ICU-acquired muscle atrophy occurs commonly and worsens outcomes in adults. The incidence and severity of muscle atrophy in critically ill children are poorly characterized.
To determine incidence, ...severity and risk factors for muscle atrophy in critically ill children.
A single-center, prospective cohort study of 34 children receiving invasive mechanical ventilation for ≥48 hours. Patients 1 week- 18 years old with respiratory failure and without preexisting neuromuscular disease or skeletal trauma were recruited from a tertiary Pediatric Intensive Care Unit (PICU) between June 2015 and May 2016. We used serial bedside ultrasound to assess thickness of the diaphragm, biceps brachii/brachialis, quadriceps femoris and tibialis anterior. Serial electrical impedance myography (EIM) was assessed in children >1 year old. Medical records were abstracted from an electronic database.
Respiratory failure requiring endotracheal intubation for ≥48 hours.
The primary outcome was percent change in muscle thickness. Secondary outcomes were changes in EIM-derived fat percentage and "quality".
Of 34 enrolled patients, 30 completed ≥2 ultrasound assessments with a median interval of 6 (IQR 6-7) days. Mean age was 5.42 years, with 12 infants <1 year (40%) and 18 children >1 year old (60%). In the entire cohort, diaphragm thickness decreased 11.1% (95%CI, -19.7% to -2.52%) between the first two assessments or 2.2%/day. Quadriceps thickness decreased 8.62% (95%CI, -15.7% to -1.54%) or 1.5%/day. Biceps (-1.71%; 95%CI, -8.15% to 4.73%) and tibialis (0.52%; 95%CI, -5.81% to 3.40%) thicknesses did not change. Among the entire cohort, 47% (14/30) experienced diaphragm atrophy (defined a priori as ≥10% decrease in thickness). Eighty three percent of patients (25/30) experienced atrophy in ≥1 muscle group, and 47% (14/30)-in ≥2 muscle groups. On multivariate linear regression, increasing age and traumatic brain injury (TBI) were associated with greater muscle loss. EIM revealed increased fat percentage and decreased muscle "quality".
In children receiving invasive mechanical ventilation, diaphragm and other skeletal muscle atrophy is common and rapid. Increasing age and TBI may increase severity of limb muscle atrophy. Prospective studies are required to link muscle atrophy to functional outcomes in critically ill children.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hematopoietic clones harboring specific mutations may expand over time. However, it remains unclear how different cellular stressors influence this expansion. Here we characterize clonal ...hematopoiesis after two different cellular stressors: cytotoxic therapy and hematopoietic transplantation. Cytotoxic therapy results in the expansion of clones carrying mutations in DNA damage response genes, including TP53 and PPM1D. Analyses of sorted populations show that these clones are typically multilineage and myeloid-biased. Following autologous transplantation, most clones persist with stable chimerism. However, DNMT3A mutant clones often expand, while PPM1D mutant clones often decrease in size. To assess the leukemic potential of these expanded clones, we genotyped 134 t-AML/t-MDS samples. Mutations in non-TP53 DNA damage response genes are infrequent in t-AML/t-MDS despite several being commonly identified after cytotoxic therapy. These data suggest that different hematopoietic stressors promote the expansion of distinct long-lived clones, carrying specific mutations, whose leukemic potential depends partially on the mutations they harbor.
Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. However, for acute myeloid leukemia (AML), ...normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-AML samples and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is “captured” as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse.
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► Normal HSPCs contain random background mutations that increase with aging ► AML genomes contain hundreds of mutations, but very few are recurrent ► Comparison of M1 and M3 AML genomes identifies initiating versus cooperating mutations ► Most AML mutations are probably background events in HSPCs, “captured” by cloning
Comparison of the genomes of two groups of patients, each with a different form of AML, allows the resolution of potential driver and cooperating mutations in each disease and reveals that the genetic history of all AML cases is marked by random, benign mutations acquired by normal HSPCs as a function of age.
In patients who had a relapse of acute myeloid leukemia after allogeneic hematopoietic stem-cell transplantation, no characteristic genetic lesions were detected, but alterations in expression of ...genes related to immune function were noted, particularly down-regulation of major histocompatibility complex class II genes.
