Pre-treatment loss to follow-up in adults with pulmonary TB in Kenya.

SETTING: County referral hospital in western Kenya. OBJECTIVES: To ascertain the proportion of pre-treatment loss to follow-up (PTLFU) and associated patient factors in adults with pulmonary TB (PTB) in western Kenya. DESIGN: A retrospective data review of laboratory and treatment registers for adults with bacteriologically confirmed PTB between January 2018 to December 2021. We defined PTLFU as failure to initiate treatment within 14 days of diagnosis. We used multivariable logistic regression modelling to identify patient factors associated with PTLFU. RESULTS: Of 476 patients with PTB, 67.2% were male; the mean age was 36.1 years; 37.0% were HIV-positive; 5.7% had a history of anti-TB treatment; 40.6% were not traceable in the treatment register; 202 (42.4%, 95% CI 38.1-46.9) experienced PTLFU. Age ≥55 years (aOR 2.6, 95% CI 1.0-6.7) and providing only an address (aOR 34.2, 95% CI 18.7-62.5) or only a telephone contact number (aOR 22.3, 95% CI 3.5-141.1) were associated with PTLFU. Sex, HIV status, history of anti-TB treatment and place of residence were not associated with PTLFU. CONCLUSION: PTLFU contributes markedly to TB patient losses in western Kenya. Strengthening systems for documenting patient information and actively monitoring PTLFU are crucial for attrition reduction.

CONTEXTE: Hôpital de référence du comté dans l'ouest du Kenya. OBJECTIFS: Vérifier la proportion de perte de suivi avant traitement (PTLFU) et les facteurs de patients associés chez les adultes atteints de TB pulmonaire (PTB) dans l'ouest du Kenya. DESIGN: Un examen rétrospectif des données des registres de laboratoire et de traitement pour les adultes atteints de PTB confirmée bactériologiquement entre janvier 2018 et décembre 2021. Nous avons défini le PTLFU comme l'incapacité à initier un traitement dans les 14 jours suivant le diagnostic. Nous avons utilisé un modèle de régression logistique multivariable pour identifier les facteurs des patients associés au PTLFU. RÉSULTATS: Sur 476 patients atteints de PTB, 67,2% étaient des hommes ; l'âge moyen était de 36,1 ans ; 37,0% étaient séropositifs ; 5,7% avaient des antécédents de traitement antituberculeux ; 40,6% n'étaient pas traçables dans le registre des traitements ; 202 (42,4% ; IC 95% 38,1­46,9) ont subi un PTLFU. L'âge ≥55 ans (aOR 2,6 ; 95% CI 1,0­6,7) et le fait de ne fournir qu'une adresse (aOR 34,2 ; 95% CI 18,7­62,5) ou qu'un numéro de téléphone (aOR 22,3 ; 95% CI 3,5­141,1) étaient associés à la PTLFU. Le sexe, le statut VIH, les antécédents de traitement antituberculeux et le lieu de résidence n'étaient pas associés à la PTLFU. CONCLUSION: La PTLFU contribue de manière significative aux pertes de patients tuberculeux dans l'ouest du Kenya. Le renforcement des systèmes de documentation des informations sur les patients et le suivi actif de la PTLFU sont essentiels pour réduire l'attrition.

Impact of untreated preoperative asymptomatic bacteriuria in patients undergoing holmium laser enucleation of prostate.

INTRODUCTION: Treatment of preoperative asymptomatic bacteriuria (ASB) before endoscopic surgery is recommended by European Association of Urology (EAU) guidelines. United Kingdom (UK) practice varies, however, owing to the historical nature of the evidence behind the guidelines, risk of increased antimicrobial resistance, the paradoxical view that treatment of ASB leads to increased infection and inefficiencies in rescheduling. We do not routinely treat ASB in our practice before holmium enucleation of the prostate (HoLEP). To determine the safety of this, we examined our experience focusing on the infective complications. METHODS: Retrospective data collection was performed on consecutive patients undergoing HoLEP between 2015 and 2020. Indication, preoperative urine cultures and infective complications were recorded. No patients were pretreated with oral antibiotics. All patients received intravenous antibiotics on induction and routine postoperative oral antibiotics at the surgeon's discretion. RESULTS: Some 443 patients were studied. No urosepsis occurred in the 125 patients with ASB compared with 2 of 318 patients (0.6%) with no growth on preoperative urine culture. Twenty-nine (7%) patients were treated with oral antibiotics for symptomatic postoperative complications (urinary tract infection without fever, epididymitis and haematuria). ASB did not predict for infective complications (urosepsis odds ratio [OR]: 0.50 p=0.66; oral antibiotics OR: 0.97 p=0.93). CONCLUSION: Not treating ASB before a HoLEP procedure is safe. This supports the judicious use of antimicrobials preoperatively. Other modalities of endoscopic surgery should be similarly assessed.

