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2018-11-26 Notice of appearance, (Letter Form), Appellants (37896, 37897)-Bell Canada, et al. National Football League, et al.: Steven G. Mason, Brandon Kain, Joanna Nairn, Richard Lizius and James S.S. Holtom will be present. Mr. Mason and Mr. Kain will present oral arguments. 6 reserved seats requested.
Interveners (37896 and 37897)-Ontario Securities Commission, et al.: Matthew Britton, Jennifer Lynch, Paloma Ellard, Don Young and David Hainey will be present at the hearing. Mr. Britton will present oral arguments. 6 reserved seats requested.
Appellant/Respondent (37748, 37896, 37897)-Attorney General of Canada: Michael H. Morris, Marianne Zoric, John Provart and Ian Demers will be present. Mr. Morris and Ms. Zoric will present oral arguments. 8 reserved seats requested.
Intervener (37748, 37896, 37897)-Canadian Bar Association: Jonathan M. Coady, Justin L. Milne, Guy Régimbald will be present.
Intervener (37896, 37897)-Telus Communications Inc.: Christopher C. Rootham and Michael Ryan will be present.
Interveners (37896) Wholesale Code Applicants (Blue Ant Media, et al): Christian Leblanc and Michael Shortt will be present.
Intervener (37748)- Canadian Council for Refugees: Jamie Liew, Jean Lash and Gerald Heckman will be present. 2 reserved seats requested.
Intervener (37748)-Canadian Association of Refugee Lawyers: Professor Audrey Macklin and Anthony Navaneelan will be present. Ms. Macklin will present oral arguments.
Intervener (37748, 37896, 37897)- First Nations Child and Family Caring Society of Canada: Sarah Clarke, Nicholas McHaffie and David Taylor will be present.
Intervener (37748, 37896, 37897)- British Columbia International Commercial Arbitration Centre Foundation: Gavin Cameron and Tom Posyniak will be present at the hearing. 1 reserved seat requested.
Intervener (37748, 37896, 37897)-Attorney General of Quebec: Stéphane Rochette will be present and will present oral arguments.
Intervener (37748, 37896, 37897)-Attorney General of Saskatchewan: Kyle McCreary and Johnna Van Parys will be present. Kyle McCreary will present oral arguments.
Intervener (37748, 37896, 37897)-Samuelson-Glushko Canadian Internet Policy and Public Interest Clinic: Alyssa Tomkins and James Plotkin will be present. Mr. Plotkin will present oral arguments.
Intervener (37748)-Association québécoise des avocats et avocates en droit de l'immigration: Peter Shams, Guillaume Cliche-Rivard, Claudia Andrea Molina and David Berger will be present. Ms. Guillaume Cliche-Rivard will present oral arguments. 1 reserved seat requested.
Intervener (37748, 37896, 37897)-Canadian Labour Congress: Steven Barrett will be present and will present oral arguments.
Respondent (37748)-Alexander Vavilov: Hadayt Nazami will be present and will present oral arguments. 4 reserved seats requested.
Intervener (37748, 37896, 37897)-Advocates for the Rule of Law: Adam Goldenberg and Asher Honickman will be present. Mr. Goldenberg will present oral arguments. 2 reserved seats requested.
Intervener (37748, 37896, 37897)- National Association of Pharmacy Regulatory Authorities: William W. Shores, Q.C. and Kirk Lambrecht, Q.C. will be present.
Intervener (37748, 37896, 37897)-Advocacy Centre for Tenants Ontario: Karen Andrews will be present.
Intervener (37896, 37897)-Association of Canadian Advertisers and the Alliance of Canadian Cinema, Television and Radio Artists: J. Thomas Curry and Sam Johansen will be present.
Intervener (37748, 37896, 37897)-Queen's Prison Law Clinic: Brendan Van Niejenhuis and Andrea Gonsalves will be present. Mr. Van Niejenhuis will present oral arguments. 1 reserved seat requested.
Intervener (37748, 37896, 37897)-Cambridge Comparative Administrative Law Forum: Paul Warchuk and Francis Lévesque will be present. Mr. Warchuk will present oral arguments.
