There is a large unmet need for a simple, accurate, noninvasive, quantitative, and high-resolution imaging modality to detect lung fibrosis at early stage and to monitor disease progression. ...Overexpression of collagen is a hallmark of organ fibrosis. Here, we describe the optimization of a collagen-targeted PET probe for staging pulmonary fibrosis.
Six peptides were synthesized, conjugated to a copper chelator, and radiolabeled with
Cu. The collagen affinity of each probe was measured in a plate-based assay. The pharmacokinetics and metabolic stability of the probes were studied in healthy rats. The capacity of these probes to detect and stage pulmonary fibrosis in vivo was assessed in a mouse model of bleomycin-induced fibrosis using PET imaging.
All probes exhibited affinities in the low micromolar range (1.6 μM < Kd < 14.6 μM) and had rapid blood clearance. The probes showed 2- to 8-fold-greater uptake in the lungs of bleomycin-treated mice than sham-treated mice, whereas the distribution in other organs was similar between bleomycin-treated and sham mice. The probe
Cu-CBP7 showed the highest uptake in fibrotic lungs and the highest target-to-background ratios. The superiority of
Cu-CBP7 was traced to a much higher metabolic stability compared with the other probes. The specificity of
Cu-CBP7 for collagen was confirmed by comparison with a nonbinding isomer.
Cu-CBP7 is a promising candidate for in vivo imaging of pulmonary fibrosis.
Maternal hypothalamic-pituitary-adrenal axis activity may prenatally program sex-specific stress-response pathways. We investigated associations between maternal cortisol during pregnancy and infant ...parasympathetic responsivity to stress among 204 mother-infant pairs. Cortisol indices included 3rd trimester hair cortisol, as well as diurnal slope and area under the curve, derived from saliva samples collected during pregnancy. Mother-infant dyads participated in the Repeated Still-Face Paradigm (SFP-R) at age 6 months. We calculated respiration-adjusted respiratory sinus arrhythmia (RSA
), an indicator of parasympathetic activation, from infant respiration and cardiac activity measured during the SFP-R. We used multivariable linear mixed models to examine each cortisol index in relation to infant RSA
and investigated sex differences using cross-product terms. Diurnal cortisol indices were not associated with RSA
. There was no association between hair cortisol and baseline RSA
. However, hair cortisol was associated with sex-specific changes in RSA
over the SFP-R such that, among girls, parasympathetic withdrawal was reduced with increasing prenatal exposure to cortisol. Consistently higher levels of prenatal cortisol exposure may lead to dampened parasympathetic responsivity to stress during infancy, particularly among girls. Maternal hair cortisol may be particularly valuable for studying the effects of prenatal cortisol exposure on infant autonomic reactivity.
Abstract
Background
Malignant pleural mesothelioma (MPM) is an aggressive thoracic malignancy with a poor prognosis. Systemic immunotherapy is an effective frontline treatment for MPM, and there is a ...scientific rationale supporting the possible efficacy of local, i.e. intra-pleural immune modulators. Trial of intra-pleural bacterial immunotherapy (TILT) investigated the feasibility of performing a randomised trial of intra-pleural bacterial immunotherapy in people with MPM, using the trials within cohorts (TwiC) methodology.
Methods
TILT was a multicentre, three-armed, randomised, feasibility TwiC of intra-pleural OK432, BCG, or usual care in people with MPM. Eligible participants were identified from within the ASSESS-meso study, a prospective, longitudinal, observational cohort study, and were randomly selected to be offered a single dose of OK432 or BCG, via an indwelling pleural catheter. The primary outcome was feasibility, evaluated against prespecified recruitment, attrition and data completeness targets. The acceptability of trial processes and interventions was assessed during qualitative interviews with participants and family members at the end of the trial. TILT was registered prospectively on the European Clinical Trials Registry (EudraCT number 2016–004,727-23) and the ISRCTN Register on 04 December 2017.
Results
Seven participants were randomised from a planned sample size of 12; thus, the 66% recruitment rate target was not met. Two participants withdrew after randomisation, breaching the pre-stated attrition threshold of 10%. It was not possible to maintain blinding of control participants, which negated a fundamental tenet of the TwiC design. The trial processes and methodology were generally acceptable to participants and relatives, despite several recipients of intra-pleural bacterial agents experiencing significant local and systemic inflammatory responses.
Conclusion
It was possible to design a clinical trial of an investigational medicinal product based on the TwiC design and to obtain the necessary regulatory approvals. However, whilst acceptable to participants and relatives, the TwiC design was not a feasible method of investigating intra-pleural bacterial immunotherapy in people with MPM. Future trials investigating this topic should consider the eligibility constraints and recruitment difficulties encountered.
Trial registration
TILT was registered prospectively on the European Clinical Trials Registry (EudraCT number
2016-004727-23
) and the ISRCTN Register (
10432197
) on 04 December 2017.