Therapy-related acute myeloid leukaemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS) are well-recognized complications of cytotoxic chemotherapy and/or radiotherapy. There are several ...features that distinguish t-AML from de novo AML, including a higher incidence of TP53 mutations, abnormalities of chromosomes 5 or 7, complex cytogenetics and a reduced response to chemotherapy. However, it is not clear how prior exposure to cytotoxic therapy influences leukaemogenesis. In particular, the mechanism by which TP53 mutations are selectively enriched in t-AML/t-MDS is unknown. Here, by sequencing the genomes of 22 patients with t-AML, we show that the total number of somatic single-nucleotide variants and the percentage of chemotherapy-related transversions are similar in t-AML and de novo AML, indicating that previous chemotherapy does not induce genome-wide DNA damage. We identified four cases of t-AML/t-MDS in which the exact TP53 mutation found at diagnosis was also present at low frequencies (0.003-0.7%) in mobilized blood leukocytes or bone marrow 3-6 years before the development of t-AML/t-MDS, including two cases in which the relevant TP53 mutation was detected before any chemotherapy. Moreover, functional TP53 mutations were identified in small populations of peripheral blood cells of healthy chemotherapy-naive elderly individuals. Finally, in mouse bone marrow chimaeras containing both wild-type and Tp53(+/-) haematopoietic stem/progenitor cells (HSPCs), the Tp53(+/-) HSPCs preferentially expanded after exposure to chemotherapy. These data suggest that cytotoxic therapy does not directly induce TP53 mutations. Rather, they support a model in which rare HSPCs carrying age-related TP53 mutations are resistant to chemotherapy and expand preferentially after treatment. The early acquisition of TP53 mutations in the founding HSPC clone probably contributes to the frequent cytogenetic abnormalities and poor responses to chemotherapy that are typical of patients with t-AML/t-MDS.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
In this study, investigators compared genome sequencing with cytogenetic analysis in 263 patients with acute myeloid leukemia or myelodysplastic syndromes. Prospective sequencing detected new genetic ...information that was not revealed by cytogenetic analysis in nearly 25% of the patients, which altered the risk category for most of these patients.
OBJECTIVES:Acute kidney injury requiring renal replacement therapy is associated with high morbidity and mortality. Complications of renal replacement therapy include hemodynamic instability with ...ensuing shortened treatments, inadequate ultrafiltration, and delay in renal recovery. Studies have shown that lowering dialysate temperature in patients with end-stage renal disease is associated with a decrease in the frequency of intradialytic hypotension. However, data regarding mitigation of hypotension by lowering dialysate temperature in patients with acute kidney injury are scarce. We conducted a prospective, randomized, cross-over pilot study to evaluate the effect of lower dialysate temperature on hemodynamic status of critically ill patients with acute kidney injury during prolonged intermittent renal replacement therapy.
DESIGN:Single-center prospective, randomized, cross-over study.
SETTING:ICUs and a step down unit in a tertiary referral center.
PATIENTS:Acute kidney injury patients undergoing prolonged intermittent renal replacement therapy.
INTERVENTIONS:Participants were randomized to start prolonged intermittent renal replacement therapy with dialysate temperature of 35°C or dialysate temperature of 37°C.
MEASUREMENTS AND MAIN RESULTS:The primary endpoint was the number of hypotensive events, as defined by any of the followingdecrease in systolic blood pressure greater than or equal to 20 mm Hg, decrease in mean arterial pressure greater than or equal to 10 mm Hg, decrease in ultrafiltration, or increase in vasopressor requirements. The number of events was analyzed by Poisson regression and other outcomes with repeated-measures analysis of variance. Twenty-one patients underwent a total of 78 prolonged intermittent renal replacement therapy sessions, 39 in each arm. The number of hypotensive events was twice as high during treatments with dialysate temperature of 37°C, compared with treatments with the cooler dialysate (1.49 ± 1.12 vs 0.72 ± 0.69; incidence rate ratio, 2.06; p ≤ 0.0001). Treatment sessions with cooler dialysate were more likely to reach prescribed ultrafiltration targets.
CONCLUSIONS:Patients with acute kidney injury undergoing prolonged intermittent renal replacement therapy with cooler dialysate experienced significantly less hypotension during treatment. Prevention of hemodynamic instability during renal replacement therapy helped to achieve ultrafiltration goals and may help to prevent volume overload in critically ill patients.