Intervener (37748, 37896, 37897)-Ecojustice Canada Society: Laura Bowman and Bronwyn Roe will be present. Ms. Bowman will present oral arguments.
Interveners (37748, 37896, 37897)- National Academy of Arbitrators, et al.: Linda R. Rothstein, Michael Fenrick, Angela E. Rae, Anne Marie Heenan and Susan L. Stewart will be present.
Amici Curiae (37748, 37896, 37897): Audrey Boctor and Daniel Jutras will be present and will both present oral arguments. 2 reserved seats requested.
Interveners (37748, 37896, 37897)- Workplace Safety and Insurance Appeals Tribunal (Ontario), et al.: David Corbett and Michelle Alton will be present. Mr. Corbett will present oral arguments.
Intervener (37748, 37896, 37897)-Attorney General of Ontario: Sarah Blake and Judie Im will be present. Ms. Blake will present oral arguments. 1 reserved seat requested.
Intervener (37748, 37896, 37897)- Attorney General of British Columbia: Micah B. Rankin and Kathleen Hamilton will be present. Mr. Rankin will present oral arguments. 1 reserved seat requested.
Intervener (37748)- Parkdale Community Legal Services: Toni Schweitzer and Ronald Poulton will be present. 6 reserved seats requested.
Intervener (37748, 37896, 37897)- Council of Canadian Administrative Tribunals: Terrence J. O’Sullivan, Paul Michell and James Renihan will be present. Mr. O’Sullivan will present oral arguments.
The Canadian Association of Refugee Lawyers; the Council of Canadian Administrative Tribunals; the Cambridge Comparative Administrative Law Forum; the Canadian Labour Congress and the Queen’s Prison Law Clinic are each granted permission to present oral argument not exceeding ten (10) minutes at the hearing of the appeals.
The Attorney General of Ontario; the Attorney General of Quebec; the Attorney General of British Columbia; the Attorney General for Saskatchewan; the Ontario Securities Commission, the British Columbia Securities Commission and the Alberta Securities Commission (jointly); the Ecojustice Canada Society; the Workplace Safety and Insurance Appeals Tribunal (Ontario), the Workers’ Compensation Appeals Tribunal (Northwest Territories and Nunavut), the Workers’ Compensation Appeals Tribunal (Nova Scotia), the Appeals Commission for Alberta Workers’ Compensation and the Workers’ Compensation Appeals Tribunal (New Brunswick) (jointly); Advocates for the Rule of Law; the Samuelson-Glushko Canadian Internet Policy and Public Interest Clinic and the Association québécoise des avocats et avocates en droit de l’immigration are each granted permission to present oral argument not exceeding five (5) minutes at the hearing of the appeals.
The Court will consider the written submissions of the Canadian Council for Refugees; the Advocacy Centre for Tenants Ontario; the British Columbia International Commercial Arbitration Centre Foundation; the National Academy of Arbitrators, the Ontario Labour-Management Arbitrators’ Association and the Conférence des arbitres du Québec (jointly); the National Association of Pharmacy Regulatory Authorities; the Parkdale Community Legal Services; the Canadian Bar Association; the Community & Legal Aid Services Programme; the First Nations Child and Family Caring Society of Canada; Telus Communications Inc.; Blue Ant Media Inc., Canadian Broadcasting Corporation, DHX Media Ltd., Groupe V Média inc., Independent Broadcast Group, Aboriginal Peoples Television Network, Allarco Entertainment Inc., BBC Kids, Channel Zero, Ethnic Channels Group Ltd., Hollywood Suite, OUTtv Network Inc., Stingray Digital Group Inc., TV5 Québec Canada, Zoomermedia Ltd. and Pelmorex Weather Networks (Television) Inc. (jointly); and the Association of Canadian Advertisers and the Alliance of Canadian Cinema, Television and Radio Artists as set out in their factums.
2018-11-15 Order on motion to extend time, by KARAKATSANIS J.
The motion to extend the filing deadlines and to present oral argument at the hearing of the appeals is granted in part. The said intervener shall be permitted to file its factum and book of authorities on October 31, 2018. The decision with respect to the request to present oral argument is deferred to a date following receipt and consideration of the written arguments of the parties and the interveners.