MINocyclinE to Reduce inflammation and blood-brain barrier leakage in small Vessel diseAse (MINERVA): A phase II, randomized, double-blind, placebo-controlled experimental medicine trial.

INTRODUCTION: Cerebral small vessel disease (SVD) is a common cause of stroke/vascular dementia with few effective treatments. Neuroinflammation and increased blood-brain barrier (BBB) permeability may influence pathogenesis. In rodent models, minocycline reduced inflammation/BBB permeability. We determined whether minocycline had a similar effect in patients with SVD. METHODS: MINERVA was a single-center, phase II, randomized, double-blind, placebo-controlled trial. Forty-four participants with moderate-to-severe SVD took minocycline or placebo for 3 months. Co-primary outcomes were microglial signal (determined using 11C-PK11195 positron emission tomography) and BBB permeability (using dynamic contrast-enhanced MRI). RESULTS: Forty-four participants were recruited between September 2019 and June 2022. Minocycline had no effect on 11C-PK11195 binding (relative risk [RR] 1.01, 95% confidence interval [CI] 0.98-1.04), or BBB permeability (RR 0.97, 95% CI 0.91-1.03). Serum inflammatory markers were not affected. DISCUSSION: 11C-PK11195 binding and increased BBB permeability are present in SVD; minocycline did not reduce either process. Whether these pathophysiological mechanisms are disease-causing remains unclear. INTERNATIONAL CLINICAL TRIALS REGISTRY PORTAL IDENTIFIER: ISRCTN15483452 HIGHLIGHTS: We found focal areas of increased microglial signal and increased blood-brain barrier permeability in patients with small vessel disease. Minocycline treatment was not associated with a change in these processes measured using advanced neuroimaging. Blood-brain barrier permeability was dynamic but MRI-derived measurements correlated well with CSF/serum albumin ratio. Advanced neuroimaging is a feasible outcome measure for mechanistic clinical trials.

Differential Synaptic Loss in ß-Amyloid Positive Versus ß-Amyloid Negative Corticobasal Syndrome.

BACKGROUND/OBJECTIVE: The corticobasal syndrome (CBS) is a complex asymmetric movement disorder, with cognitive impairment. Although commonly associated with the primary 4-repeat-tauopathy of corticobasal degeneration, clinicopathological correlation is poor, and a significant proportion is due to Alzheimer's disease (AD). Synaptic loss is a pathological feature of many clinical and preclinical tauopathies. We therefore measured the degree of synaptic loss in patients with CBS and tested whether synaptic loss differed according to ß-amyloid status. METHODS: Twenty-five people with CBS, and 32 age-/sex-/education-matched healthy controls participated. Regional synaptic density was estimated by [11C]UCB-J non-displaceable binding potential (BPND), AD-tau pathology by [18F]AV-1451 BPND, and gray matter volume by T1-weighted magnetic resonance imaging. Participants with CBS had ß-amyloid imaging with 11C-labeled Pittsburgh Compound-B ([11C]PiB) positron emission tomography. Symptom severity was assessed with the progressive supranuclear palsy-rating-scale, the cortical basal ganglia functional scale, and the revised Addenbrooke's Cognitive Examination. Regional differences in BPND and gray matter volume between groups were assessed by ANOVA. RESULTS: Compared to controls, patients with CBS had higher [18F]AV-1451 uptake, gray matter volume loss, and reduced synaptic density. Synaptic loss was more severe and widespread in the ß-amyloid negative group. Asymmetry of synaptic loss was in line with the clinically most affected side. DISCUSSION: Distinct patterns of [11C]UCB-J and [18F]AV-1451 binding and gray matter volume loss, indicate differences in the pathogenic mechanisms of CBS according to whether it is associated with the presence of Alzheimer's disease or not. This highlights the potential for different therapeutic strategies in CBSs. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Are central and systemic inflammation associated with fatigue in cerebral small vessel disease?

