Mfd Dynamically Regulates Transcription via a Release and Catch-Up Mechanism.

The bacterial Mfd ATPase is increasingly recognized as a general transcription factor that participates in the resolution of transcription conflicts with other processes/roadblocks. This function stems from Mfd's ability to preferentially act on stalled RNA polymerases (RNAPs). However, the mechanism underlying this preference and the subsequent coordination between Mfd and RNAP have remained elusive. Here, using a novel real-time translocase assay, we unexpectedly discovered that Mfd translocates autonomously on DNA. The speed and processivity of Mfd dictate a "release and catch-up" mechanism to efficiently patrol DNA for frequently stalled RNAPs. Furthermore, we showed that Mfd prevents RNAP backtracking or rescues a severely backtracked RNAP, allowing RNAP to overcome stronger obstacles. However, if an obstacle's resistance is excessive, Mfd dissociates the RNAP, clearing the DNA for other processes. These findings demonstrate a remarkably delicate coordination between Mfd and RNAP, allowing efficient targeting and recycling of Mfd and expedient conflict resolution.

Buprenorphine for acute pain in older adults: a systematic review with meta-analysis.

BACKGROUND: Buprenorphine, a partial opioid agonist, has emerging evidence as an alternative to full agonist opioids for treatment of acute pain. This systematic review aimed to evaluate the safety and efficacy of buprenorphine for acute pain in older adults. METHODS: PubMed Medline, Embase, Cochrane Central Register of Controlled Trials, CINHAL, Web of Science database, and Google Scholar were searched. We included articles that reported buprenorphine as an intervention to treat acute pain among patients 60 years or older. Primary outcome was difference in pain scores for patients treated with buprenorphine compared to other analgesia. Secondary outcomes included adverse events, opioid consumption, and patient satisfaction. Meta-analysis was conducted on difference in pain scores and differences in nausea and vomiting. RESULTS: Twenty-two studies were included (n = 2610). Buprenorphine was administered as nerve blocks in six studies, transdermal in eight, intravenous or intramuscular in five, sublingual in two studies, and both intravenous and sublingual in one study. 10 out of 20 (50%) studies found improved pain control in buprenorphine groups. Meta-analysis found no significant difference in pain scores between buprenorphine and control analgesia at 24 hours (Cohen's d = -0.29 [95% CI -0.85 to 0.27]) and 7 days (Cohen's d = -0.89 [95% CI -2.66-0.88]). Six studies (54.5%) found reduced opioid consumption in patients receiving buprenorphine. There was no difference in adverse effects in most studies. CONCLUSIONS: This review did not find buprenorphine to be superior to alternative analgesia; however the mixed results provide scientific rationale for future studies testing buprenorphine in older populations.

Normative Values for Cardiopulmonary Exercise Stress Testing Using Ramp Cycle Ergometry in Children and Adolescents.

OBJECTIVES: To provide sex, age, and race specific reference values for ramp cycle ergometer cardiopulmonary exercise test (CPET) in children in the US. STUDY DESIGN: Retrospective review was conducted of all cardiopulmonary CPET data from our Exercise Physiology Laboratory on healthy children and adolescents (6-18 years) with body mass index between the 5th and 95th percentiles and structurally normal hearts who performed a ramp cycle ergometry stress test between 1999 and 2015. Twenty-eight exercise variables were included: peak oxygen consumption, oxygen consumption at ventilatory anaerobic threshold, peak work rate, resting and peak heart rate and blood pressure, resting pulmonary function testing, and ventilatory responses to progressive exercise using breath-by-breath gas exchange. Owing to the nonlinear association between CPET results and age, fractional polynomials were used in the mixed-effects regression models to describe the sex- and age-specific normative values with 95% CIs, after adjusting for race and body mass index. RESULTS: We analyzed data on 1829 children (average age, 13.6 ± 2.6 years; 52% male). After 12 years of age, males generally had higher peak values for aerobic capacity and work rate. There were progressive increases with age for both sexes in resting pulmonary function and ventilatory response to exercise, peak aerobic and work rate, and oxygen pulse. Notably, there was an age-related decrease in ventilatory equivalents of oxygen and carbon dioxide at the ventilatory anaerobic threshold. CONCLUSIONS: Future research using prospective, inclusive, and statistically planned cohorts with standardized laboratory approaches and confirmed interoperability should be considered as a focus for validating normative pediatric CPET values in the future.

Single-unit vs multiple-unit transfusion in hemodynamically stable postpartum anemia: a pragmatic randomized controlled trial.

BACKGROUND: The American Academy of Blood Banks recommends single-unit red cell transfusion protocols across medicine to reduce transfusion complications and the use of a scarce resource. There are minimal data regarding single-unit protocols in obstetrics. OBJECTIVE: We aimed to compare single-unit vs multiple-unit transfusion protocols for treatment of hemodynamically stable postpartum anemia. STUDY DESIGN: We performed a randomized trial comparing initial transfusion with 1 unit of packed red blood cells (single-unit protocol) to 2 units of packed red blood cells (multiple-unit protocol) from March 2018 to July 2019. Women who required transfusion >6 hours postpartum were approached for consent. Unstable vital signs, hemoglobin level <5 g/dL, hemoglobinopathy, and cardiomyopathy were exclusion criteria for enrollment. Hemoglobin assessment and standardized clinical evaluation were performed 4 to 6 hours posttransfusion; additional packed red blood cells were given if indicated. The primary outcome was total units transfused. Secondary outcomes included length of stay, endometritis, wound separation or infection, venous thromboembolism, and intensive care unit admission within 30 days postpartum. Breastfeeding, depression, maternal attachment, and fatigue scores were assessed at 4 to 9 weeks postpartum. A total of 66 women were required to detect a 20% reduction in units transfused with a single-unit protocol (power=80%; α=0.05). RESULTS: A total of 66 women were randomized (33 per arm). There were no differences between groups in demographic or clinical characteristics, including delivery mode, blood loss, and randomization hemoglobin levels. The mean number of units transfused was lower in the single-unit protocol than in the multiple-unit protocol (1.2 U vs 2.1 U; P<.001). Only 18.2% of women in the single-unit arm required additional packed red blood cells. At posttransfusion assessment, women in the single-unit arm had lower hemoglobin levels (7.8 g/dL vs 8.7 g/dL; P<.001), but there were no differences in vital signs or symptoms between groups. There were also no differences in length of stay, 30-day complications, or 4 to 9 week postpartum outcomes. CONCLUSION: In women with hemodynamically stable postpartum anemia, a single-unit protocol avoided a second unit of packed red blood cells in >80% of women without significant impact on morbidity. Our work supports the use of single-unit initial transfusion in this population.