A novel assay for endotoxin, based on the ability of antigen-antibody complexes to prime neutrophils for an augmented respiratory burst response, was studied in a cohort study of 857 patients ...admitted to an intensivecare unit (ICU). On the day of ICU admission, 57.2% of patients had either intermediate (⩾0.40 endotoxin activity EA units) or high (⩾0.60 units) EA levels. Gram-negative infection was present in 1.4% of patients with low EA levels, 4.9% with intermediate levels, and 6.9% with high levels; EA had a sensitivity of 85.3% and a specificity of 44.0% for the diagnosis of gram-negative infection. Rates of severe sepsis were 4.9%, 9.2%, and 13.2%, and ICU mortality was 10.9%, 13.2%, and 16.8% for patients with low, intermediate, and high EA levels, respectively. Stepwise logistic regression analysis showed that elevated Acute Physiology and Chronic Health Evaluation II score, gram-negative infection, and emergency admission status were independent predictors of EA.
IMPORTANCE: Despite the increasing prevalence of pregravid obesity, systematic evaluation of the association of maternal obesity with fetal growth trajectories is lacking. OBJECTIVE: To characterize ...differences in fetal growth trajectories between obese and nonobese pregnant women, and to identify the timing of any observed differences. DESIGN, SETTING, AND PARTICIPANTS: The Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies–Singletons study enrolled cohorts of pregnant women at 12 US health care institutions. Obese women (with prepregnancy body mass index > 30) and nonobese women (prepregnancy body mass indexes, 19-29.9) without major chronic diseases were recruited between 8 weeks and 0 days’ gestation and 13 weeks and 6 days’ gestation. A mixed longitudinal randomization scheme randomized participants into 1 of 4 schedules for 2-dimensional and 3-dimensional ultrasonograms to capture weekly fetal growth data throughout the remainder of their pregnancies. MAIN OUTCOMES AND MEASURES: On each ultrasonogram, fetal humerus length, femur length, biparietal diameter, head circumference, and abdominal circumference were measured. Fetal growth curves were estimated using linear mixed models with cubic splines. Median differences in the fetal measures at each gestational week of the obese and nonobese participants were examined using the likelihood ratio and Wald tests after adjustment for maternal characteristics. RESULTS: The study enrolled 468 obese and 2334 nonobese women between 8 weeks and 0 days’ gestation and 13 weeks and 6 days’ gestation. After a priori exclusion criteria, 443 obese and 2320 nonobese women composed the final cohort. Commencing at 21 weeks’ gestation, femur length and humerus length were significantly longer for fetuses of obese woman than those of nonobese women. Differences persisted in obese and nonobese groups through 38 weeks’ gestation (median femur length, 71.0 vs 70.2 mm; P = .01; median humerus length, 62.2 vs 61.6 mm; P = .03). Averaged across gestation, head circumference was significantly larger in fetuses of obese women than those of nonobese women (P = .02). Fetal abdominal circumference was not greater in the obese cohort than in the nonobese cohort but was significantly larger than in fetuses of normal-weight women (with body mass indexes between 19.0-24.9) commencing at 32 weeks (median, 282.1 vs 280.2 mm; P = .04). Starting from 30 weeks’ gestation, estimated fetal weight was significantly larger for the fetuses of obese women (median, 1512 g 95% CI, 1494-1530 g vs 1492 g 95% CI, 1484-1499 g) and the difference grew as gestational age increased. Birth weight was higher by almost 100 g in neonates born to obese women than to nonobese women (mean, 3373.2 vs 3279.5 g). CONCLUSIONS AND RELEVANCE: As early as 32 weeks’ gestation, fetuses of obese women had higher weights than fetuses of nonobese women. The mechanisms and long-term health implications of these findings are not yet established.
Bacteriophage genomes harbor the broadest chemical diversity of nucleobases across all life forms. Certain DNA viruses that infect hosts as diverse as cyanobacteria, proteobacteria, and ...actinobacteria exhibit wholesale substitution of aminoadenine for adenine, thereby forming three hydrogen bonds with thymine and violating Watson-Crick pairing rules. Aminoadenine-encoded DNA polymerases, homologous to the Klenow fragment of bacterial DNA polymerase I that includes 3'-exonuclease but lacks 5'-exonuclease, were found to preferentially select for aminoadenine instead of adenine in deoxynucleoside triphosphate incorporation templated by thymine. Polymerase genes occur in synteny with genes for a biosynthesis enzyme that produces aminoadenine deoxynucleotides in a wide array of
bacteriophages. Congruent phylogenetic clustering of the polymerases and biosynthesis enzymes suggests that aminoadenine has propagated in DNA alongside adenine since archaic stages of evolution.
