Abstract
Background
We report preclinical and first-in-human-brain-cancer data using a targeted poly (ADP-ribose) polymerase 1 (PARP1) binding PET tracer, 18FPARPi, as a diagnostic tool to ...differentiate between brain cancers and treatment-related changes.
Methods
We applied a glioma model in p53-deficient nestin/tv-a mice, which were injected with 18FPARPi and then sacrificed 1 h post-injection for brain examination. We also prospectively enrolled patients with brain cancers to undergo dynamic 18FPARPi acquisition on a dedicated positron emission tomography/magnetic resonance (PET/MR) scanner. Lesion diagnosis was established by pathology when available or by Response Assessment in Neuro-Oncology (RANO) or RANO-BM response criteria. Resected tissue also underwent PARPi-FL staining and PARP1 immunohistochemistry.
Results
In a preclinical mouse model, we illustrated that 18FPARPi crossed the blood–brain barrier and specifically bound to PARP1 overexpressed in cancer cell nuclei. In humans, we demonstrated high 18FPARPi uptake on PET/MR in active brain cancers and low uptake in treatment-related changes independent of blood–brain barrier disruption. Immunohistochemistry results confirmed higher PARP1 expression in cancerous than in noncancerous tissue. Specificity was also corroborated by blocking fluorescent tracer uptake with an excess unlabeled PARP inhibitor in patient cancer biospecimen.
Conclusions
Although larger studies are necessary to confirm and further explore this tracer, we describe the promising performance of 18FPARPi as a diagnostic tool to evaluate patients with brain cancers and possible treatment-related changes.
Temporary increases in plasma HIV RNA ('blips') are common in HIV patients on combination antiretroviral therapy (cART). Blips above 500 copies/mL have been associated with subsequent viral rebound. ...It is not clear if this relationship still holds when measurements are made using newer more sensitive assays.
We selected antiretroviral-naive patients that then recorded one or more episodes of viral suppression on cART with HIV RNA measurements made using more sensitive assays (lower limit of detection below 50 copies/ml). We estimated the association in these episodes between blip magnitude and the time to viral rebound.
Four thousand ninety-four patients recorded a first episode of viral suppression on cART using more sensitive assays; 1672 patients recorded at least one subsequent suppression episode. Most suppression episodes (87 %) were recorded with TaqMan version 1 or 2 assays. Of the 2035 blips recorded, 84 %, 12 % and 4 % were of low (50-199 copies/mL), medium (200-499 copies/mL) and high (500-999 copies/mL) magnitude respectively. The risk of viral rebound increased as blip magnitude increased with hazard ratios of 1.20 (95 % CI 0.89-1.61), 1.42 (95 % CI 0.96-2.19) and 1.93 (95 % CI 1.24-3.01) for low, medium and high magnitude blips respectively; an increase of hazard ratio 1.09 (95 % CI 1.03 to 1.15) per 100 copies/mL of HIV RNA.
With the more sensitive assays now commonly used for monitoring patients, blips above 200 copies/mL are increasingly likely to lead to viral rebound and should prompt a discussion about adherence.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aim
To assess the prevalence, types and indications for fluid bolus therapy in neonates with haemodynamic compromise.
Methods
This was a pragmatic, international, multicentre observational study in ...neonatal units across Australasia, Europe and North America with a predefined study period of 10–15 study days per participating neonatal unit between December 2015 and March 2017. Infants ≤28 days of age who received a fluid bolus for the management of haemodynamic compromise (≥10 mL/kg given at ≤6 h) were included.
Results
A total of 163 neonates received a bolus over 8479 eligible patient days in 41 neonatal units. Prevalence of fluid bolus therapy varied between centres from 0 to 28.6% of admitted neonates per day, with a pooled prevalence rate of 1.5% (95% confidence interval 1.1–1.9%). The most common fluid used was 0.9% sodium chloride (129/163; 79%), and the volume of fluid administered was most commonly 10 mL/kg (115/163; 71%) over a median of 30 min (interquartile range 20–60). The most frequent indications were hypotension (n = 56; 34%), poor perfusion (n = 20; 12%) and metabolic acidosis (n = 20; 12%). Minimal or no clinical improvement was reported by clinicians in 66 of 163 cases (40%).
Conclusions
Wide international variations in types, indications and effects of fluid bolus administration in haemodynamically compromised neonates suggest uncertainty in the risk–benefit profile. This is likely to reflect the lack of robust evidence to support the efficacy of different fluid types, doses and appropriate indications. Together, these highlight a need for further clinically relevant studies.
ePDF and ePUB available Open Access under CC-BY-NC-ND licence.
This book brings together leading international authors from a number of fields to provide an up-to-date understanding of part-time work ...at national, sector, industry and workplace levels. The contributors critically examine part-time employment in different institutional settings across Europe, the USA, Australia and Korea.
This analysis serves as a prism to investigate wider trends, particularly in female employment, including the continued increase in part-time work and processes that are increasingly creating dualisation and inequality between 'good' and 'bad' jobs.
PDF
