire µFA directly from the 2nd order cumulant expansion of the powder averaged dMRI signal obtained from direct linear regression (i.e. diffusion kurtosis) which requires fewer powder-averaged signals than other STE fitting techniques and can be rapidly computed. We found that the optimal dMRI parameters for white matter µFA imaging were a maximum b-value of 2000 s/mm2 and a ratio of STE to LTE tensor encoded acquisitions of 1.7 for our system specifications. We then compared two implementations of the direct regression approach to the well-established gamma model in 4 healthy volunteers on a 3 Tesla system. One implementation used mean diffusivity (D) obtained from a 2nd order fit of the cumulant expansion, while the other used a linear estimation of D from the low b-values. Both implementations of the direct regression approach showed strong linear correlations with the gamma model (ρ = 0.97 and ρ = 0.90) but mean biases of -0.11 and - 0.02 relative to the gamma model were also observed, respectively. All three µFA measurements showed good test-retest reliability (ρ ≥ 0.79 and bias = 0). To demonstrate the potential scan time advantage of the direct approach, 2 mm isotropic resolution µFA was demonstrated over a 10 cm slab using a subsampled data set with fewer powder-averaged signals that would correspond to a 3.3-min scan. Accordingly, our results introduce an optimization procedure that has enabled nearly full brain µFA in only several minutes.

Spontaneous and deliberate creative cognition during and after psilocybin exposure.

Creativity is an essential cognitive ability linked to all areas of our everyday functioning. Thus, finding a way to enhance it is of broad interest. A large number of anecdotal reports suggest that the consumption of psychedelic drugs can enhance creative thinking; however, scientific evidence is lacking. Following a double-blind, placebo-controlled, parallel-group design, we demonstrated that psilocybin (0.17 mg/kg) induced a time- and construct-related differentiation of effects on creative thinking. Acutely, psilocybin increased ratings of (spontaneous) creative insights, while decreasing (deliberate) task-based creativity. Seven days after psilocybin, number of novel ideas increased. Furthermore, we utilized an ultrahigh field multimodal brain imaging approach, and found that acute and persisting effects were predicted by within- and between-network connectivity of the default mode network. Findings add some support to historical claims that psychedelics can influence aspects of the creative process, potentially indicating them as a tool to investigate creativity and subsequent underlying neural mechanisms. Trial NL6007; psilocybin as a tool for enhanced cognitive flexibility; https://www.trialregister.nl/trial/6007 .

Spontaneous internalization of Class I major histocompatibility complex molecules in T lymphoid cells.

A low proportion of T lymphocytes in normal mouse spleen contains small intracytoplasmic vesicles showing Class I MHC molecules. After stimulation in vitro in a mixed lymphocyte reaction or by addition of Con A, the proportion of T cells with such intracytoplasmic vesicles increases progressively and becomes the majority. Labeling with fluorochrome-conjugated antibodies has shown that the vesicles are formed by internalization of molecules from the plasma membrane. The process is spontaneous and does not require cross-linking by antibodies or other ligands; it is selective inasmuch as other molecules (Thy-1 and T200 antigens) are not included and it is specific since it is not performed by other cells such as B lymphoid cells or fibroblasts. On the whole the process shows similarities with the internalization and recycling of other receptors, such as the receptors for different macromolecules of metabolic or informational significance, as seen in other cells. On the other hand, the specificity of Class I MHC mobilization in T lymphoid cells suggest a role for this process which is related to the immune function of these molecules.

Production of autoantibodies by CD5-expressing B lymphocytes from patients with chronic lymphocytic leukemia.

CD5-expressing B lymphocytes from patients with selected chronic lymphoproliferative disorders were used to determine whether monoclonal populations of CD5+ human B cells produce autoantibodies. CD5+ B cells from 19 patients with chronic lymphocytic leukemia (CLL) and one with diffuse well-differentiated lymphocytic lymphoma (DWDL) were cultured, with and without mitogenic stimulation, to obtain Ig from these cells. 17 of the 20 samples produced Ig in vitro. mAb from nine of the 17 patients were reactive with either IgG, ssDNA, or dsDNA. In every instance, the autoantibodies displayed monotypic L chain usage that correlated precisely with the L chain expressed on the CD5+ leukemic B cell surface. These monoclonal autoantibodies varied in their degree of antigenic specificity; some were quite specific, reacting with only one antigen, whereas others were polyspecific, reacting with two or all three autoantigens tested. Three features distinguish these autoantibodies from those observed in prior studies of CD5+ B cells. First, they are clearly the products of monoclonal populations of CD5+ cells; second, several react with dsDNA, a specificity not previously reported and often seen in association with significant autoimmune disorders; and third, two of the monoclonal autoantibodies secreted by the CD5+ clones were of the IgG class. Although not all of the Ig-producing, CD5-expressing clones elaborated mAbs reactive with the autoantigens tested, greater than 50% did. It is possible that with a broader autoantigenic panel or with larger quantities of CLL/DWDL-derived Ig, even more autoantibody-producing clones might be identified. These studies may have important implications for the antigenic specificity of subsets of human B lymphocytes as well as for lymphoproliferative and autoimmune disorders in general.

