Patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor anaplastic lymphoma kinase (
gene fusions benefit from treatment with ALK inhibitors (ALKi). Analysis of cell-free ...circulating tumor DNA (cfDNA) may provide a noninvasive way to identify
fusions and actionable resistance mechanisms without an invasive biopsy.
The Guardant360 (G360; Guardant Health) deidentified database of NSCLC cases was queried to identify 88 consecutive patients with 96 plasma-detected
fusions. G360 is a clinical cfDNA next-generation sequencing (NGS) test that detects point mutations, select copy number gains, fusions, insertions, and deletions in plasma.
Identified fusion partners included
(85.4%),
(6%), and
, and
(totaling 8.3%). Forty-two
-positive patients had no history of targeted therapy (cohort 1), with tissue
molecular testing attempted in 21 (5 negative, 5 positive, and 11 tissue insufficient). Follow-up of 3 of the 5 tissue-negative patients showed responses to ALKi. Thirty-one patients were tested at known or presumed ALKi progression (cohort 2); 16 samples (53%) contained 1 to 3
resistance mutations. In 13 patients, clinical status was unknown (cohort 3), and no resistance mutations or bypass pathways were identified. In 6 patients with known
activating mutations, an
fusion was identified on progression (cohort 4; 4
, 1
one both
and
); five harbored
T790M.
In this cohort of cfDNA-detected
fusions, we demonstrate that comprehensive cfDNA NGS provides a noninvasive means of detecting targetable alterations and characterizing resistance mechanisms on progression.
.
To date, limited information is available describing the incidence and impact of de novo donor-specific anti-human leukocyte antigen (HLA) antibodies (dnDSA) in the primary renal transplant patient. ...This report details the dnDSA incidence and actual 3-year post-dnDSA graft outcomes.
The study includes 189 consecutive nonsensitized, non-HLA-identical patients who received a primary kidney transplant between March 1999 and March 2006. Protocol testing for DSA via LABScreen single antigen beads (One Lambda) was done before transplantation and at 1, 3, 6, 9, and 12 months after transplantation then annually and when clinically indicated.
Of 189 patients, 47 (25%) developed dnDSA within 10 years. The 5-year posttransplantation cumulative incidence was 20%, with the largest proportion of patients developing dnDSA in the first posttransplantation year (11%). Young patients (18-35 years old at transplantation), deceased-donor transplant recipients, pretransplantation HLA (non-DSA)-positive patients, and patients with a DQ mismatch were the most likely to develop dnDSA. From DSA appearance, 9% of patients lost their graft at 1 year. Actual 3-year death-censored post-dnDSA graft loss was 24%.
We conclude that 11% of the patients without detectable DSA at transplantation will have detectable DSA at 1 year, and over the next 4 years, the incidence of dnDSA will increase to 20%. After dnDSA development, 24% of the patients will fail within 3 years. Given these findings, future trials are warranted to determine if treatment of dnDSA-positive patients can prevent allograft failure.
Increased blood pressure variability (BPV) is linked to cardiovascular disease and mortality, yet few modifiable BPV risk factors are known. We aimed to assess the relationship between sleep quality ...and activity level on longitudinal BPV in a cohort of community-dwelling adults (age ≥18) from 17 countries. Using Withings home measurement devices, we examined sleep quality and physical activity over one year, operationalized as mean daily step count and number of sleep interruptions, both transformed into tertiles. The primary study outcome was high BPV, defined as the top tertile of systolic blood pressure standard deviation. Our cohort comprised 29,375 individuals (mean age = 58.6 years) with 127.8±90.1 mean days of measurements. After adjusting for age, gender, country, body mass index, measurement days, mean blood pressure, and total time in bed, the odds ratio of having high BPV for those in the top tertile of sleep interruptions (poor sleep) was 1.37 (95% CI, 1.28-1.47) and 1.44 (95% CI, 1.35-1.54) for those in the lowest tertile of step count (physically inactive). Combining these exposures revealed a significant excess relative risk of 0.20 (95% CI, 0.04-0.35, p = 0.012), confirming their super-additive effect. Comparing individuals with the worst exposure status (lowest step count and highest sleep interruptions, n = 2,690) to those with the most optimal status (highest step count and lowest sleep interruptions, n = 3,531) yielded an odds ratio of 2.01 (95% CI, 1.80-2.25) for high BPV. Our findings demonstrate that poor sleep quality and physical inactivity are associated with increased BPV both independently and super-additively.