BACKGROUND: Fatigue is a common symptom in cerebral small vessel disease (SVD), but its pathogenesis is poorly understood. It has been suggested that inflammation may play a role. We determined whether central (neuro) inflammation and peripheral inflammation were associated with fatigue in SVD. METHODS: Notably, 36 patients with moderate-to-severe SVD underwent neuropsychometric testing, combined positron emission tomography and magnetic resonance imaging (PET-MRI) scan, and blood draw for the analysis of inflammatory blood biomarkers. Microglial signal was taken as a proxy for neuroinflammation, assessed with radioligand 11C-PK11195. Of these, 30 subjects had full PET datasets for analysis. We assessed global 11C-PK11195 binding and hotspots of 11C-PK11195 binding in the normal-appearing white matter, lesioned tissue, and combined total white matter. Peripheral inflammation was assessed with serum C-reactive protein (CRP) and using the Olink cardiovascular III proteomic panel comprising 92 biomarkers of cardiovascular inflammation and endothelial activation. Fatigue was assessed using the fatigue severity scale (FSS), the visual analog fatigue scale, and a subscale of the Geriatric Depression Scale. RESULTS: Mean (SD) age was 68.7 (11.2) years, and 63.9% were male. Of these, 55.6% showed fatigue on the FSS. Fatigued participants had higher disability scores (p = 0.02), higher total GDS scores (p = 0.02), and more commonly reported a history of depression (p = 0.04). 11C-PK11195 ligand binding in the white matter was not associated with any measure of fatigue. Serum CRP was significantly associated with average fatigue score on FSS (ρ = 0.48, p = 0.004); this association persisted when controlling for age, sex, disability score, and depression (ß = 0.49, 95% CI (0.17, 2.26), p = 0.03). Blood biomarkers from the Olink panel showed no association with fatigue. CONCLUSION: In symptomatic SVD patients, neuroinflammation, assessed with microglial marker 11C-PK11195, was not associated with fatigue. We found some evidence for a role of systematic inflammation, evidenced by an association between fatigue severity and raised CRP, but further studies are required to understand this relationship and inform whether it could be therapeutically modified to reduce fatigue severity. DATA ACCESS STATEMENT: Data for this study are available from the corresponding author upon reasonable request.

Rare high branching pattern from the first part of the right axillary artery.

A 77-year-old female cadaver was observed to have a rare branching pattern of the right axillary artery (AA). The first part of the AA typically gives off only a superior thoracic artery (STA) but was observed to give off three branches in the case: a lateral thoracic artery (LTA), a thoracoacromial trunk, and a large common trunk (CT). The LTA travelled to provide a variant STA to the 1st and 2nd intercostal spaces. The CT provided an accessory LTA and accessory thoracodorsal artery before bifurcating into a subscapular artery (SA) and posterior humeral circumflex artery. As expected, the SA further divided into the circumflex scapular artery and thoracodorsal artery. A pectoral artery and the anterior humeral circumflex artery originated directly from the second and third parts of the AA, respectively. Knowledge of AA branching variations is of great clinical significance to anatomists, radiologists, and surgeons due to the high rate of injury to this artery.

Neuroinflammation is linked to dementia risk in Parkinson's disease.

The development of dementia is a devastating aspect of Parkinson's disease (PD), affecting nearly half of patients within 10 years post-diagnosis. For effective therapies to prevent and slow progression to PD dementia (PDD), the key mechanisms that determine why some people with PD develop early dementia, while others remain cognitively unaffected, need to be understood. Neuroinflammation and tau protein accumulation have been demonstrated in post-mortem PD brains, and in many other neurodegenerative disorders leading to dementia. However, whether these processes mediate dementia risk early on in the PD disease course is not established. To this end, we used PET neuroimaging with 11C-PK11195 to index neuroinflammation and 18F-AV-1451 for misfolded tau in early PD patients, stratified according to dementia risk in our 'Neuroinflammation and Tau Accumulation in Parkinson's Disease Dementia' (NET-PDD) study. The NET-PDD study longitudinally assesses newly-diagnosed PD patients in two subgroups at low and high dementia risk (stratified based on pentagon copying, semantic fluency, MAPT genotype), with comparison to age- and sex-matched controls. Non-displaceable binding potential (BPND) in 43 brain regions (Hammers' parcellation) was compared between groups (pairwise t-tests), and associations between BPND of the tracers tested (linear-mixed-effect models). We hypothesized that people with higher dementia risk have greater inflammation and/or tau accumulation in advance of significant cognitive decline. We found significantly elevated neuroinflammation (11C-PK11195 BPND) in multiple subcortical and restricted cortical regions in the high dementia risk group compared with controls, while in the low-risk group this was limited to two cortical areas. The high dementia risk group also showed significantly greater neuroinflammation than the low-risk group concentrated on subcortical and basal ganglia regions. Neuroinflammation in most of these regions was associated with worse cognitive performance (Addenbrooke's Cognitive Examination-III score). Overall neuroinflammation burden also correlated with serum levels of pro-inflammatory cytokines. In contrast, increases in 18F-AV-1451 (tau) BPND in PD versus controls were restricted to subcortical regions where off-target binding is typically seen, with no relationship to cognition found. Whole-brain 18F-AV-1451 burden correlated with serum phosphorylated tau181 levels. Although there was minimal regional tau accumulation in PD, regional neuroinflammation and tau burden correlated in PD participants, with the strongest association in the high dementia risk group, suggesting possible co-localization of these pathologies. In conclusion, our findings suggest that significant regional neuroinflammation in early PD might underpin higher risk for PDD development, indicating neuroinflammation as a putative early modifiable aetiopathological disease factor to prevent or slow dementia development using immunomodulatory strategies.

