The Fontan operation in infants less than 2 years of age

AbstractYoung age remains a reported risk factor for a successful Fontan operation despite improved survival rates. Since March 1978, the Fontan operation has been performed in 47 patients. To avoid a primary or secondary polliative shunt, an early Fontan procedure (Group 1: mean age 1.5 ± 0.5 years, range 0.6 to 2) has been performed in 17 children with the outcome similar to that of the remaining 30 older patients (Group 2: mean age 7.5 ± 5 years, range 2.4 to 23 years). Preoperatively both groups had acceptable hemodynamic status for a successful Fontan result.Operative variables including cardiopulmonary bypass time, aortic cross-clamp time and core temperature were similar between groups and did not affect mortality. The postoperative mortality rate including early surgical (0% vs. 13%, respectively), late (18% vs. 12%) and total (18% vs. 23%) was similar between Groups 1 and 2 (p > 0.05). Immediate postoperative arrhythmias were more frequent in Group 1 (71% vs. 25%, p < 0.01) with no related mortality, while late arrhythmias occurred with equal frequency (29% vs. 39%, p > 0.05). Group 1 infants required a longer hospital stay (22 ± 9 vs. 14 ± 5 days, p < 0.01).Thus, young age is not a risk factor for successful outcome of the Fontan operation in patients with acceptable preoperative hemodynamic status. An early Fontan operation may also avoid prolonged palliative procedures and their potential deleterious effects

Systematic review and meta-analysis appraising efficacy and safety of adrenaline for adult cardiopulmonary resuscitation

BACKGROUND: There is a beneficial effect of adrenaline during adult cardiopulmonary resuscitation (CPR) from cardiac arrest but there is also uncertainty about its safety and effectiveness. The aim of this study was to evaluate the use of adrenaline versus non-adrenaline CPR. METHODS: PubMed, ScienceDirect, Embase, CENTRAL (Cochrane Central Register of Controlled Trials) and Google Scholar databases were searched from their inception up to 1st July 2020. Two reviewers independently assessed eligibility and risk of bias, with conflicts resolved by a third reviewer. Risk ratio (RR) or mean difference of groups were calculated using fixed or random-effect models. RESULTS: Nineteen trials were identified. The use of adrenaline during CPR was associated with a significantly higher percentage of return of spontaneous circulation (ROSC) compared to non-adrenaline treatment (20.9% vs. 5.9%; RR = 1.87; 95% confidence interval [CI] 1.37-2.55; p < 0.001). The use of adrenaline in CPR was associated with ROSC at 19.4% and for non-adrenaline treatment - 4.3% (RR = 3.23; 95% CI 1.89-5.53; p < 0.001). Survival to discharge (or 30-day survival) when using adrenaline was 6.8% compared to non-adrenaline treatment (5.5%; RR = 0.99; 95% CI 0.76-1.30; p = 0.97). However, the use of adrenaline was associated with a worse neurological outcome (1.6% vs. 2.2%; RR = 0.57; 95% CI 0.42-0.78; p < 0.001). CONCLUSIONS: This review suggests that resuscitation with adrenaline is associated with the ROSC and survival to hospital discharge, but no higher effectiveness was observed at discharge with favorable neurological outcome. The analysis showed higher effectiveness of ROSC and survival to hospital discharge in non-shockable rhythms. But more multicenter randomized controlled trials are needed in the future

18F-PSMA-1007 PET/CT for response assessment in patients with metastatic renal cell carcinoma undergoing tyrosine kinase or checkpoint inhibitor therapy: preliminary results

