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On December 13, 2019, the Yale School of Public Health hosted a symposium titled "Per- and Polyfluoroalkyl Substances (PFAS): Challenges and Opportunities" in New Haven, Connecticut. The meeting focused on the current state of the science on these chemicals, highlighted the challenges unique to PFAS, and explored promising opportunities for addressing them. It brought together participants from Yale University, the National Institute of Environmental Health Sciences, the University of Massachusetts Amherst, the University of Connecticut, the Connecticut Agricultural Experiment Station, the Connecticut Departments of Public Health and Energy and Environmental Protection, and the public and private sectors. Presentations during the symposium centered around several primary themes. The first reviewed the current state of the science on the health effects associated with PFAS exposure and noted key areas that warranted future research. As research in this field relies on specialized laboratory analyses, the second theme considered commercially available methods for PFAS analysis as well as several emerging analytical approaches that support health studies and facilitate the investigation of a broader range of PFAS. Since mitigation of PFAS exposure requires prevention and cleanup of contamination, the third theme highlighted new nanotechnology-enabled PFAS remediation technologies and explored the potential of green chemistry to develop safer alternatives to PFAS. The fourth theme covered collaborative efforts to assess the vulnerability of in-state private wells and small public water supplies to PFAS contamination by adjacent landfills, and the fifth focused on strategies that promote successful community engagement. This symposium supported a unique interdisciplinary coalition established during the development of Connecticut's PFAS Action Plan, and discussions occurring throughout the symposium revealed opportunities for collaborations among Connecticut scientists, state and local officials, and community advocates. In doing so, it bolstered the State of Connecticut's efforts to implement the ambitious initiatives that its PFAS Action Plan recommends., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier B.V.)

Introduction: This study was designed to determine the incidence of surgical site infections (SSIs) after orthopaedic surgery in an ambulatory surgery center (ASC) and to identify patient and surgical risk factors associated with SSI., Methods: Patients who underwent orthopaedic surgery at an ASC over a 6.5-year period were reviewed for evidence of SSI. Data on patient and surgical factors were collected, and stepwise multivariate logistic regression determined the risk factors for SSI., Results: The incidence of SSIs was 0.32%. Five independent factors were associated with SSI: anatomic area (odds ratio [OR] = 18.60, 11.24, 6.75, and 4.01 for the hip, foot/ankle, knee/leg, and hand/elbow versus shoulder, respectively), anesthesia type (OR = 4.49 combined general and regional anesthesia versus general anesthesia), age ≥70 (OR = 2.85), diabetes mellitus (OR = 2.27), and tourniquet time (OR = 1.01 per minute tourniquet time)., Discussion: The risk of infection after orthopaedic surgery in ASCs is low, but patient and surgical factors are independently associated with SSIs.

Medical science liaisons (MSLs) are field-based pharmaceutical or biomedical industry professionals whose role demands specialized product knowledge and skill in executing customer-facing activities. This report describes a survey of key opinion leaders (KOLs) to identify MSL skills most highly valued and those in need of enrichment with the objective of designing an advanced training curriculum for experienced MSLs. A total of 66 MSLs representing diverse therapeutic areas verbally administered a 9-question survey at the conclusion of a routine MSL-KOL interaction. There were 296 surveys completed, with most respondents (239 of 281; 82%) indicating that they meet with MSLs from other companies. Ninety-five percent (218 of 230) responded that the value provided by MSLs was comparable to that offered by other companies. When asked about top MSL attributes, KOLs mentioned product knowledge, scientific credibility, therapeutic area knowledge, timeliness of response, and communication skills. In terms of resources provided by MSLs, KOLs most often mentioned scientific information, unbiased product information, therapeutic area developments (including pipeline discussions), disease state information, and potential involvement in research or as an advisor. Based on the quantitative and qualitative results of this survey, a workshop curriculum focusing on advanced communication skills and networking techniques was developed and conducted successfully.

Background: Neonatal scalp abscesses are a rare but potentially very serious condition., Objectives: This report serves to demonstrate meningitis as a potential complication of neonatal scalp abscess. In addition, we review the current literature on the subject and comment on the most appropriate evaluation and treatment., Case Report: We describe six cases of neonatal scalp abscesses with one complication of enterococcal meningitis., Conclusion: The emergency practitioner should recognize that a neonate with a scalp abscess needs to be evaluated for potential serious complications and treated empirically to cover for organisms of vaginal origin., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The BTB/POZ domain defines a conserved region of about 120 residues and has been found in over 40 proteins to date. It is located predominantly at the N terminus of Zn-finger DNA-binding proteins, where it may function as a repression domain, and less frequently in actin-binding and poxvirus-encoded proteins, where it may function as a protein-protein interaction interface. A prototypic human BTB/POZ protein, PLZF (promyelocytic leukemia zinc finger) is fused to RARalpha (retinoic acid receptor alpha) in a subset of acute promyelocytic leukemias (APLs), where it acts as a potent oncogene. The exact role of the BTB/POZ domain in protein-protein interactions and/or transcriptional regulation is unknown. We have overexpressed, purified, characterized, and crystallized the BTB/POZ domain from PLZF (PLZF-BTB/POZ). Gel filtration, dynamic light scattering, and equilibrium sedimentation experiments show that PLZF-BTB/POZ forms a homodimer with a Kd below 200 nM. Differential scanning calorimetry and equilibrium denaturation experiments are consistent with the PLZF-BTB/POZ dimer undergoing a two-state unfolding transition with a Tm of 70.4 degrees C, and a DeltaG of 12.8 +/- 0.4 kcal/mol. Circular dichroism shows that the PLZF-BTB/POZ dimer has significant secondary structure including about 45% helix and 20% beta-sheet. We have prepared crystals of the PLZF-BTB/POZ that are suitable for a high resolution structure determination using x-ray crystallography. The crystals form in the space group I222 or I212121 with a = 38.8, b = 77.7, and c = 85.3 A and contain 1 protein subunit per asymmetric unit with approximately 40% solvent. Our data support the hypothesis that the BTB/POZ domain mediates a functionally relevant dimerization function in vivo. The crystal structure of the PLZF-BTB/POZ domain will provide a paradigm for understanding the structural basis underlying BTB/POZ domain function.