A rare combination of recurrent pneumonia, diarrhoea, and visual loss in a patient after thymectomy: good syndrome.

This report describes a 68-year-old Chinese man who was diagnosed with Good syndrome 6 years after initial presentation when he underwent thymectomy. He presented with recurrent pneumonia, diarrhoea, weight loss, and visual symptoms. Extensive examination for anaemia and neutropenia was done, yet no conclusive diagnosis could be derived. During his last admission for pneumonia, his history of AB thymoma suggested the possibility of Good syndrome. Immunological testing revealed low T cells, absent B cells, and low immunoglobulin M and immunoglobulin G levels. Moreover, he had histologically identified cytomegalovirus pneumonia, cytomegalovirus colitis, and fundoscopic features of cytomegalovirus retinitis. He was treated with a 2-week course of intravenous ganciclovir, lifelong oral valganciclovir, and monthly immunoglobulin infusion. It took 6 years for the diagnosis to be established, therefore, early attention and vigorous search for such potentially treatable conditions in post-thymectomy patients presenting with recurrent infections is recommended.

Me, myself, bye: regional alterations in glutamate and the experience of ego dissolution with psilocybin.

There is growing interest in the therapeutic utility of psychedelic substances, like psilocybin, for disorders characterized by distortions of the self-experience, like depression. Accumulating preclinical evidence emphasizes the role of the glutamate system in the acute action of the drug on brain and behavior; however this has never been tested in humans. Following a double-blind, placebo-controlled, parallel group design, we utilized an ultra-high field multimodal brain imaging approach and demonstrated that psilocybin (0.17 mg/kg) induced region-dependent alterations in glutamate, which predicted distortions in the subjective experience of one's self (ego dissolution). Whereas higher levels of medial prefrontal cortical glutamate were associated with negatively experienced ego dissolution, lower levels in hippocampal glutamate were associated with positively experienced ego dissolution. Such findings provide further insights into the underlying neurobiological mechanisms of the psychedelic, as well as the baseline, state. Importantly, they may also provide a neurochemical basis for therapeutic effects as witnessed in ongoing clinical trials.

Intracellular accumulation of T-cell receptor complex molecules in a human T-cell line.

This work was aimed at understanding the mechanisms of T-lymphocyte function by studying the cellular distribution and traffic of molecules of the T-cell receptor complex. The accumulation of specific molecules in intracytoplasmic vesicles is related to the activation of T lymphocytes. Some of these molecules include acid hydrolases, the transferrin receptor, and class I antigens of the major histocompatibility complex. Molecules of the T-cell receptor complex have now also been found in intracytoplasmic vesicles in a human T-cell line derived from a lymphoblastic leukemia. Such vesicles were tightly associated with the cytoplasmic microtubule network. One functional aspect of this association is a cellular pathway by which vesicles traveling to and from the cell surface converge in an area of the cells that is rich in processing enzymes.

Symptom burden and quality of life in end-stage renal disease: a study of 179 patients on dialysis and palliative care.

Palliative care for end-stage renal disease (ESRD) is developing in Hong Kong. This is the first local study to explore the symptom burden and quality of life (QOL) of ESRD patients on chronic dialysis and palliative care. This was a prospective cross-sectional study conducted on ESRD patients in a hospital in Hong Kong from January 2006 to April 2007. Data collected included demographics, socioeconomic status, modified Charlson Comorbidity Index (CCI), prevalence and intensity of 23 ESRD-related symptoms as rated by numerical rating scale (0-10), Brief Pain Inventory and QOL by MOS SF-36. A total of 179 ESRD patients completed the study; 45 patients (25.1%) were in the palliative care group and 134 patients (74.9%) in the dialysis group. The palliative care group were older (73.1 +/- 7.1 vs 58.2 +/- 11.4 years, P < 0.001), had marginally higher modified CCI (8.5 +/- 1.9 vs 6.1 +/- 2.4, P = 0.05), had more diabetics (62.2 vs 35.8%, P < 0.001) and were of poorer socioeconomic status than the dialysis group. The mean number of symptoms was 8.2 +/- 3.9 and 9.3 +/- 4.7 in the palliative care and the dialysis group, respectively (P = NS). Fatigue, cold aversion, pruritus, lower torso weakness and difficulty sleeping were the five most prevalent symptoms in both groups, and were also among the most intense symptoms. QOL was significantly impaired in both groups. Scores of all QOL domains correlated negatively with the number of symptoms (P < 0.001). Our ESRD patients under palliative care and dialysis had overlapping symptom prevalence and intensity, significant symptom burden and impaired QOL.

