Cladogenesis and replacement in the fossil record of Microsyopidae (?Primates) from the southern Bighorn Basin, Wyoming.

The early Eocene of the southern Bighorn Basin, Wyoming, is notable for its nearly continuous record of mammalian fossils. Microsyopinae (?Primates) is one of several lineages that shows evidence of evolutionary change associated with an interval referred to as Biohorizon A. Arctodontomys wilsoni is replaced by a larger species, Arctodontomys nuptus, during the biohorizon interval in what is likely an immigration/emigration or immigration/local extinction event. The latter is then superseded by Microsyops angustidens after the end of the Biohorizon A interval. Although this pattern has been understood for some time, denser sampling has led to the identification of a specimen intermediate in morphology between A. nuptus and M. angustidens, located stratigraphically as the latter is appearing. Because specimens of A. nuptus have been recovered approximately 60 m above the appearance of M. angustidens, it is clear that A. nuptus did not suffer pseudoextinction. Instead, evidence suggests that M. angustidens branched off from a population of A. nuptus, but the latter species persisted. This represents possible evidence of cladogenesis, which has rarely been directly documented in the fossil record. The improved understanding of both evolutionary transitions with better sampling highlights the problem of interpreting gaps in the fossil record as punctuations.

Women With Spontaneous Coronary Artery Dissection Are at Increased Risk of Iatrogenic Coronary Artery Dissection.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic cause of acute coronary syndrome (ACS) that affects women disproportionately. Previous case series have found that patients with SCAD undergoing cardiac catheterisation have high rates of iatrogenic coronary damage. We formally compared the rate of iatrogenic coronary artery dissection in women with and without SCAD undergoing cardiac catheterisation over a 11-year period. METHODS: Women with SCAD were identified by a search of the cardiac catheterisation database 2007-2017 for the keywords 'SCAD', 'spontaneous coronary artery dissection', 'spontaneous coronary dissection', and 'spontaneous dissection'. For each identified case, the medical record and the coronary angiogram images were reviewed to confirm spontaneous coronary dissection. For cases of recurrent SCAD, duplicates were removed so that each patient was included only once in this analysis. For each identified case of SCAD, a control case was chosen from women aged <70 years, without SCAD, undergoing cardiac catheterisation for an ACS during the same 10-year period. One control case was chosen to match each SCAD patient as closely as possible for age and year of cardiac catheterisation. Iatrogenic coronary dissection was defined as new, proximal, flow limiting coronary artery dissection in a different coronary segment to the presenting spontaneous coronary dissection. RESULTS: Eighty-five (85) cases of women with SCAD were identified. Mean age was not different between SCAD and non-SCAD women (51±11 and 51±10 years, respectively). The SCAD group had lower rates of ST elevation myocardial infarction, lower rises in serum creatine kinase (CK) and troponin levels, lower rates of diabetes and smoking, and far less placement of stents during the procedure than the control group. The rate of additional iatrogenic dissection relating to the cardiac catheterisation procedure was 4 of 85 (4.7%) versus 0 of 85 (0%), p=0.04 in SCAD and control groups, respectively, despite a much lower rate of percutaneous coronary intervention in the SCAD group. No common factors could be identified regarding particular equipment or procedural factors associated with iatrogenic dissection. CONCLUSION: The rate of iatrogenic dissection in women with SCAD during cardiac catheterisation is confirmed to be high and significantly higher than a contemporaneous age-matched group of women without SCAD. This observation likely indicates generalised coronary fragility in this disease, and emphasises the importance of the utmost care in the engagement, injection and intervention involving the coronary arteries in this disease. Development of a non-invasive coronary imaging modality or biomarker able to diagnose SCAD non-invasively would be a great advance in the care of patients with this condition, because it would avoid the need for invasive coronary angiography for diagnosis.

The extended Price equation quantifies species selection on mammalian body size across the Palaeocene/Eocene Thermal Maximum.

Species selection, covariation of species' traits with their net diversification rates, is an important component of macroevolution. Most studies have relied on indirect evidence for its operation and have not quantified its strength relative to other macroevolutionary forces. We use an extension of the Price equation to quantify the mechanisms of body size macroevolution in mammals from the latest Palaeocene and earliest Eocene of the Bighorn and Clarks Fork Basins of Wyoming. Dwarfing of mammalian taxa across the Palaeocene/Eocene Thermal Maximum (PETM), an intense, brief warming event that occurred at approximately 56 Ma, has been suggested to reflect anagenetic change and the immigration of small bodied-mammals, but might also be attributable to species selection. Using previously reconstructed ancestor-descendant relationships, we partitioned change in mean mammalian body size into three distinct mechanisms: species selection operating on resident mammals, anagenetic change within resident mammalian lineages and change due to immigrants. The remarkable decrease in mean body size across the warming event occurred through anagenetic change and immigration. Species selection also was strong across the PETM but, intriguingly, favoured larger-bodied species, implying some unknown mechanism(s) by which warming events affect macroevolution.

Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response.

We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 x 10(12) vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of approximately 8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression.

Bridging Anatomy, Histology, and Pathology: A Novel Curriculum Component Incorporating Self-directed Learning for First-Year Medical Students.

During cadaveric dissection or prosection, medical students frequently encounter pathology that can be a springboard to further learning. We designed a novel educational activity linking anatomy, histology, and pathology that incorporated self-directed learning and teamwork, followed by feedback and instruction from pathologists. Post-activity, more than 97% of students rated the activity as useful (Likert scale of 1 to 5), indicating this activity should be continued in the future. Strengths included self-directed learning, content and design, and teamwork, peer, and faculty interactions. Clarity of assignment expectations, range of pathologies, and virtual presentation format remained areas for improvement.

AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B.

Hemophilia B is an X-linked coagulopathy caused by absence of functional coagulation factor IX (F.IX). Previously, we established an experimental basis for gene transfer as a method of treating the disease in mice and hemophilic dogs through intramuscular injection of a recombinant adeno-associated viral (rAAV) vector expressing F.IX. In this study we investigated the safety of this approach in patients with hemophilia B. In an open-label dose-escalation study, adult men with severe hemophilia B (F.IX < 1%) due to a missense mutation were injected at multiple intramuscular sites with an rAAV vector. At doses ranging from 2 x 10(11) vector genomes (vg)/kg to 1.8 x 10(12) vg/kg, there was no evidence of local or systemic toxicity up to 40 months after injection. Muscle biopsies of injection sites performed 2 to 10 months after vector administration confirmed gene transfer as evidenced by Southern blot and transgene expression as evidenced by immunohistochemical staining. Pre-existing high-titer antibodies to AAV did not prevent gene transfer or expression. Despite strong evidence for gene transfer and expression, circulating levels of F.IX were in all cases less than 2% and most were less than 1%. Although more extensive transduction of muscle fibers will be required to develop a therapy that reliably raises circulating levels to more than 1% in all subjects, these results of the first parenteral administration of rAAV demonstrate that administration of AAV vector by the intramuscular route is safe at the doses tested and effects gene transfer and expression in humans in a manner similar to that seen in animals.