Synaptic density affects clinical severity via network dysfunction in syndromes associated with frontotemporal lobar degeneration.

There is extensive synaptic loss from frontotemporal lobar degeneration, in preclinical models and human in vivo and post mortem studies. Understanding the consequences of synaptic loss for network function is important to support translational models and guide future therapeutic strategies. To examine this relationship, we recruited 55 participants with syndromes associated with frontotemporal lobar degeneration and 24 healthy controls. We measured synaptic density with positron emission tomography using the radioligand [11C]UCB-J, which binds to the presynaptic vesicle glycoprotein SV2A, neurite dispersion with diffusion magnetic resonance imaging, and network function with task-free magnetic resonance imaging functional connectivity. Synaptic density and neurite dispersion in patients was associated with reduced connectivity beyond atrophy. Functional connectivity moderated the relationship between synaptic density and clinical severity. Our findings confirm the importance of synaptic loss in frontotemporal lobar degeneration syndromes, and the resulting effect on behaviour as a function of abnormal connectivity.

Development and psychometric evaluation of item banks for memory and attention - supplements to the EORTC CAT Core instrument.

BACKGROUND: Cancer patients may experience a decrease in cognitive functioning before, during and after cancer treatment. So far, the Quality of Life Group of the European Organisation for Research and Treatment of Cancer (EORTC QLG) developed an item bank to assess self-reported memory and attention within a single, cognitive functioning scale (CF) using computerized adaptive testing (EORTC CAT Core CF item bank). However, the distinction between different cognitive functions might be important to assess the patients' functional status appropriately and to determine treatment impact. To allow for such assessment, the aim of this study was to develop and psychometrically evaluate separate item banks for memory and attention based on the EORTC CAT Core CF item bank. METHODS: In a multistep process including an expert-based content analysis, we assigned 44 items from the EORTC CAT Core CF item bank to the memory or attention domain. Then, we conducted psychometric analyses based on a sample used within the development of the EORTC CAT Core CF item bank. The sample consisted of 1030 cancer patients from Denmark, France, Poland, and the United Kingdom. We evaluated measurement properties of the newly developed item banks using confirmatory factor analysis (CFA) and item response theory model calibration. RESULTS: Item assignment resulted in 31 memory and 13 attention items. Conducted CFAs suggested good fit to a 1-factor model for each domain and no violations of monotonicity or indications of differential item functioning. Evaluation of CATs for both memory and attention confirmed well-functioning item banks with increased power/reduced sample size requirements (for CATs ≥ 4 items and up to 40% reduction in sample size requirements in comparison to non-CAT format). CONCLUSION: Two well-functioning and psychometrically robust item banks for memory and attention were formed from the existing EORTC CAT Core CF item bank. These findings could support further research on self-reported cognitive functioning in cancer patients in clinical trials as well as for real-word-evidence. A more precise assessment of attention and memory deficits in cancer patients will strengthen the evidence on the effects of cancer treatment for different cancer entities, and therefore contribute to shared and informed clinical decision-making.

Health worker views on pre-treatment loss to follow-up in adults with pulmonary TB in Western Kenya.

SETTING: County referral hospital in Western Kenya. OBJECTIVES: To explore factors contributing to pre-treatment loss to follow-up (PTLFU) in adults with pulmonary TB and propose solutions to address PTLFU from healthcare worker (HCW) perspectives. DESIGN: This was an exploratory qualitative study using thematic analysis. RESULTS: We conducted 19 key informant interviews with HCWs representing laboratory, clinical care, management and the community. Participant age ranged from 26 to 62 years; 14 (74%) were females; and most (74%) had worked in TB care for ⩽5 years. They reported that patients experienced stigma and had misconceptions about TB that contributed to PTLFU. HCWs were hesitant to work in the TB clinic, which contributed to suboptimal patient care, leading to PTLFU. Unclear linkage between laboratory and clinician, and limited financial resources to track patients were among the healthcare system factors that led to PTLFU. HCWs suggested having proper patient preparation, assigning resources to track patients and holding regular interdisciplinary meetings as practical solutions to address PTLFU. CONCLUSION: HCWs reported multiple factors that may influence PTLFU and recommended various solutions to address these. Knowledge of TB management, patient preparation, resources to track patients and multidisciplinary meetings will be central to addressing PTLFU.