Two experiments examine the interplay of injunctive and descriptive norms on intentions to engage in pro-environmental behavior. In Experiment 1, Australian participants were exposed to supportive or ...unsupportive group descriptive and injunctive norms about energy conservation. Results revealed that a conflict between the group-level injunctive and descriptive norm was associated with weaker behavioral intentions: The beneficial effects of a supportive injunctive norm were undermined when presented with an unsupportive descriptive norm. Experiment 2 replicated this effect in both a Western (UK) and non-Western (China) context, and found that the extent to which norms were aligned or not determined intentions even after controlling for attitudes, perceptions of control, and interpersonal-level injunctive and descriptive norms. These experiments demonstrate that conflict between injunctive and descriptive norms leads to weaker intentions to engage in pro-environmental behavior, highlighting the need to consider the interplay between injunctive and descriptive norms to understand how norms influence behavioral intentions.
► Two experiments examine the interplay of injunctive and descriptive norms. ► Conflict between the injunctive and descriptive norm produces weaker intentions. ► This is true in individualist (Australia; UK) and collectivist (China) cultures.
In the present study, we have presented and validated a plastic scintillation detector (PSD) system designed for real-time multiprobe in vivo measurements.
The PSDs were built with a dose-sensitive ...volume of 0.4 mm(3). The PSDs were assembled into modular detector patches, each containing five closely packed PSDs. Continuous dose readings were performed every 150 ms, with a gap between consecutive readings of <0.3 ms. We first studied the effect of electron multiplication. We then assessed system performance in acrylic and anthropomorphic pelvic phantoms.
The PSDs were compatible with clinical rectal balloons and were easily inserted into the anthropomorphic phantom. With an electron multiplication average gain factor of 40, a twofold increase in the signal/noise ratio was observed, making near real-time dosimetry feasible. Under calibration conditions, the PSDs agreed with the ion chamber measurements to 0.08%. Precision, evaluated as a function of the total dose delivered, ranged from 2.3% at 2 cGy to 0.4% at 200 cGy.
Real-time PSD measurements are highly accurate and precise. These PSDs can be mounted onto rectal balloons, transforming these clinical devices into in vivo dose detectors without modifying current clinical practice. Real-time monitoring of the dose delivered near the rectum during prostate radiotherapy should help radiation oncologists protect this sensitive normal structure.
IMPORTANCE: The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown. OBJECTIVE: To assess the effect of tirzepatide, with diet and physical activity, on ...the maintenance of weight reduction. DESIGN, SETTING, AND PARTICIPANTS: This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes. INTERVENTIONS: Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period. RESULTS: Participants (n = 670; mean age, 48 years; 473 71% women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was −5.5% with tirzepatide vs 14.0% with placebo (difference, −19.4% 95% CI, −21.2% to −17.7%; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo. CONCLUSIONS AND RELEVANCE: In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04660643
Diffuse large B-cell lymphoma (DLBCL) presents as a limited-stage disease in 25% to 30% of patients, with better overall survival (OS) than that for advanced-stage disease but with continuous relapse ...regardless of treatment approach. The preferred treatment is abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and radiation therapy. On the basis of promising results of positron emission tomography (PET)-directed treatment approaches, we designed a National Clinical Trials Network (NCTN) study to improve outcomes and decrease toxicity.
Patients with nonbulky (< 10 cm) stage I/II untreated DLBCL received 3 cycles of standard R-CHOP therapy and underwent a centrally reviewed interim PET/computed tomography scan (iPET). Those with a negative iPET proceeded with 1 additional cycle of R-CHOP, whereas those with a positive iPET received involved field radiation therapy followed by ibritumomab tiuxetan radioimmunotherapy.
Of 158 patients enrolled, 132 were eligible and 128 underwent iPET, which was positive in 14 (11%) of the patients. With a median follow-up of 4.92 years (range, 1.1-7.7 years), only 6 patients progressed and 3 died as a result of lymphoma. Eleven patients died as a result of nonlymphoma causes at a median age of 80 years. The 5-year progression-free survival estimate was 87% (95% CI, 79% to 92%) and the OS estimate was 89% (95% CI, 82% to 94%), with iPET-positive and iPET-negative patients having similar outcomes.
To our knowledge, S1001 is the largest prospective study in the United States of limited-stage DLBCL in the rituximab era, with the best NCTN results in this disease subset. With PET-directed therapy, 89% of the patients with a negative iPET received R-CHOP × 4, and only 11% had a positive iPET and required radiation, with both groups having excellent outcomes. The trial establishes R-CHOP × 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients.
Accurately identifying pregnancies with accelerated or diminished fetal growth is challenging and generally based on cross-sectional percentile estimates of fetal weight. Longitudinal growth velocity ...might improve identification of abnormally grown fetuses.
We sought to complement fetal size standards with fetal growth velocity, develop a model to compute fetal growth velocity percentiles for any given set of gestational week intervals, and determine association between fetal growth velocity and birthweight.