INTRODUCTION Tyrosine kinase (TKI) and checkpoint inhibitors (CI) prolonged overall survival in metastatic renal cell carcinoma (mRCC). Early prediction of treatment response is highly desirable for the individualization of patient management and improvement of therapeutic outcome; however, serum biochemistry is unable to predict therapeutic efficacy. Therefore, we compared 18F-PSMA-1007 PET imaging for response assessment in mRCC patients undergoing TKI or CI therapy compared to CT-based response assessment as the current imaging reference standard. METHODS 18F-PSMA-1007 PET/CT was performed in mRCC patients prior to initiation of systemic treatment and 8~weeks after therapy initiation. Treatment response was evaluated separately on 18F-PSMA-PET and CT. Changes on PSMA-PET (SUVmean) were assessed on a per patient basis using a modified PERCIST scoring system. Complete response (CRPET) was defined as absence of any uptake in all target lesions on posttreatment PET. Partial response (PRPET) was defined as decrease in summed SUVmean of > 30%. The appearance of new, PET-positive lesions or an increase in summed SUVmean of > 30% was defined as progressive disease (PDPET). A change in summed SUVmean of ± 30% defined stable disease (SDPET). RECIST 1.1 criteria were used for response assessment on CT. Results of radiographic response assessment on PSMA-PET and CT were compared. RESULTS Overall, 11 mRCC patients undergoing systemic treatment were included. At baseline PSMA-PET1, all mRCC patients showed at least one PSMA-avid lesion. On follow-up PET2, 3 patients showed CRPET, 3 PRPET, 4 SDPET, and 1 PDPET. According to RECIST 1.1, 1 patient showed PRCT, 9 SDCT, and 1 PDCT. Overall, concordant classifications were found in only 2 cases (2 SDCT + PET). Patients with CRPET on PET were classified as 3 SDCT on CT using RECIST 1.1. By contrast, the patient classified as PRCT on CT showed PSMA uptake without major changes during therapy (SDPET). However, among 9 patients with SDCT on CT, 3 were classified as CRPET, 3 as PRPET, 1 as PDPET, and only 2 as SDPET on PSMA-PET. CONCLUSION On PSMA-PET, heterogeneous courses were observed during systemic treatment in mRCC patients with highly diverging results compared to RECIST 1.1. In the light of missing biomarkers for early response assessment, PSMA-PET might allow more precise response assessment to systemic treatment, especially in patients classified as SD on CT

68Ga-EMP-100 PET/CT-a novel ligand for visualizing c-MET expression in metastatic renal cell carcinoma-first in-human biodistribution and imaging results

BACKGROUND 68Ga-EMP-100 is a novel positron emission tomography (PET) ligand that directly targets tumoral c-MET expression. Upregulation of the receptor tyrosin kinase c-MET in renal cell carcinoma (RCC) is correlated with overall survival in metastatic disease (mRCC). Clinicopathological staging of c-MET expression could improve patient management prior to systemic therapy with for instance inhibitors targeting c-MET such as cabozantinib. We present the first in-human data of 68Ga-EMP-100 in mRCC patients evaluating uptake characteristics in metastases and primary RCC. METHODS Twelve patients with mRCC prior to anticipated cabozantinib therapy underwent 68Ga-EMP-100 PET/CT imaging. We compared the biodistribution in normal organs and tumor uptake of mRCC lesions by standard uptake value (SUVmean) and SUVmax measurements. Additionally, metastatic sites on PET were compared to contrast-enhanced computed tomography (CT) and the respective, quantitative PET parameters were assessed and then compared inter- and intra-individually. RESULTS Overall, 87 tumor lesions were analyzed. Of these, 68/87 (79.3%) were visually rated c-MET-positive comprising a median SUVmax of 4.35 and SUVmean of 2.52. Comparing different tumor sites, the highest uptake intensity was found in tumor burden at the primary site (SUVmax 9.05 (4.86-29.16)), followed by bone metastases (SUVmax 5.56 (0.97-15.85)), and lymph node metastases (SUVmax 3.90 (2.13-6.28)) and visceral metastases (SUVmax 3.82 (0.11-16.18)). The occurrence of visually PET-negative lesions (20.7%) was distributed heterogeneously on an intra- and inter-individual level; the largest proportion of PET-negative metastatic lesions were lung and liver metastases. The highest physiological 68Ga-EMP-100 accumulation besides the urinary bladder content was seen in the kidneys, followed by moderate uptake in the liver and the spleen, whereas significantly lower uptake intensity was observed in the pancreas and the intestines. CONCLUSION Targeting c-MET expression, 68Ga-EMP-100 shows distinctly elevated uptake in mRCC patients with partially high inter- and intra-individual differences comprising both c-MET-positive and c-MET-negative lesions. Our first clinical results warrant further systemic studies investigating the clinical use of 68Ga-EMP-100 as a biomarker in mRCC patients

vrille, Pdp1, and dClock Form a Second Feedback Loop in the Drosophila Circadian Clock