The effect of doxazosin, a selective alpha-1 adrenergic inhibitor, on hemostasis was investigated in 9 cynomolgus monkeys. During 12 weeks of doxazosin treatment (1 mg/kg per day), serum lipids, lipoprotein cholesterols, blood coagulation, platelet aggregation and template bleeding times were measured and compared with predrug values. In addition, platelet adhesion to cultured human umbilical vein endothelial cells (HUVEC) in the presence or absence of doxazosin was evaluated. Platelet aggregation was also determined in monkeys following chronic oral exposure to aspirin (162 mg/day). Doxazosin administration was associated with significant reductions in serum total cholesterol (TC) (-16%) and low density lipoprotein cholesterol (LDL-C) (-23%), while high density lipoprotein cholesterol (HDL-C) levels increased 66%. Doxazosin did not alter any parameters of blood coagulation measured; however, bleeding times were increased significantly (33%) in doxazosin-treated animals. Although collagen-stimulated platelet aggregation was not influenced by either chronic doxazosin or aspirin treatment, the maximal extent of ADP-stimulated platelet aggregation was significantly reduced (-26% and -18%, respectively) compared with the control monkeys. Platelets from untreated control animals displayed reductions in the extent of ADP-stimulated aggregation of 13% and 23%, respectively, when incubated in vitro with 200 and 300 micrograms/ml of doxazosin. Additionally, the decrease in aggregation response of platelets obtained from doxazosin-treated monkeys was accompanied by a rapid reversal of platelet aggregation. Adhesion to HUVEC by platelets isolated from doxazosin-treated animals was significantly decreased; however, adhesion was not altered when platelets from untreated control animals were incubated with HUVEC in the presence of doxazosin. Thus, the ex vivo and in vitro studies reported in this communication suggest that doxazosin administration to nonhuman primates is associated with beneficial alterations in plasma lipids, platelet aggregation, bleeding times and platelet adhesion to endothelial cells, parameters which are thought to influence risk of cardiovascular disease in both animals and humans.

Thin layer chromatograms for phospholipids obtained from 11 human Giardia lamblia isolates and their culture media have shown that phosphatidylcholine and sphingomyelin are the predominant phospholipid classes in all samples. A decrease in the relative percentage of the different classes, especially of phosphatidylcholine, was noticed in the medium after Giardia growth. Fatty acid analysis of the parasite phosphatidylcholine demonstrated that while oleate and palmitate were the major fatty acids in most isolates, arachidonate predominated in two of those studied. Some isolates contained small amounts of myristate, which was not present in the phosphatidylcholine of the culture medium. Moreover, stearate and linoleate predominated in phosphatidylcholine obtained from both media types. The saturated/unsaturated fatty acid ratio also varied for the different isolates. These results appear to suggest heterogeneity in the metabolic activity and utilization of lipid molecules between Giardia isolates.

The mechanism(s) by which diets containing corn or coconut oil (31% of energy as fat) totally free of cholesterol or with 0.1% added cholesterol by weight (0.3 mg/kcal) affect plasma high density lipoprotein cholesterol (HDL-C), apoprotein (apo) A-I levels, apo A-I kinetics, and hepatic apo A-I mRNA concentrations were investigated in 26 cebus monkeys. Coconut oil-fed monkeys had elevated levels of plasma total cholesterol (217%), very low density lipoprotein plus low density lipoprotein cholesterol (331%), HDL-C (159%), and apo A-I (117%) compared with corn oil-fed animals. Although the addition of cholesterol to the corn oil diet significantly increased these parameters, no such effects were seen when cholesterol was added to the coconut-oil diet. Both the type of fat and cholesterol in the diet significantly affected HDL apo A-I metabolism by decreasing apo A-I fractional catabolic rate and increasing apo A-I production rate in the coconut oil-fed groups. The decrease in apo A-I fractional catabolic rate in the coconut oil-fed animals was also associated with an increase in the HDL core lipid to surface ratio. Liver apo A-I mRNA abundance was elevated in the coconut oil-fed groups; however, dietary cholesterol had no affect on these levels. The lack of parallel effects of dietary fat and cholesterol on apo A-I production rate and liver apo A-I mRNA levels suggests that the increase in the apo A-I production rate observed in the coconut oil-fed groups resulted from the fat-induced rise in liver apo A-I mRNA abundance, whereas the cholesterol-induced rise in the apo A-I production rate resulted from a mechanism other than changes in liver apo A-I mRNA levels.

