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In 2016, a 68-year-old patient with a disseminated multidrug-resistant Acinetobacter baumannii infection was successfully treated using lytic bacteriophages. Here we report the genomes of the nine phages used for treatment and three strains of A. baumannii isolated prior to and during treatment. The phages used in the initial treatment are related, T4-like myophages. Analysis of 19 A. baumannii isolates collected before and during phage treatment shows that resistance to the T4-like phages appeared two days following the start of treatment. We generate complete genomic sequences for three A. baumannii strains (TP1, TP2 and TP3) collected before and during treatment, supporting a clonal relationship. Furthermore, we use strain TP1 to select for increased resistance to five of the phages in vitro, and identify mutations that are also found in phage-insensitive isolates TP2 and TP3 (which evolved in vivo during phage treatment). These results support that in vitro investigations can produce results that are relevant to the in vivo environment. A patient with a multidrug-resistant bacterial infection was successfully treated in 2016 using phage therapy. Here, the authors sequence the genomes of the therapeutic phages and three bacterial strains isolated before and during treatment, and show that the same mutations conferring phage resistance are found in in vitro-generated mutants and in phage-insensitive strains isolated from the patient.

In 2016, a 68-year-old patient with a disseminated multi-drug resistant Acinetobacter baumannii infection was treated using lytic bacteriophages in one of the first modern human clinical uses of phage therapy in the United States. Due to the emergency nature of the treatment there was little time to thoroughly characterize the phages used in this intervention or the pathogen itself. Here we report the genomes of the nine phages used for treatment and three strains of A. baumannii isolated prior to and during treatment. The eight phages used in the initial treatment were found to be a group of closely related T4-like myophages; the ninth phage, AbTP3Φ1, was found to be an unrelated Fri1-like podophage. Analysis of 19 A. baumannii isolates collected before and during phage treatment showed that resistance to the T4-like phages appeared as early as two days following the start of treatment. Three A. baumannii strains (TP1, TP2 and TP3) collected before and during treatment were sequenced to closure, and all contained a 3.9 Mb chromosome of sequence type 570 with a KL116 capsule locus and identical 8.7 kb plasmids. Phage-insensitive mutants of A. baumannii strain TP1 were generated in vitro and the majority of identified mutations were located in the bacterial capsule locus. The presence of the same mutation in both the in vitro mutants and in phage-insensitive isolates TP2 and TP3, which evolved in vivo during phage treatment, indicate that in vitro investigations can produce results that are relevant and predictive for the in vivo environment.