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Time-restricted feeding (TRF) is a type of intermittent fasting in which no calories are commonly consumed for approximately 12-18 hours on a daily basis. The health benefits of this eating pattern ...have been shown in overweight adults, with improvements in cardiometabolic risk factors as well as the preservation of lean mass during weight loss. Although TRF has been well studied in younger and middle-aged adults, few studies have evaluated the effects of TRF in older adults. Thus, the goal of this study was to evaluate older-adult perspectives regarding the real-world advantages, disadvantages, and challenges to adopting a TRF eating pattern among participants aged 65 and over. A four-week single-arm pre- and post-test design was used for this clinical pilot trial TRF intervention study. Participants were instructed to fast for approximately 16 h per day with the daily target range between 14 and 18 h. Participants were provided with the TRF protocol at a baseline visit, along with a pictorial guide that depicted food items and beverages that were allowed and not allowed during fasting windows to reinforce that calorie-containing items were to be avoided. The trial interventionist called each participant weekly to promote adherence, review the protocol, monitor for adverse events, and provide support and guidance for any challenges faced during the intervention. Participants were instructed to complete daily eating time logs by recording the times at which they first consumed calories and when they stopped consuming calories. At the end of the intervention, participants completed an exit interview and a study-specific Diet Satisfaction Survey (Table 1) to assess their satisfaction, feasibility, and overall experience with the study intervention. Of the 10 participants who commenced the study (mean age = 77.1 y; 6 women, 4 men), nine completed the entire protocol. Seven of the ten participants reported easy adjustment to a 16-hour fast and rated the difference from normal eating patterns as minimal. Eight participants reported no decrease in energy during fasting periods, with greater self-reported activity levels in yardwork and light exercise. Adverse events were rare, and included transient headaches, which dissipated with increased water intake, and dizziness in one participant, which subsided with a small snack. The findings of the current trial suggest that TRF is an eating approach that is well tolerated by most older adults. Six participants, however, did not fully understand the requirements of the fasting regimen, despite being provided with specific instructions and a pictorial guide at a baseline visit. This suggests that more instruction and/or participant contact is needed in the early stages of a TRF intervention to promote adherence.
BACKGROUNDAnti–HLA-DQ antibodies are the predominant HLA class II donor-specific antibodies (DSAs) after transplantation. Recently, de novo DQ DSA has been associated with worse allograft outcomes. ...The aim of this study was to determine the further complement-binding characteristics of the most harmful DQ DSA.
METHODSSingle-antigen bead technology was used to screen 284 primary kidney transplant recipients for the presence of posttransplantation DQ DSA. Peak DSA sera of 34 recipients with only de novo DQ DSA and of 20 recipients with de novo DQ plus other DSAs were further analyzed by a modified single-antigen bead assay using immunoglobulin (Ig)-G subclass-specific reporter antibodies and a C1q-binding assay.
RESULTSCompared with recipients who did not have DSA, those with de novo persistent DQ-only DSA and with de novo DQ plus other DSAs had more acute rejection (AR) episodes (22%, P=0.005; and 36%, P=0.0009), increased risk of allograft loss (hazards ratio, 3.7, P=0.03; and hazards ratio, 11.4, P=0.001), and a lower 5-year allograft survival. De novo DQ-only recipients with AR had more IgG1/IgG3 combination and C1q-binding antibodies (51%, P=0.01; and 63%, P=0.001) than patients with no AR. Furthermore, the presence of C1q-binding de novo DQ DSA was associated with a 30% lower 5-year allograft survival (P=0.003).
CONCLUSIONSThe presence of de novo persistent, complement-binding DQ DSA negatively impacts kidney allograft outcomes. Therefore, early posttransplantation detection, monitoring, and removal of complement-binding DQ might be crucial for improving long-term kidney transplantation outcomes.