The diagnosis of deep venous thromboembolic disease is still challenging despite the progress of current thrombus imaging modalities and new diagnostic algorithms. We recently reported the high ...target uptake and thrombus imaging efficacy of the novel fibrin-specific PET probe (64)Cu-FBP8. Here, we tested the feasibility of (64)Cu-FBP8 PET to detect source thrombi and culprit emboli after deep vein thrombosis and pulmonary embolism (DVT-PE). To support clinical translation of (64)Cu-FBP8, we performed a human dosimetry estimation using time-dependent biodistribution in rats.
Sprague-Dawley rats (n = 7) underwent ferric chloride application on the femoral vein to trigger thrombosis. Pulmonary embolism was induced 30 min or 2 d after DVT by intrajugular injection of a preformed blood clot labeled with (125)I-fibrinogen. PET imaging was performed to detect the clots, and SPECT was used to confirm in vivo the location of the pulmonary emboli. Ex vivo γ counting and histopathology were used to validate the imaging findings. Detailed biodistribution was performed in healthy rats (n = 30) at different time points after (64)Cu-FBP8 administration to estimate human radiation dosimetry. Longitudinal whole-body PET/MR imaging (n = 2) was performed after (64)Cu-FBP8 administration to further assess radioactivity clearance.
(64)Cu-FBP8 PET imaging detected the location of lung emboli and venous thrombi after DVT-PE, revealing significant differences in uptake between target and background tissues (P < 0.001). In vivo SPECT imaging and ex vivo γ counting confirmed the location of the lung emboli. PET quantification of the venous thrombi revealed that probe uptake was greater in younger clots than in older ones, a result confirmed by ex vivo analyses (P < 0.001). Histopathology revealed an age-dependent reduction of thrombus fibrin content (P = 0.006), further supporting the imaging findings. Biodistribution and whole-body PET/MR imaging showed a rapid, primarily renal, body clearance of (64)Cu-FBP8. The effective dose was 0.021 mSv/MBq for males and 0.027 mSv/MBq for females, supporting the feasibility of using (64)Cu-FBP8 in human trials.
We showed that (64)Cu-FBP8 PET is a feasible approach to image DVT-PE and that radiogenic adverse health effects should not limit the clinical translation of (64)Cu-FBP8.
The delivery of compassionate care leads to safer care but this will only occur with an engaged workforce under effective leadership. In addition, there is a need to understand the behaviours that ...drive nurses to make particular decisions about care. This article describes the pilot of a simple survey tool (ENGAGE) to ascertain levels of staff engagement to use as an enabler of effective change. It also describes a unique pilot initiative of focus group work, quality improvements and leadership coaching on two hospital wards. This work centred on the patient–nurse relationship and challenged the traditional teaching of preventing harm. Initial results were promising: while many staff did not feel nurtured or guided by their manager or acknowledged by the senior team, they did feel glad to come to work and empowered to improve patient care. Three months after the first ENGAGE survey, a repeat found significantly improved levels of engagement. Alongside this were improvements in avoidable harms and patient experience. Staff were motivated to improve care and admitted they did not really see their patients as individuals with identity and personality. Managers were motivated to improve engagement and take their wards forward.
The meaning of compassion Day, Helen
British journal of nursing (Mark Allen Publishing),
2015 Mar 26-Apr 8, Volume:
24, Issue:
6
Journal Article
Peer reviewed
Compassion is one of the most highly talked about areas in nursing. While compassion may be viewed as an integral and natural part of nursing care delivery, there is an increasing desire to try to ...measure it and, indeed, question if it can be taught. However, there are many complex variables that affect the degree of compassion delivered by nurses, not least their own beliefs and value systems. Here, Day describes the output of a safer and compassionate care event that suggests there may be a measurable differentiation between how compassionate nurses are.
Hybrid closed‐loop (HCL) systems are characterised by integrating continuous glucose monitoring (CGM) with insulin pumps which automate insulin delivery via specific algorithms and user‐initiated ...insulin delivery. The aim of the study was to evaluate the effectiveness of HCLs on Hba1c, time‐in‐range (TIR), time in hypoglycaemia, fear of hypoglycaemia, sleep and quality of life measure in children and young people (CYP) with T1D and their carers. Data on HbA1c, TIR and hypoglycaemia frequency were reviewed at baseline prior to starting HCL and 3 months after commencement. As part of clinical care, all patients and carers were provided with key education on the use of the HCL system by trained diabetes healthcare professionals. CYP aged 12 years and above independently completed the validated Hypoglycaemia Fear Survey (HFS). Parents of patients <12 were asked to complete a modified version of the HFS‐Parent (HFS‐P) survey. There were 39 CYP (22 men) with T1D included with a mean age of 11.8 ± 4.4 at commencement of HCL. Median duration of diabetes was 3.8 years (interquartile range 1.3–6.0). There were 55% of patients who were prepubertal at the time of HCL commencement. 91% were on the Control‐IQ system and 9% on the CamAPS FX system. HCL use demonstrated significant improvements at 3 months in the following: HbA1c in mmol/mol (63.0 vs. 56.6, p = 0.03), TIR (50.5 vs. 67.0, p = 0.001) and time in hypoglycaemia (4.3% vs. 2.8%, p = 0.004). HFS scores showed improved behaviour (34.0 vs. 27.5.9, p = 0.02) and worry (40.2 vs. 31.6, p = 0.03), and HFS‐P scores also showed improved behaviour (p < 0.001) and worry (p = 0.01). Our study shows that HCL at 3 months improves glucose control, diabetes management and quality of life measures such as fear and worry of hypoglycaemia for CYP and carers.