CONTEXTE: Hôpital de référence du comté dans l'ouest du Kenya. OBJECTIFS: Explorer les facteurs contribuant à la perte de suivi avant traitement (PTLFU) chez les adultes atteints de TB pulmonaire et proposer des solutions pour traiter la PTLFU du point de vue des travailleurs de la santé (HCW). MÉTHODE: Il s'agit d'une étude qualitative exploratoire utilisant l'analyse thématique. RÉSULTATS: Nous avons mené 19 entretiens avec des informateurs clés représentant les laboratoires, les soins cliniques, la gestion et la communauté. Les participants étaient âgés de 26 à 62 ans, 14 (74%) étaient des femmes et la plupart (74%) travaillaient dans le domaine de la TB depuis ⩽5 ans. Ils ont indiqué que les patients étaient stigmatisés et avaient des idées fausses sur la TB, ce qui contribuait à la PTLFU. Les HCW hésitaient à travailler dans la clinique de la TB, ce qui a contribué à une prise en charge sous-optimale des patients, conduisant à la PTLFU. Le manque de clarté du lien entre le laboratoire et le clinicien et les ressources financières limitées pour suivre les patients font partie des facteurs du système de santé qui ont conduit à la PTLFU. Les HCW ont suggéré de préparer correctement les patients, d'affecter des ressources au suivi des patients et d'organiser des réunions interdisciplinaires régulières comme solutions pratiques pour remédier à la PTLFU. CONCLUSION: Les HCW ont fait état de multiples facteurs susceptibles d'influencer la PTLFU et ont recommandé diverses solutions pour y remédier. La connaissance de la prise en charge de la TB, la préparation des patients, les ressources pour suivre les patients et les réunions multidisciplinaires seront essentielles pour traiter la PTLFU.

Longitudinal Synaptic Loss in Primary Tauopathies: An In Vivo [11 C]UCB-J Positron Emission Tomography Study.

BACKGROUND: Synaptic loss is characteristic of many neurodegenerative diseases; it occurs early and is strongly related to functional deficits. OBJECTIVE: In this longitudinal observational study, we determine the rate at which synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and we test the relationship with disease progression. METHODS: Our cross-sectional cohort included 32 participants with probable PSP and 16 with probable CBD (all amyloid-negative corticobasal syndrome), recruited from tertiary care centers in the United Kingdom, and 33 sex- and age-matched healthy control subjects. Synaptic density was estimated by positron emission tomography imaging with the radioligand [11 C]UCB-J that binds synaptic vesicle 2A. Clinical severity and cognition were assessed by the PSP Rating Scale and the Addenbrooke's cognitive examination. Regional [11 C]UCB-J nondisplaceable binding potential was estimated in Hammersmith Atlas regions of interest. Twenty-two participants with PSP/CBD had a follow-up [11 C]UCB-J positron emission tomography scan after 1 year. We calculated the annualized change in [11 C]UCB-J nondisplaceable binding potential and correlated this with the change in clinical severity. RESULTS: We found significant annual synaptic loss within the frontal lobe (-3.5%, P = 0.03) and the right caudate (-3.9%, P = 0.046). The degree of longitudinal synaptic loss within the frontal lobe correlated with the rate of change in the PSP Rating Scale (R = 0.47, P = 0.03) and cognition (Addenbrooke's Cognitive Examination-Revised, R = -0.62, P = 0.003). CONCLUSIONS: We provide in vivo evidence for rapid progressive synaptic loss, correlating with clinical progression in primary tauopathies. Synaptic loss may be an important therapeutic target and outcome variable for early-phase clinical trials of disease-modifying treatments. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Microglial activation in the frontal cortex predicts cognitive decline in frontotemporal dementia.