Acute myeloid leukemia (AML) patients rarely have long first remissions (LFRs; >5 y) after standard-of-care chemotherapy, unless classified as favorable risk at presentation. Identification of the ...mechanisms responsible for long vs. more typical, standard remissions may help to define prognostic determinants for chemotherapy responses. Using exome sequencing, RNA-sequencing, and functional immunologic studies, we characterized 28 normal karyotype (NK)-AML patients with >5 y first remissions after chemotherapy (LFRs) and compared them to a well-matched group of 31 NK-AML patients who relapsed within 2 y (standard first remissions SFRs). Our combined analyses indicated that genetic-risk profiling at presentation (as defined by European LeukemiaNet ELN 2017 criteria) was not sufficient to explain the outcomes of many SFR cases. Single-cell RNA-sequencing studies of 15 AML samples showed that SFR AML cells differentially expressed many genes associated with immune suppression. The bone marrow of SFR cases had significantly fewer CD4
Th1 cells; these T cells expressed an exhaustion signature and were resistant to activation by T cell receptor stimulation in the presence of autologous AML cells. T cell activation could be restored by removing the AML cells or blocking the inhibitory major histocompatibility complex class II receptor, LAG3. Most LFR cases did not display these features, suggesting that their AML cells were not as immunosuppressive. These findings were confirmed and extended in an independent set of 50 AML cases representing all ELN 2017 risk groups. AML cell-mediated suppression of CD4
T cell activation at presentation is strongly associated with unfavorable outcomes in AML patients treated with standard chemotherapy.
Abstract
Objective
To investigate differences in oxytocin (OXT) biodistribution between nonobese and obese parturients during labor.
Study Design
Patients with body mass index (BMI) of either ≥ 18 ...≤ 24.9 kg/m
2
(“nonobese”) or ≥ 30 kg/m
2
(“obese”) undergoing elective induction of labor were included (
N
= 25 each). Blood samples were collected at baseline (T
0
), and 20 minutes after maximal OXT augmentation or adequate uterine contractions (T
1
) for OXT and oxytocinase assays. A mixed-model repeated-measures analysis of variance was used to test for group versus time interaction and analysis of covariance to detect a difference in OXT level at T
1
. Data presented as mean ± standard deviation or median (interquartile range), with
p
< 0.05 considered significant.
Results
The mean BMIs (kg/m
2
) were 22.1 ± 1.6 and 35.9 ± 5.1 in the nonobese and obese groups, respectively. No differences were observed in either the duration of OXT infusion, total dose of OXT, or plasma OXT (pg/mL) either at T
0
or T
1
. However, plasma oxytocinase (ng/mL) was significantly lower at T
0
(1.41 0.67, 3.51 vs. 0.40 0.29, 1.12;
p
= 0.03) in the obese group.
Conclusion
We provide preliminary evidence that the disposition of OXT may not be different between obese and nonobese women during labor.
There has been a continuing increase in the incidence of end-stage renal disease (ESRD) in the United States, including the fraction that has been attributed to hypertension. This study was done to ...seek relationships between ESRD and pretreatment clinical data and between ESRD and early treated blood pressure data in a population of hypertensive veterans. We identified a total of 5730 black and 6182 nonblack male veterans as hypertensive from 1974 through 1976 in 32 Veterans Administration Hypertension Screening and Treatment Program clinics. Their mean age was 52.5 plus/minus 10.2 years, and their mean pretreatment blood pressure was 154.3 plus/minus 19.0/100.8 plus/minus 9.8 mm Hg. During a minimum of 13.9 years of follow-up, 5337 (44.8%) of these patients died and 245 developed ESRD. For 1055 of these subjects, pretreatment systolic blood pressure (SBP) was greater than 180 mm Hg; 901 were diabetic; 1471 had a history of urinary tract problems; and 2358 of the 9644 who were treated had an early fall in SBP of more than 20 mm Hg. We used proportional hazards modeling to fit multivariate survival models to determine the effect of the available pretreatment data and early treated blood pressure levels on ESRD. This model demonstrated the independent increased risk of ESRD associated with being black or diabetic (risk ratio, 2.2 or 1.8), having a history of urinary tract problems (risk ratio, 2.2), or having high pretreatment SBP (for SBP 165 to 180 mm Hg, risk ratio was 2.8; for SBP > 180 mm Hg, risk ratio was 7.6). In addition, myocardial infarction during follow-up increased the risk of subsequent ESRD almost twofold, and congestive heart failure increased it more than fivefold. The rate of ESRD in those whose SBP fell more than 20 mm Hg decreased by two thirds. (Hypertension. 1995;25part 1:587-594.)
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