This was a prospective cohort study with data collected at 12 US sites (2009 through 2013) from 1733 nonobese, low-risk pregnancies included in the singleton standard. Following a standardized sonogram at 10w0d–13w6d, each woman was randomized to 1 of 4 follow-up visit schedules with 5 additional study sonograms (targeted ranges: 16–22, 24–29, 30–33, 34–37, and 38–41 weeks). Study visits could occur ± 1 week from the targeted GA. Ultrasound biometric measurements included biparietal diameter, head circumference, abdominal circumference, and femur length, and estimated fetal weight was calculated. We used linear mixed models with cubic splines for the fixed effects and random effects to flexibly model ultrasound trajectories. We computed velocity percentiles in 2 ways: (1) difference between 2 consecutive weekly measurements (ie, weekly velocity), and (2) difference between any 2 ultrasounds at a clinically reasonable difference between 2 gestational ages (ie, velocity calculator). We compared correlation between fetal growth velocity percentiles and estimated fetal weight percentiles at 4-week intervals, with 32 (±1) weeks’ gestation for illustration. Growth velocity was computed as estimated fetal growth rate (g/wk) between ultrasound at that gestational age and from prior visit ie, for 28–32 weeks’ gestational age: velocity = (estimated fetal weight 32–28)/(gestational age 32–28). We examined differences in birthweight by whether or not estimated fetal weight and estimated fetal weight velocity were <5th or ≥5th percentiles using χ2.
Fetal growth velocity was nonmonotonic, with acceleration early in pregnancy, peaking at 13, 14, 15, and 16 weeks for biparietal diameter, head circumference, femur length, and abdominal circumference, respectively. Biparietal diameter, head circumference, and abdominal circumference had a second acceleration at 19–22, 19–21, and 27–31 weeks, respectively. Estimated fetal weight velocity peaked around 35 weeks. Fetal growth velocity varied slightly by race/ethnicity although comparisons reflected differences for parameters at various gestational ages. Estimated fetal weight velocity percentiles were not highly correlated with fetal size percentiles (Pearson r = 0.40–0.41, P < .001), suggesting that these measurements reflect different aspects of fetal growth and velocity may add additional information to a single measure of estimated fetal weight. At 32 (SD ± 1) weeks, if both estimated fetal weight velocity and size were <5th percentile, mean birthweight was 2550 g; however, even when size remained <5th percentile but velocity was ≥5th percentile, birthweight increased to 2867 g, reflecting the important contribution of higher growth velocities. For estimated fetal weight ≥5th percentile, but growth velocity <5th, birthweight was smaller (3208 vs 3357 g, respectively, P < .001).
We provide fetal growth velocity data to complement our previous work on fetal growth size standards, and have developed a calculator to compute fetal growth velocity. Preliminary findings suggest that growth velocity adds additional information over knowing fetal size alone.
Mediastinal infections are a potentially devastating complication of cardiac operations. This study analyzed the frequency, risk factors, and perioperative outcomes of mediastinal infections after ...cardiac operations.
In 2010, 5,158 patients enrolled in a prospective study evaluating infections after cardiac operations and their effect on readmissions and mortality for up to 65 days after the procedure. Clinical and demographic characteristics, operative variables, management practices, and outcomes were compared for patients with and without mediastinal infections, defined as deep sternal wound infection, myocarditis, pericarditis, or mediastinitis.
There were 43 mediastinal infections in 41 patients (cumulative incidence, 0.79%; 95% confidence interval CI 0.60% to 1.06%). Median time to infection was 20.0 days, with 65% of infections occurring after the index hospitalization discharge. Higher body mass index (hazard ratio HR 1.06; 95% CI, 1.01 to 1.10), higher creatinine (HR, 1.25; 95% CI, 1.13 to 1.38), peripheral vascular disease (HR, 2.47; 95% CI, 1.21 to 5.05), preoperative corticosteroid use (HR, 3.33; 95% CI, 1.27 to 8.76), and ventricular assist device or transplant surgery (HR, 5.81; 95% CI, 2.36 to 14.33) were associated with increased risk of mediastinal infection. Postoperative hyperglycemia (HR, 3.15; 95% CI, 1.32 to 7.51) was associated with increased risk of infection in nondiabetic patients. Additional length of stay attributable to mediastinal infection was 11.5 days (bootstrap 95% CI, 1.88 to 21.11). Readmission rates and mortality were five times higher in patients with mediastinal infection than in patients without mediastinal infection.
Mediastinal infection after a cardiac operation is associated with substantial increases in length of stay, readmissions, and death. Reducing these infections remains a high priority, and improving post-operative glycemic management may reduce their risk in patients without diabetes.
In this study involving patients with new-onset postoperative atrial fibrillation who received either rate control or rhythm control, there was no significant difference in rates of hospitalization, ...complications, or persistent atrial fibrillation 60 days after onset.
In recent years, much research has focused on the prevention of atrial fibrillation after cardiac surgery, but highly effective interventions are lacking. Thus, postoperative atrial fibrillation remains the most common complication after cardiac surgery, with an incidence of 20 to 50%.
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This complication has major adverse consequences for patients and the health care system, including increased rates of death, complications, and hospitalizations and inflated costs.
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Therefore, efforts to determine the most effective preventive strategies and management practices are important. There are two general approaches to managing postoperative atrial fibrillation: heart-rate control (hereafter “rate control”) and rhythm control with . . .
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