Convergent evolution has been demonstrated across all levels of biological organization, from parallel nucleotide substitutions to convergent evolution of complex phenotypes, but whether instances of convergence are the result of selection repeatedly finding the same optimal solution to a recurring problem or are the product of mutational biases remains unsettled. We generated 20 replicate lineages allowed to fix a single mutation from each of four bacteriophage genotypes under identical selective regimes to test for parallel changes within and across genotypes at the levels of mutational effect distributions and gene, protein, amino acid, and nucleotide changes. All four genotypes shared a distribution of beneficial mutational effects best approximated by a distribution with a finite upper bound. Parallel adaptation was high at the protein, gene, amino acid, and nucleotide levels, both within and among phage genotypes, with the most common first-step mutation in each background fixing on an average in 7 of 20 replicates and half of the substitutions in two of the four genotypes occurring at shared sites. Remarkably, the mutation of largest beneficial effect that fixed for each genotype was never the most common, as would be expected if parallelism were driven by selection. In fact, the mutation of smallest benefit for each genotype fixed in a total of 7 of 80 lineages, equally as often as the mutation of largest benefit, leading us to conclude that adaptation was largely mutation-driven, such that mutational biases led to frequent parallel fixation of mutations of suboptimal effect.

Background: The use of propofol for palliative sedation of children is not well documented. Objective: Here we describe our experience with the use of propofol palliative sedation therapy (PST) to alleviate intractable end-of-life suffering in three pediatric oncology patients, and propose an algorithm for the selection of such candidates for PST. Patients and Methods: We identified inpatients who had received propofol PST within 20 days of death at our institution between 2003 and 2010. Their medical records were reviewed for indicators of pain, suffering, and sedation from 48 hours before PST to the time of death. We also tabulated consumption of opioids and other symptom management medications, pain scores, and adverse events of propofol, and reviewed clinical notes for descriptors of suffering and/or palliation. Results: Three of 192 (1.6%) inpatients (aged 6-15 years) received propofol PST at the end of life. Consumption of opioids and other supportive medications decreased during PST in two cases. In the third case, pain scores remained high and sedation was the only effective comfort measure. Clinical notes suggested improved comfort and rest in all patients. Propofol infusions were continued until the time of death. Conclusions: Our experience demonstrates that propofol PST is a useful palliative option for pediatric patients experiencing intractable suffering at the end of life. We describe an algorithm that can be used to identify such children who are candidates for PST.

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ObjectivesOf the Social Determinants of Health (SDoH), we evaluated socioeconomic and neighborhood-related factors which may affect children with medical complexity (CMC) admitted to a Pediatric Intensive Care Unit (PICU) in Shelby County, Tennessee with severe sepsis and their association with PICU length of stay (LOS). We hypothesized that census tract-level socioeconomic and neighborhood factors were associated with prolonged PICU LOS in CMC admitted with severe sepsis in the underserved community.MethodsThis single-center retrospective observational study included CMC living in Shelby County, Tennessee admitted to the ICU with severe sepsis over an 18-month period. Severe sepsis CMC patients were identified using an existing algorithm incorporated into the electronic medical record at a freestanding children's hospital. SDoH information was collected and analyzed using patient records and publicly available census-tract level data, with ICU length of stay as the primary outcome.Results83 encounters representing 73 patients were included in the analysis. The median PICU LOS was 9.04 days (IQR 3.99–20.35). The population was 53% male with a median age of 4.1 years (IQR 1.96–12.02). There were 57 Black/African American patients (68.7%) and 85.5% had public insurance. Based on census tract-level data, about half (49.4%) of the CMC severe sepsis population lived in census tracts classified as suffering from high social vulnerability. There were no statistically significant relationships between any socioeconomic and neighborhood level factors and PICU LOS.ConclusionPediatric CMC severe sepsis patients admitted to the PICU do not have prolonged lengths of ICU stay related to socioeconomic and neighborhood-level SDoH at our center. A larger sample with the use of individual-level screening would need to be evaluated for associations between social determinants of health and PICU outcomes of these patients.

Background: Talectomy has been used as a salvage procedure to correct severe and rigid foot deformities in patients with underlying neuromuscular conditions. Previous clinical reports have failed to compare outcomes based on the underlying condition. We report predictors of outcomes in patients who were treated with talectomy over 23 yr. Methods: We retrospectively reviewed the patients who underwent total talectomy from 1987 to 2010. Clinical results were graded as “good” and “poor” depending on postoperative pain, degree of equinus, skin findings, and the ability to brace. Postoperative lateral radiographs of the ankle were reviewed to determine tibiocalcaneal angle and retained talus. Statistical analysis was used to evaluate the effect of underlying diagnosis and tibiocalcaneal angle on the clinical outcome. Results: Thirty-eight patients (58 feet) were included in the study. The average length of follow-up was 5.1 yr. Fifty operated feet (86.2%) had a “good” outcome. Average tibiocalcaneal angle was 73.92 degrees in patients with outcomes categorized as good compared to 99.75 degrees in patients with outcomes categorized as poor (P=0.012). Of the feet with myelomeningocele, 96.3% (26 feet) had outcomes categorized as good compared to 75% of feet (9 of 12) with arthrogryposis. The clinical outcome was significantly better in patients with myelomeningocele compared to patients with arthrogryposis (P=0.04). Conclusions: Talectomy can be used as a salvage procedure to achieve a pain-free, plantigrade, and braceable foot in patients with a variety of musculoskeletal disorders. A tibiocalcaneal angle of less than 90 degrees at final follow-up and a diagnosis of myelomeningocele correlated with “good” clinical outcomes, aiding clinicians in preoperative stratification based on underlying diagnosis. Level of Evidence: Level III.