Objective Commonly, patients undergoing craniotomy are admitted to an intensive care setting postoperatively to allow for close monitoring. We aim to determine the frequency with which patients who ...have undergone elective craniotomies require intensive care unit (ICU)–level interventions or experience significant complications during the postoperative period to identify a subset of patients for whom an alternative to ICU-level care may be appropriate. Methods Following Institutional Review Board approval, a prospective, consecutive cohort of adult patients undergoing elective craniotomy was established at the Massachusetts General Hospital between the dates of April 2010 and March 2011. Inclusion criteria were intradural operations requiring craniotomy performed on adults (18 years of age or older). Exclusion criteria were cases of an urgent or emergent nature, patients who remained intubated postoperatively, and patients who had a ventriculostomy drain in place at the conclusion of the case. Results Four hundred patients were analyzed. Univariate analysis revealed that patients with diabetes ( P = 0.00047), those who required intraoperative blood product administration ( P = 0.032), older patients ( P < 0.0001), those with higher intraoperative blood losses ( P = 0.041), and those who underwent longer surgical procedures ( P = 0.021) were more likely to require ICU-level interventions or experience significant postoperative complications. Multivariate analysis only found diabetes ( P = 0.0005) and age ( P = 0.0091) to be predictive of a patient's need for postoperative ICU admission. Conclusions Diabetes and older age predict the need for ICU-level intervention after elective craniotomy. Properly selected patients may not require postcraniotomy ICU monitoring. Further study of resource utilization is necessary to validate these preliminary findings, particularly in different hospital types.
Historically, clinical trials of regimens to treat chronic infection with hepatitis C virus (HCV) have used, as their primary efficacy endpoint, a sustained virological response (SVR)—defined as HCV ...RNA levels below a designated threshold of quantification—24 weeks after the end of treatment (SVR24). More recently, regulatory authorities have begun to accept SVR at 12 weeks post‐treatment (SVR12) as a valid efficacy endpoint because of its high rate of concordance with SVR24. However, the concordance between SVR12 and SVR24 has not been systematically assessed with new regimens of recently approved direct‐acting antiviral agents. The aim of this study was to assess the concordance between SVR at various post‐treatment time points in phase III clinical trials of sofosbuvir (SOF)‐containing regimens. We conducted a retrospective analysis of five trials enrolling 863 patients infected with HCV genotypes 1‐6. The concordance between SVR at 4 weeks post‐treatment (SVR4) and SVR12, and between SVR12 and SVR24, were determined, as well as positive predictive values (PPVs) and negative predictive values (NPVs). Overall, 779 of 796 patients (98.0%) with an SVR4 also achieved an SVR12, making the PPV of SVR4 for SVR12 98% and the NPV 100%. Of the 779 patients with an SVR12, 777 (99.7%) also achieved an SVR24, making the PPV of SVR12 for SVR24 >99% and the NPV 100%. Of patients who relapsed post‐therapy, 77.6% did so within 4 weeks of completing therapy. Conclusion: Data from phase III studies demonstrate that with SOF‐based regimens, with or without interferon, SVR12 and SVR24 correlate closely. Thus, SVR12 can be used effectively to determine “cure” rates in trials and in clinical practice. (Hepatology 2015;61:41–45)
Summary
Genotype 2 hepatitis C virus (HCV) accounts for up to 30% of chronic HCV infections in Japan. The standard of care for patients with genotype 2 HCV – peginterferon and ribavirin for 24 weeks ...– is poorly tolerated, especially among older patients and those with advanced liver disease. We conducted a phase 3, open‐label study to assess the efficacy and safety of an all‐oral combination of the NS5B polymerase inhibitor sofosbuvir and ribavirin in patients with chronic genotype 2 HCV infection in Japan. We enrolled 90 treatment‐naïve and 63 previously treated patients at 20 sites in Japan. All patients received sofosbuvir 400 mg plus ribavirin (weight‐based dosing) for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after therapy (SVR12). Of the 153 patients enrolled and treated, 60% had HCV genotype 2a, 11% had cirrhosis, and 22% were over the aged 65 or older. Overall, 148 patients (97%) achieved SVR12. Of the 90 treatment‐naïve patients, 88 (98%) achieved SVR12, and of the 63 previously treated patients, 60 (95%) achieved SVR12. The rate of SVR12 was 94% in patients with cirrhosis and in those aged 65 and older. No patients discontinued study treatment due to adverse events. The most common adverse events were nasopharyngitis, anaemia and headache. Twelve weeks of sofosbuvir and ribavirin resulted in high rates of SVR12 in treatment‐naïve and previously treated patients with chronic genotype 2 HCV infection. The treatment was safe and well tolerated by patients, including the elderly and those with cirrhosis.