Frontotemporal dementia is clinically and neuropathologically heterogeneous, but neuroinflammation, atrophy and cognitive impairment occur in all of its principal syndromes. Across the clinical spectrum of frontotemporal dementia, we assess the predictive value of in vivo neuroimaging measures of microglial activation and grey-matter volume on the rate of future cognitive decline. We hypothesized that inflammation is detrimental to cognitive performance, in addition to the effect of atrophy. Thirty patients with a clinical diagnosis of frontotemporal dementia underwent a baseline multimodal imaging assessment, including [11C]PK11195 PET to index microglial activation and structural MRI to quantify grey-matter volume. Ten people had behavioural variant frontotemporal dementia, 10 had the semantic variant of primary progressive aphasia and 10 had the non-fluent agrammatic variant of primary progressive aphasia. Cognition was assessed at baseline and longitudinally with the revised Addenbrooke's Cognitive Examination, at an average of 7-month intervals (for an average of ∼2 years, up to ∼5 years). Regional [11C]PK11195 binding potential and grey-matter volume were determined, and these were averaged within four hypothesis-driven regions of interest: bilateral frontal and temporal lobes. Linear mixed-effect models were applied to the longitudinal cognitive test scores, with [11C]PK11195 binding potentials and grey-matter volumes as predictors of cognitive performance, with age, education and baseline cognitive performance as covariates. Faster cognitive decline was associated with reduced baseline grey-matter volume and increased microglial activation in frontal regions, bilaterally. In frontal regions, microglial activation and grey-matter volume were negatively correlated, but provided independent information, with inflammation the stronger predictor of the rate of cognitive decline. When clinical diagnosis was included as a factor in the models, a significant predictive effect was found for [11C]PK11195 BPND in the left frontal lobe (-0.70, P = 0.01), but not for grey-matter volumes (P > 0.05), suggesting that inflammation severity in this region relates to cognitive decline regardless of clinical variant. The main results were validated by two-step prediction frequentist and Bayesian estimation of correlations, showing significant associations between the estimated rate of cognitive change (slope) and baseline microglial activation in the frontal lobe. These findings support preclinical models in which neuroinflammation (by microglial activation) accelerates the neurodegenerative disease trajectory. We highlight the potential for immunomodulatory treatment strategies in frontotemporal dementia, in which measures of microglial activation may also improve stratification for clinical trials.

Do Regions of Increased Inflammation Progress to New White Matter Hyperintensities?: A Longitudinal Positron Emission Tomography-Magnetic Resonance Imaging Study.

BACKGROUND: Recent studies have demonstrated increased microglial activation using 11C-PK11195 positron emission tomography imaging, indicating central nervous system inflammation, in cerebral small vessel disease. However, whether such areas of neuroinflammation progress to tissue damage is uncertain. We determined whether white matter destined to become white matter hyperintensities (WMH) at 1 year had evidence of altered inflammation at baseline. METHODS: Forty subjects with small vessel disease (20 sporadic and 20 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and 20 controls were recruited to this case-control observational study from in- and out-patient clinics at Addenbrooke's Hospital, Cambridge, UK and imaged at baseline with both 11C-PK11195 positron emission tomography and magnetic resonance imaging; and magnetic resonance imaging including diffusion tensor imaging was repeated at 1 year. WMH were segmented at baseline and 1 year, and areas of new lesion identified. Baseline 11C-PK11195 binding potential and diffusion tensor imaging parameters in these voxels, and normal appearing white matter, was measured. RESULTS: Complete positron emission tomography-magnetic resonance imaging data was available for 17 controls, 16 sporadic small vessel disease, and 14 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy participants. 11C-PK11195 binding in voxels destined to become new WMH was lower than in normal appearing white matter, which did not progress to WMH (-0.133[±0.081] versus -0.045 [±0.044]; P<0.001). Mean diffusivity was higher and mean fractional anisotropy lower in new WMH voxels than in normal appearing white matter (900 [±80]×10-6 versus 1045 [±149]×10-6 mm2/s and 0.37±0.05 versus 0.29±0.06, both P<0.001) consistent with new WMH showing tissue damage on diffusion tensor imaging a year prior to developing into new WMH; similar results were seen across the 3 groups. CONCLUSIONS: White matter tissue destined to develop into new WMH over the subsequent year is associated with both lower neuroinflammation, and white matter ultrastructural damage at baseline. Our results suggest that this tissue is already damaged 1 year prior to lesion formation. This may reflect that the role of neuroinflammation in the lesion development process occurs at an early stage, although more studies over a longer period would be needed to investigate this further.

Assessment of cryogenic pretreatment for simulating environmental weathering in the formation of surrogate micro- and nanoplastics from agricultural mulch film.

Microplastics (MPs) and nanoplastics (NPs) from mulch films and other plastic materials employed in vegetable and small fruit production pose a major threat to agricultural ecosystems. For conducting controlled studies on MPs' and NPs' (MNPs') ecotoxicity to soil organisms and plants and fate and transport in soil, surrogate MNPs are required that mimic MNPs that form in agricultural fields. We have developed a procedure to prepare MPs from plastic films or pellets using mechanical milling and sieving, and conversion of the resultant MPs into NPs through wet grinding, both steps of which mimic the degradation and fragmentation of plastics in nature. The major goal of this study was to determine if cryogenic exposure of two biodegradable mulch films effectively mimics the embrittlement caused by environmental weathering in terms of the dimensional, thermal, chemical, and biodegradability properties of the formed MNPs. We found differences in size, surface charge, thermal and chemical properties, and biodegradability in soil between MNPs prepared from cryogenically treated vs. environmentally weathered films, related to the photochemical reactions occurring in the environment that were not mimicked by cryogenic treatment, such as depolymerization and cross-link formation. We also investigated the size reduction process for NPs and found that the size distribution was bimodal, with populations centered at 50 nm and 150-300 nm, and as the size reduction process progressed, the former subpopulation's proportion increased. The biodegradability of MPs in soil was greater than for NPs, a counter-intuitive trend since greater surface area exposure for NPs would increase biodegradability. The result isassociated with differences in surface and chemical properties and to minor components that are readily leached out during the formation of NPs. In summary, the use of weathered plastics as feedstock would likely produce MNPs that are more realistic than cryogenically-treated unweathered films for use in experimental studies.