Chronic kidney disease (CKD) is characterized by a progressive loss of renal function that leads to an accumulation of uremic toxins in the circulation, despite regular dialysis. In CKD, uremic ...toxins can cross the blood‐brain barrier and cause neuroinflammation. Consequently, patients with CKD experience various symptoms, including fatigue and impaired cognitive function. A significant barrier to investigation of uremic toxicity and its impact on cognitive function has been the difficulty of performing studies in humans, due in part to the lack of access to relevant tissues. To examine the pathogenic mechanism of uremic toxicity in the development of cognitive impairments, a partial nephrectomy (PNx) mouse model was used as the experimental system. Sham and PNx mice were maintained for 12‐14 weeks after 5/6 nephrectomy and then assessed for motor function, cognitive function, and neuronal activity. Kidney function, as measured by glomerular filtration rate, was reduced by 40% in PNx mice, which corresponded to a 65% reduction in kidney mass. Blood urea nitrogen levels were 2.3 times higher in PNx mice, but no significant changes in plasma creatinine levels were observed. Despite reduced kidney function, PNx mice performed at the same level as sham controls in ambulatory activity, working spatial memory, and object recognition. There was also no evidence of increased anxiety. However, in the Puzzle Box paradigm, in which mice were tested for problem solving skills over multiple days with increasingly difficult tasks, PNx mice on average took three times longer to overcome the obstacle in the final two tasks. Ex vivo examination of neuronal activity following exposure to a novel environment revealed a 30% reduction in c‐Fos positive neurons in the hippocampal dentate gyrus in PNx mice. Similarly, the population of fast‐spiking parvalbumin positive interneurons, which are essential for coordinating neuronal activities, were also reduced in PNx mice. Collectively, the data support a correlation between reduced neuronal activity and impaired cognitive performance in PNx mice. These impairments are likely a consequence of exposure to elevated levels of uremic toxins in the brain due to reduced kidney function.
Pulmonary fibrosis is scarring of the lungs that can arise from radiation injury, drug toxicity, environmental or genetic causes, and for unknown reasons idiopathic pulmonary fibrosis (IPF). ...Overexpression of collagen is a hallmark of organ fibrosis. We describe a peptide-based positron emission tomography (PET) probe (
Ga-CBP8) that targets collagen type I. We evaluated
Ga-CBP8 in vivo in the bleomycin-induced mouse model of pulmonary fibrosis.
Ga-CBP8 showed high specificity for pulmonary fibrosis and high target/background ratios in diseased animals. The lung PET signal and lung
Ga-CBP8 uptake (quantified ex vivo) correlated linearly (
= 0.80) with the amount of lung collagen in mice with fibrosis. We further demonstrated that the
Ga-CBP8 probe could be used to monitor response to treatment in a second mouse model of pulmonary fibrosis associated with vascular leak. Ex vivo analysis of lung tissue from patients with IPF supported the animal findings. These studies indicate that
Ga-CBP8 is a promising candidate for noninvasive imaging of human pulmonary fibrosis.
Objective: This study examined whether ADHD was an independent contributor to grade retention when adjusting for IQ, learning disorders, and social class. Method: Outcome data was from participants ...in studies at Massachusetts General Hospital (n = 404 ADHD, n = 349 controls) who underwent psychiatric interviews, socioeconomic status measures, and IQ testing. Results: 28% of individuals with ADHD repeated a grade compared with 7% of controls (p < .001). Among participants with ADHD, social class, and IQ were significant predictors of high school dropout or repeated grade. An interaction effect of ADHD and gender was also found with females with ADHD having a higher risk ratio for repeated grade/dropout compared with males with ADHD. Conclusion: Participants with ADHD were significantly more likely to repeat a grade, adjusting for all other variables indicating the critical importance of early identification of ADHD to help mitigate adverse educational outcomes. (J. of Att. Dis. 2016; 20(5) 383-389)
PDF