Background White matter hyperintensity (WMH) on magnetic resonance imaging (MRI) of the brain is associated with vascular cognitive impairment, cardiovascular disease, and stroke. We hypothesized ...that portable magnetic resonance imaging (pMRI) could successfully identify WMHs and facilitate doing so in an unconventional setting. Methods and Results In a retrospective cohort of patients with both a conventional 1.5 Tesla MRI and pMRI, we report Cohen's kappa (κ) to measure agreement for detection of moderate to severe WMH (Fazekas ≥2). In a subsequent prospective observational study, we enrolled adult patients with a vascular risk factor being evaluated in the emergency department for a nonstroke complaint and measured WMH using pMRI. In the retrospective cohort, we included 33 patients, identifying 16 (49.5%) with WMH on conventional MRI. Between 2 raters evaluating pMRI, the interrater agreement on WMH was strong (κ=0.81), and between 1 rater for conventional MRI and the 2 raters for pMRI, intermodality agreement was moderate (κ=0.66, 0.60). In the prospective cohort we enrolled 91 individuals (mean age, 62.6 years; 53.9% men; 73.6% with hypertension), of which 58.2% had WMHs on pMRI. Among 37 Black and Hispanic individuals, the Area Deprivation Index was higher (versus White, 51.8±12.9 versus 37.9±11.9;
<0.001). Among 81 individuals who did not have a standard-of-care MRI in the preceding year, we identified WMHs in 43 of 81 (53.1%). Conclusions Portable, low-field imaging could be useful for identifying moderate to severe WMHs. These preliminary results introduce a novel role for pMRI outside of acute care and the potential role for pMRI to reduce disparities in neuroimaging.
ABSTRACT
Introduction
Hypocalcemia at hospital presentation is associated with increased mortality in trauma patients with hemorrhagic shock. The 2019 updates to the Joint Trauma System Damage ...Control Resuscitation (DCR) Clinical Practice Guideline recommend calcium supplementation for ionized calcium (iCa) measurements <1.2 mmol/L. Ionized calcium goals for en route critical care (ERCC) following DCR are less defined, and the impact of in-flight hypocalcemia events among critically injured combat wounded is unknown. This study aimed to describe the association between hypocalcemia and mortality for combat-wounded with brain injury and polytrauma requiring transport by Critical Care Air Transport Teams (CCATT).
Methods
We performed a secondary analysis of a retrospective cohort of patients with moderate-to-severe traumatic brain injury transported by CCATT out of combat theater between January 2007 and May 2014. Additional inclusion criteria included polytrauma and at least one documented in-flight iCa measurement. We categorized exposures based on the minimum in-flight iCa measurement as severe hypocalcemia (iCa <0.9 mmol/L), hypocalcemia (iCa 0.9-1.11 mmol/L), and never hypocalcemic (iCa ≥1.12 mmol/L). The primary outcome measure was mortality. We calculated descriptive statistics and performed multivariate logistic regression to assess the association between hypocalcemia and mortality.
Results
We analyzed 190 subjects, with a median age of 24 years (interquartile range IQR 21 to 29 years) and 97.7% male gender. Explosive injuries (82.1%) and gunshot wounds (6.3%) were the most common mechanisms of injury. The median injury severity score was 34 (IQR 27 to 43). During the flight, 11.6% of patients had severe hypocalcemia, and 39.5% had hypocalcemia. Among patients with any hypocalcemia measurement in-flight (n = 97), 41.2% had hypocalcemia on pre-flight iCa, 28.9% received blood products in-flight, and 23.7% received in-flight calcium supplementation. Only 32.4% of patients with hypocalcemia or severe hypocalcemia in the setting of vasopressor administration received in-flight calcium supplementation. There was no significant difference in mortality between severe hypocalcemia (9.1%), hypocalcemia (5.3%), and never hypocalcemic (3.2%) patients even after controlling for pre-flight variables.
Conclusion
In-flight hypocalcemia events were common among critically ill combat-wounded polytrauma patients transported by CCATT but were not associated with differences in mortality. Future training should emphasize the need for calcium correction among ERCC patients requiring vasopressors. Future studies with larger sample sizes of patients receiving ERCC are needed to assess the association between in-flight calcium supplementation with clinical outcomes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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