Patient-reported outcome measures for physical function in cancer patients: content comparison of the EORTC CAT Core, EORTC QLQ-C30, SF-36, FACT-G, and PROMIS measures using the International Classification of Functioning, Disability and Health.

BACKGROUND: Patient-reported physical function (PF) is a key endpoint in cancer clinical trials. Using complex statistical methods, common metrics have been developed to compare scores from different patient-reported outcome (PRO) measures, but such methods do not account for possible differences in questionnaire content. Therefore, the aim of our study was a content comparison of frequently used PRO measures for PF in cancer patients. METHODS: Relying on the framework of the International Classification of Functioning, Disability and Health (ICF) we categorized the item content of the physical domains of the following measures: EORTC CAT Core, EORTC QLQ-C30, SF-36, PROMIS Cancer Item Bank for Physical Function, PROMIS Short Form for Physical Function 20a, and the FACT-G. Item content was linked to ICF categories by two independent reviewers. RESULTS: The 118 items investigated were assigned to 3 components ('d - Activities and Participation', 'b - Body Functions', and 'e - Environmental Factors') and 11 first-level ICF categories. All PF items of the EORTC measures but one were assigned to the first-level ICF categories 'd4 - Mobility' and 'd5 - Self-care', all within the component 'd - Activities and Participation'. The SF-36 additionally included item content related to 'd9 - Community, social and civic life' and the PROMIS Short Form for Physical Function 20a also included content related to 'd6 - domestic life'. The PROMIS Cancer Item Bank (v1.1) covered, in addition, two first-level categories within the component 'b - Body Functions'. The FACT-G Physical Well-being scale was found to be the most diverse scale with item content partly not covered by the ICF framework. DISCUSSION: Our results provide information about conceptual differences between common PRO measures for the assessment of PF in cancer patients. Our results complement quantitative information on psychometric characteristics of these measures and provide a better understanding of the possibilities of establishing common metrics.

The "new" oligometastatic disease state and associated therapies in non-small cell lung cancer: A narrative review.

Patients with non-small cell lung cancer (NSCLC) at stage IV have typically been considered incurable. Nonetheless, there is growing evidence that certain patient groups with fewer metastases, or so-called oligometastatic disease, which may have a more indolent biological nature than widespread metastatic diseases, may survive longer if definitive local treatment is administered to all metastatic sites. According to several retrospective investigations, this subgroup had a better prognosis than other stage IV patients, and the eighth edition of TNM staging was revised to reflect these findings. As a result of rapidly emerging systemic therapies, such as immune checkpoint inhibitors and a growing number of targeted therapies, more patients with this uncommon clinical opportunity have been identified and have received greater clinical attention. Currently, there is no established protocol for the management of oligometastatic disease, and the majority of therapeutic decisions are made through multidisciplinary discussion. In addition to systemic treatment, the two primary local therapeutic options for oligometastatic diseases are surgery and radiotherapy. A few phase 2 trials suggest that aggressive local ablative therapy may significantly improve the prognosis of patients with oligometastatic NSCLC. This review summarizes the most recent data on the management of oligometastatic NSCLC, with a focus on the prognostic significance of local ablative therapy in these patients.

Synaptic Loss in Frontotemporal Dementia Revealed by [11 C]UCB-J Positron Emission Tomography.