Some isolates of the plant pathogen Nectria haematococca detoxify the isoflavonoid phytoalexin (-)maackiain by hydroxylation at carbon 6a. Precursor feeding studies strongly suggest that the penultimate step in (+)pisatin biosynthesis by Pisum sativum is 6a-hydroxylation of (+)maackiain. We have used (18)O labeling to test the involvement of oxygenases in these two reactions. When fungal metabolism of maackiain took place under (18)O(2), the product was labeled with 99% efficiency; no label was incorporated by metabolism in H(2) (18)O. Pisatin synthesized by pea pods in the presence of (18)O(2) or H(2) (18)O was a mixture of molecules containing up to three labeled oxygen atoms. Primary mass spectra of such mixtures were complex but were greatly simplified by tandem MS. This analysis indicated that the 6a oxygen of pisatin was derived from H(2)O and not from O(2). Labeling patterns for the other five oxygen atoms were consistent with the proposed pathway for biosynthesis of pisatin and related isoflavonoids. We conclude that the fungal hydroxylation of maackiain is catalyzed by an oxygenase, but the biosynthetic route to the 6a hydroxyl of pisatin is unknown.

The in vitro sensitivity of marrow CFU(E) to erythropoietin was assessed in normal, regenerating, and plethoric marrow and correlated to the cell-cycle distribution of the cells. Although all marrow samples demonstrated a approximately 75% S-phase distribution, regenerating, but not plethoric marrow, exhibited a 5- to 10-fold greater requirement for erythropoietin in vitro. It is concluded that altered responsiveness to erythropoietin may occur independently of alterations in the CFU(E) cell cycle. Secondly, alterations in erythropoietin sensitivity occur under conditions of marrow regeneration but not polycythemic suppression.

The effect of prazosin on hemodynamics, hemostasis, and serum lipid and lipoprotein levels was investigated in normal and hypercholesterolemic rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) monkeys. Administration of prazosin (2 mg/kg bodyweight, orally, twice a day) for three weeks caused significant reductions in plasma cholesterol, including low- plus very low-density lipoprotein cholesterol, apolipoprotein B, and triglyceride levels. Drug therapy was associated with increased high-density lipoprotein cholesterol levels, although in one group of monkeys this rise also was associated with a reduction in apolipoprotein A1. Prazosin treatment significantly decreased mean arterial pressure in normal and hypercholesterolemic monkeys. As was expected, acute administration of phenylephrine caused mean arterial pressure to rise, with animals receiving normal- or high-cholesterol-containing diets showing similar responses. After prazosin treatment, however, a greater inhibition in the phenylephrine pressor response was observed in hypercholesterolemic monkeys compared with normal animals. Platelet aggregation in response to adenosine 5'-diphosphate, prothrombin time, and activated partial thromboplastin time were not altered by prazosin. Thus, in our nonhuman primate models of hypercholesterolemia, administration of prazosin resulted in reduction in lipid and apoprotein levels with no change in hemostasis.

The effect of doxazosin administration on hemodynamics, hemostasis, and serum lipid and lipoprotein levels was investigated in cynomolgus monkeys (Macaca fascicularis) with diet-induced hypercholesterolemia. Acute administration of doxazosin (1 and 5 mg/kg) reduced resting mean arterial pressure by 20% without affecting heart rate, and completely inhibited the pressor response to phenylephrine. Platelet aggregation, prothrombin time, and activated partial thromboplastin time were not altered by the drug. Long-term doxazosin administration (1, 10, and 20 mg/kg/day) was associated with significant reductions in levels of total serum cholesterol (13%), very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) cholesterol (14%), and apolipoprotein B (15%) without any significant effects on high-density lipoprotein (HDL) cholesterol and apolipoprotein A-1. A 76% reduction in serum triglycerides, independent of drug level, was also seen in doxazosin-treated monkeys. In monkeys removed from drug treatment, serum cholesterol initially exceeded and then returned to pretreatment levels, whereas serum triglycerides remained low for 3 weeks. In our hypercholesterolemic monkey model, the administration of doxazosin resulted in beneficial changes in lipid and apolipoprotein profiles, hemostasis, and hemodynamics.

The cell-cycle properties of marrow CFUE were assessed in normal regenerating cell preparations. In addition, the erythropoietin sensitivity of CFUE was correlated to the cell-cycle distribution of these cells. The results suggest a coupling of erythropoietin sensitivity to the S-phase of the CFUE cell cycle in so far as CFUE in G2/M/G1 were 2 to 10 times less sensitive to the hormone. It is concluded that the CFUE cell cycle per se is not a focus for erythropoietic regulation.