Objectives: Osteochondral allografts of the patellar are currently matched solely based on tibial width. It is currently unknown whether matching by tibial width is a reasonable surrogate measurement to allow for optimum chondral surface matching or if patellar size and/or surface morphology (i.e., Wiberg classification) should be taken into account. This consideration may be especially important for chondral defects on the patellar apex. The purpose of this study was to use circumferential step-off height and chondral surface mapping to determine if differences in patellar surface morphology (i.e., Wiberg classification) play a role in the ability of donor patellar osteochondral allografts to match the native patellar surface when treating osteochondral defects involving the central ridge of the patella. The secondary purpose was to explore the relationship between tibial width and patellar size (width and height) to determine if tibial width strongly related to patellar size to allow it to act as a surrogate measure for patellar size. Methods: Twenty (10 Wiberg I and 10 Wiberg II/III) fresh frozen patellae were designated as the recipient. Each recipient was size-matched (within ± 2mm tibial width) to both a Wiberg I and a Wiberg II/III patellar donor to produce 20 size-matched trios. All patellas were classified as Wiberg I, II, or III by visual inspection. The patellar height and widths were also measured. The recipient patella underwent initial nanoCT scanning to quantify the native chondral surface morphology. A 16mm circular osteochondral “defect” centered on the central ridge of the patella was then created in the recipient patella. Within each set of three patellae, the donor Wiberg I and Wiberg II/III patellae were randomly assigned, using a random number generator, to be transplanted first or second. The randomly ordered donor Wiberg I or Wiberg II/III plug was harvested from a homologous location and transplanted into the recipient. The recipient was then nano-CT scanned, digitally reconstructed, registered to the initial nano-CT scan of the recipient patella. It was then processed in Dragon Fly to determine circumferential step-off heights between the native and donor surfaces at three degree intervals. This was calculated for the entire circumference and for each quadrant (superior, medial, inferior, lateral) to determine if the ste-off heights varied by locations. MATLAB was used to determine the height deviation (dRMS) between the native and donor surfaces at over 3000 surface points (Figure 1). The initial transplant was carefully removed and the process was then repeated for the other donor allograft. Pearson correlation coefficient, 2-way ANOVA with Tukey’s multiple comparison, and paired t-tests were used when appropriate. Sample size of 10 trios was determined based on previous work in our lab (clinically relevant difference of 0.75mm, SD = 0.5mm, α = 0.05, power 0.8; 7 samples per group). Results: There was no significant difference in mean step-off heights between matched and unmatched Wiberg allograft plugs (Table 1). When analyzing all patellas, the superior (p = 0.01) and lateral (p = 0.001) quadrants demonstrated step-off heights that were significantly greater compared to the inferior quadrant, however these findings were not clinically significant. There was a statistically significant difference in height deviation over the whole surface between native and donor plugs when comparing matched and unmatched Wiberg plugs (p=0.049), however this finding was not clinically significant (Table 2). There was no difference across individual quadrants. There was a linear correlation when comparing tibial width to patellar width (r = 0.82) and patellar height (r = 0.68). Conclusions: Differences in Wiberg classification did not lead to clinically relevant differences in step-off height or surface height deviations for the whole donor plug or by quadrant. Tibial width is a reasonable measure to predict patellar size (width and height). It is therefore reasonable to continue matching osteochondral allografts of the patella based on the easy to measure value of tibial width without consideration for patellar size or Wiberg classification. Table 1. Mean ± SD step-off height measurements (in mm) for the medial, lateral, superior, and inferior quadrants, and whole patella for matched (n = 20), unmatched (n = 20), and all (n = 40) patallas. Note that all patellas superior and lateral was statistically different than inferior (*0=0.01 +0=0.001) Circumferential Step-Off Height Matched Wiberg (n=20) Unmatched Wiberg (n=20) All Patellas (n=40) Medial 0.44 ± 0.21 0.57 ± 0.35 0.51 ± 0.30 Lateral 0.54 ± 0.20 0.66 ± 0.42 0.60 ± 0.33* Superior 0.57 ± 0.23 0.55 ± 0.21 0.56 ± 0.22+ Inferior 0.32 ± 0.17 0.41 ± 0.19 0.36 ± 0.18 Total 0.55 ± 0.18 0.60 ± 0.26 0.57 ± 0.22 Table 2. Mean ± SD surface deviation (in mm) for medial, lateral, superior, and inferior quadrants, and whole patella for matched (n =20) and unmatched (n = 20) Wiberg donor transplants Circumferential Step-Off Height Matched Wiberg (n=20) Unmatched Wiberg (n=20) P Medial 0.48 ± 0.20 0.51 ± 0.26 0.994 Lateral 0.42 ± 0.24 0.49 ± 0.22 0.889 Superior 0.48 ± 0.23 0.59 ± 0.30 0.576 Inferior 0.43 ± 0.24 0.58 ± 0.35 0.262 Total 0.50 ± 0.14 0.64 ± 0.25 0.049

Remarkable advances in high-throughput sequencing have enabled major biological discoveries and clinical applications, but achieving wider distribution and use depends critically on further improvements in scale and cost reduction. Nanopore sequencing has long held the promise for such progress, but has had limited market penetration. This is because efficient and accurate nanopore sequencing of nucleic acids has been challenged by fundamental signal-to-noise limitations resulting from the poor spatial resolution and molecular distinction of nucleobases. Here, we describe Sequencing by Expansion (SBX), a single-molecule sequencing technology that overcomes these limitations by using a biochemical conversion process to encode the sequence of a target nucleic acid molecule into an Xpandomer, a highly measurable surrogate polymer. Expanding over 50 times longer than the parent DNA templates, Xpandomers are engineered with high signal-to-noise reporter codes to enable facile, high-accuracy nanopore sequencing. We demonstrate the performance of SBX and present the specialized molecular structures, chemistries, enzymes and methods that enable it. The innovative molecular and systems engineering in SBX create a transformative technology to address the needs of existing and emerging sequencing applications.

The broader definition of fiduciary increases risks that could cause some companies to limit or cease providing certain services and products. [...]many current service support functions that educate consumers and provide non-fiduciary guidance will be curtailed. [...]cybersecurity and privacy are now regulatory issues as well. [...]financial services companies are at great risk. The Greatest Impact In summary, the forces that will have the greatest impact on financial services in the short term are: * Escalated levels of regulatory activity * The changing consumer and consumer preferences * Technology - in the form of larger-scale data analytics and cybersecurity risk * Innovation - in particular, looking beyond North America for ideas and inspiration * Talent management and the evolution of recruiting, training, and retention programs While these certainly represent an overwhelming array of considerations, the cost of neglecting them is even greater.