Acute angle closure glaucoma following head and orbital trauma.

The case is reported of a 52-year-old woman who suffered a minor head injury and orbital trauma and returned 2 days later with a unilateral headache, vomiting and photophobia. This was initially thought to be secondary to her head injury but, once severe visual impairment and a dilated unreactive pupil developed, the true diagnosis became obvious. A diagnosis of acute angle closure glaucoma was made and she was treated with no complications. This case highlights acute angle closure glaucoma as an important diagnosis to consider in patients who present with unilateral headache and dilated pupil after head injury.

Competence of final year otolaryngology residents with the bedside head impulse test.

BACKGROUND: The bedside head impulse test (bHIT) is a clinical method of assessing the vestibulo-ocular reflex (VOR). It is a critical component of the bedside assessment of dizzy patients, and can help differentiate acute stroke from vestibular neuritis. However, there is evidence showing the bHIT is often not performed in appropriate clinical settings or is performed poorly. To date, there have been no studies evaluating the bHIT competence of graduating physicians. METHODS: 23 final year Otolaryngology -Head &Neck Surgery (OTL-HNS) residents in Canada were evaluated on the use of bHIT using a written multiple-choice examination, interpretation of bHIT videos, and performance of a bHIT. Ratings of subject bHIT performance were completed by two expert examiners (DT, DL) using the previously published Ottawa Clinic Assessment Tool (OCAT). RESULTS: Using a cut-off of an OCAT score of 4 or greater, only 22% (rater DT) and 39% (rater DL) of residents were found able to perform the bHIT independently. Inter-rater reliability was fair (0.51, interclass correlation). The mean scores were 65% (14.1% standard deviation) on the video interpretation and 71% (20.2% standard deviation) on the multiple-choice questions. The scores on multiple choice examination did not correlate with bHIT ratings (Pearson r = 0.07) but there was fair correlation between video interpretation and bHIT ratings (Pearson r = 0.45). CONCLUSION: Final year OTL-HNS residents in Canada are not adequately trained in performing the bHIT, though low interrater reliability may limit the evaluation of this bedside skill. Multiple choice examinations do not reflect bHIT skill. These findings have implications for development of competency-based curricula and evaluations in Canada in critical physical exam skills.

Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial.

BACKGROUND: Laser treatment for diabetic retinopathy is often associated with visual field reduction and other ocular side-effects. Our aim was to assess whether long-term lipid-lowering therapy with fenofibrate could reduce the progression of retinopathy and the need for laser treatment in patients with type 2 diabetes mellitus. METHODS: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a multinational randomised trial of 9795 patients aged 50-75 years with type 2 diabetes mellitus. Eligible patients were randomly assigned to receive fenofibrate 200 mg/day (n=4895) or matching placebo (n=4900). At each clinic visit, information concerning laser treatment for diabetic retinopathy-a prespecified tertiary endpoint of the main study-was gathered. Adjudication by ophthalmologists masked to treatment allocation defined instances of laser treatment for macular oedema, proliferative retinopathy, or other eye conditions. In a substudy of 1012 patients, standardised retinal photography was done and photographs graded with Early Treatment Diabetic Retinopathy Study (ETDRS) criteria to determine the cumulative incidence of diabetic retinopathy and its component lesions. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN64783481. FINDINGS: Laser treatment was needed more frequently in participants with poorer glycaemic or blood pressure control than in those with good control of these factors, and in those with a greater burden of clinical microvascular disease, but the need for such treatment was not affected by plasma lipid concentrations. The requirement for first laser treatment for all retinopathy was significantly lower in the fenofibrate group than in the placebo group (164 [3.4%] patients on fenofibrate vs 238 [4.9%] on placebo; hazard ratio [HR] 0.69, 95% CI 0.56-0.84; p=0.0002; absolute risk reduction 1.5% [0.7-2.3]). In the ophthalmology substudy, the primary endpoint of 2-step progression of retinopathy grade did not differ significantly between the two groups overall (46 [9.6%] patients on fenofibrate vs 57 [12.3%] on placebo; p=0.19) or in the subset of patients without pre-existing retinopathy (43 [11.4%] vs 43 [11.7%]; p=0.87). By contrast, in patients with pre-existing retinopathy, significantly fewer patients on fenofibrate had a 2-step progression than did those on placebo (three [3.1%] patients vs 14 [14.6%]; p=0.004). An exploratory composite endpoint of 2-step progression of retinopathy grade, macular oedema, or laser treatments was significantly lower in the fenofibrate group than in the placebo group (HR 0.66, 95% CI 0.47-0.94; p=0.022). INTERPRETATION: Treatment with fenofibrate in individuals with type 2 diabetes mellitus reduces the need for laser treatment for diabetic retinopathy, although the mechanism of this effect does not seem to be related to plasma concentrations of lipids.