OBJECTIVE: Synaptic loss is an early feature of neurodegenerative disease models, and is severe in post mortem clinical studies, including frontotemporal dementia. Positron emission tomography (PET) with radiotracers that bind to synaptic vesicle glycoprotein 2A enables quantification of synaptic density in vivo. This study used [11 C]UCB-J PET in participants with behavioral variant frontotemporal dementia (bvFTD), testing the hypothesis that synaptic loss is severe and related to clinical severity. METHODS: Eleven participants with clinically probable bvFTD and 25 age- and sex-matched healthy controls were included. Participants underwent dynamic [11 C]UCB-J PET, structural magnetic resonance imaging, and a neuropsychological battery, including the revised Addenbrooke Cognitive Examination, and INECO frontal screening. General linear models compared [11 C]UCB-J binding potential maps and gray matter volume between groups, and assessed associations between synaptic density and clinical severity in patients. Analyses were also performed using partial volume corrected [11 C]UCB-J binding potential from regions of interest (ROIs). RESULTS: Patients with bvFTD showed severe synaptic loss compared to controls. [11 C]UCB-J binding was reduced bilaterally in medial and dorsolateral frontal regions, inferior frontal gyri, anterior and posterior cingulate gyrus, insular cortex, and medial temporal lobe. Synaptic loss in the frontal and cingulate regions correlated significantly with cognitive impairments. Synaptic loss was more severe than atrophy. Results from ROI-based analyses mirrored the voxelwise results. INTERPRETATION: In accordance with preclinical models, and human postmortem evidence, there is widespread frontotemporal loss of synapses in symptomatic bvFTD, in proportion to severity. [11 C]UCB-J PET could support translational studies and experimental medicine strategies for new disease-modifying treatments for neurodegeneration. ANN NEUROL 2023;93:142-154.

Developing A Conceptual Framework for Early Intervention Vocational Rehabilitation for People Following Spinal Cord Injury.

PURPOSE: Early intervention vocational rehabilitation (EIVR) can improve return to work (RTW) outcomes for people with spinal cord injury (SCI). However, mechanisms explaining how and why EIVR works are not well understood. This study aims to develop a conceptual framework describing key mechanisms of EIVR intervention effect following SCI. METHODS: We synthesised data from a realist literature review with data from interviews of people with SCI (n = 30), a survey of people with SCI who had received EIVR (n = 37), a focus group of EIVR providers and a focus group of community vocational providers. We first synthesised the literature review and interviews to develop an initial programme theory describing the contexts in which mechanisms are activated to produce EIVR outcomes. Then we used data from the survey and focus groups to further refine the EIVR programme theory. Finally, a conceptual framework was developed to support knowledge dissemination. RESULTS: By ensuring consistent messaging across the multi-disciplinary team, EIVR programmes establish and maintain hope that work is possible following injury. Conversations about work allow individuals to determine the priority of work following injury. These conversations can also improve self-efficacy by providing individualized support to envisage pathways toward RTW goals and maintain worker identity. The synthesised study findings highlight the contexts and resources required to trigger activation of these mechanisms. CONCLUSIONS: EIVR key mechanisms of effect are not specific to SCI as a health condition, therefore enabling this framework to be applied to other populations who face similar impairments and return to work barriers.

MINocyclinE to Reduce inflammation and blood brain barrier leakage in small Vessel diseAse (MINERVA) trial study protocol.

Background: Cerebral small vessel disease (SVD) is a common cause of stroke and cognitive impairment. Recent data has implicated neuroinflammation and increased blood-brain barrier (BBB) permeability in its pathogenesis, but whether such processes are causal and can be therapeutically modified is uncertain. In a rodent model of SVD, minocycline was associated with reduced white matter lesions, inflammation and BBB permeability. Aims: To determine whether blood-brain barrier permeability (measured using dynamic contrast-enhanced MRI) and microglial activation (measured by positron emission tomography using the radioligand 11C-PK11195) can be modified in SVD. Design: Phase II randomised double blind, placebo-controlled trial of minocycline 100 mg twice daily for 3 months in 44 participants with moderate to severe SVD defined as a clinical lacunar stroke and confluent white matter hyperintensities. Outcomes: Primary outcome measures are volume and intensity of focal increases of blood-brain barrier permeability and microglial activation determined using PET-MRI imaging. Secondary outcome measures include inflammatory biomarkers in serum, and change in conventional MRI markers and cognitive performance over 1 year follow up. Discussion: The MINERVA trial aims to test whether minocycline can influence novel pathological processes thought to be involved in SVD progression, and will provide insights into whether central nervous system inflammation in SVD can be therapeutically modulated.

Amyloid- ß and tau deposition influences cognitive and functional decline in Down syndrome.

This study investigates whether tau has (i) an independent effect from amyloid-ß on changes in cognitive and functional performance and (ii) a synergistic relationship with amyloid-ß in the exacerbation of decline in aging Down syndrome (DS). 105 participants with DS underwent baseline PET [18F]-AV1451 and PET [11C]PiB scans to quantify tau deposition in Braak regions II-VI and the Striatum and amyloid-ß status respectively. Linear Mixed Effects models were implemented to assess how tau and amyloid-ß deposition are related to change over three time points. Tau was a significant independent predictor of cognitive and functional change. The three-way interaction between time, [11C]PiB status and tau was significant in the models of episodic memory and visuospatial cognition. Baseline tau is a significant predictor of cognitive and functional decline, over and above the effect of amyloid-ß status. Results suggest a synergistic relationship between amyloid-ß status and tau as predictors of change in memory and visuospatial cognition.