AbstractThe Drosophila circadian clock consists of two interlocked transcriptional feedback loops. In one loop, dCLOCK/CYCLE activates period expression, and PERIOD protein then inhibits dCLOCK/CYCLE activity. dClock is also rhythmically transcribed, but its regulators are unknown. vrille (vri) and Par Domain Protein 1 (Pdp1) encode related transcription factors whose expression is directly activated by dCLOCK/CYCLE. We show here that VRI and PDP1 proteins feed back and directly regulate dClock expression. Repression of dClock by VRI is separated from activation by PDP1 since VRI levels peak 3-6 hours before PDP1. Rhythmic vri transcription is required for molecular rhythms, and here we show that the clock stops in a Pdp1 null mutant, identifying Pdp1 as an essential clock gene. Thus, VRI and PDP1, together with dClock itself, comprise a second feedback loop in the Drosophila clock that gives rhythmic expression of dClock, and probably of other genes, to generate accurate circadian rhythms

A non-coding RNA balancing act: miR-346-induced DNA damage is limited by the long non-coding RNA NORAD in prostate cancer

Background: miR‑346 was identified as an activator of Androgen Receptor (AR) signalling that associates with DNA damage response (DDR)‑linked transcripts in prostate cancer (PC). We sought to delineate the impact of miR‑346 on DNA damage, and its potential as a therapeutic agent. Methods: RNA‑IP, RNA‑seq, RNA‑ISH, DNA fibre assays, in vivo xenograft studies and bioinformatics approaches were used alongside a novel method for amplification‑free, single nucleotide‑resolution genome‑wide mapping of DNA breaks (INDUCE‑seq). Results: miR‑346 induces rapid and extensive DNA damage in PC cells ‑ the first report of microRNA‑induced DNA damage. Mechanistically, this is achieved through transcriptional hyperactivation, R‑loop formation and replication stress, leading to checkpoint activation and cell cycle arrest. miR‑346 also interacts with genome‑protective lncRNA NORAD to disrupt its interaction with PUM2, leading to PUM2 stabilisation and its increased turnover of DNA damage response (DDR) transcripts. Confirming clinical relevance, NORAD expression and activity strongly correlate with poor PC clinical outcomes and increased DDR in biopsy RNA‑seq studies. In contrast, miR‑346 is associated with improved PC survival. INDUCE‑seq reveals that miR‑346‑induced DSBs occur preferentially at binding sites of the most highly‑transcriptionally active transcription factors in PC cells, including c‑Myc, FOXA1, HOXB13, NKX3.1, and importantly, AR, resulting in target transcript downregulation. Further, RNA‑seq reveals widespread miR‑346 and shNORAD dysregulation of DNA damage, replication and cell cycle processes. NORAD drives target‑directed miR decay (TDMD) of miR‑346 as a novel genome protection mechanism: NORAD silencing increases mature miR‑346 levels by several thousand‑fold, and WT but not TDMD‑mutant NORAD rescues miR‑346‑induced DNA damage. Importantly, miR‑346 sensitises PC cells to DNA‑damaging drugs including PARP inhibitor and chemotherapy, and induces tumour regression as a monotherapy in vivo, indicating that targeting miR‑346:NORAD balance is a valid therapeutic strategy

Circadian Phase Resetting via Single and Multiple Control Targets

Circadian entrainment is necessary for rhythmic physiological functions to be appropriately timed over the 24-hour day. Disruption of circadian rhythms has been associated with sleep and neuro-behavioral impairments as well as cancer. To date, light is widely accepted to be the most powerful circadian synchronizer, motivating its use as a key control input for phase resetting. Through sensitivity analysis, we identify additional control targets whose individual and simultaneous manipulation (via a model predictive control algorithm) out-perform the open-loop light-based phase recovery dynamics by nearly 3-fold. We further demonstrate the robustness of phase resetting by synchronizing short- and long-period mutant phenotypes to the 24-hour environment; the control algorithm is robust in the presence of model mismatch. These studies prove the efficacy and immediate application of model predictive control in experimental studies and medicine. In particular, maintaining proper circadian regulation may significantly decrease the chance of acquiring chronic illness