2018-10-29 Intervener's book of authorities, (Book Form), (2 volumes), Amended covers required, Electronic copy missing-both rec'd 2018/11/01; Joint with 37897, Completed on: 2018-11-01 Telus Communications Inc.
2018-10-29 Intervener's factum, (Book Form), Joint with 37897, Completed on: 2018-10-29 Telus Communications Inc.
2018-10-29 Intervener's book of authorities, (Book Form), Completed on: 2018-10-29 Blue Ant Media Inc., Canadian Broadcasting Corporation, DHX Media Ltd., Groupe V Média inc.
2018-10-29 Intervener's factum, (Book Form), Completed on: 2018-10-29 Blue Ant Media Inc., Canadian Broadcasting Corporation, DHX Media Ltd., Groupe V Média inc.
2018-10-01 Correspondence (sent by the Court) to, the parties. Request for submissions on Publication Ban.
The motions for leave to intervene are granted and each of the said 27 interveners or groups of interveners shall each be entitled to serve and file a factum not to exceed 10 pages in length in these appeals on or before October 29, 2018.
The decision with respect to the requests to present oral argument is deferred to a date following receipt and consideration of the written arguments of the parties and the interveners.
The interveners or groups of interveners are not entitled to raise new issues or to adduce further evidence or otherwise to supplement the record of the parties.
Pursuant to Rule 59(1)(a) of the Rules of the Supreme Court of Canada, the interveners or groups of interveners shall pay to the appellants and respondents any additional disbursements resulting from their interventions.
AND IT IS HEREBY FURTHER ORDERED THAT the appellant in the appeal Minister of Citizenship and Immigration v. Alexander Vavilov (37748), and the appellants and respondent in the appeals Bell Canada, et al. v. Attorney General of Canada (37896) and National Football League, et al. v. Attorney General of Canada (37897), are each permitted to serve and file a single joint factum, not to exceed 10 pages in length, in reply to the interveners, on or before November 19, 2018. Furthermore, they are each permitted to serve and file a single joint reply factum, not to exceed 10 pages in length, in response to the factum of the amici curiae, on or before November 19, 2018.
2018-09-17 Reply to the motion for leave to intervene, (Letter Form), original copy filed on Sept. 18, 2018., Completed on: 2018-09-17 Blue Ant Media Inc., Canadian Broadcasting Corporation, DHX Media Ltd., Groupe V Média inc.
2018-09-13 Reply to the motion for leave to intervene, (Letter Form), Completed on: 2018-09-13 Telus Communications Inc.
2018-09-11 Response to the motion for leave to intervene, (Letter Form), request to make a joint response to the submisisons of the amici and the interveners.
2018-09-04 Notice of name, (Letter Form) Blue Ant Media Inc., Canadian Broadcasting Corporation, DHX Media Ltd., Groupe V Média inc.
2018-09-04 Motion for leave to intervene, (Book Form), filing fees to come - rec'd on Sept.6/2018., Completed on: 2018-09-06, (Printed version filed on 2018-09-04) Blue Ant Media Inc., Canadian Broadcasting Corporation, DHX Media Ltd., Groupe V Média inc.
2018-08-27 Certificate (on limitations to public access), (Letter Form) Telus Communications Inc.
2018-08-27 Notice of name, (Letter Form) Telus Communications Inc.
2018-08-27 Intervener's book of authorities, (Book Form), on motion for leave to intervene, Completed on: 2018-08-27 Telus Communications Inc.
2018-08-27 Motion for leave to intervene, (Book Form), includes book of authorities., Completed on: 2018-08-27 Telus Communications Inc.
2018-08-13 Correspondence (sent by the Court) to, Amicus - letter further to the Order of the Chief Justice, dated August 7, 2018, appointing amici curiae.
Ms. Audrey Boctor and Mr. Daniel Jutras are appointed as amici curiae to assist the Court by serving and filing a single factum common to all three appeals not exceeding forty (40) pages and a book of authorities, if any, on or before November 6, 2018, and by making oral submissions at the hearing of the appeal.
The reasonable fees and disbursements of Ms. Audrey Boctor and Mr. Daniel Jutras shall be paid, on consent, by the Attorney General of Canada.
2018-05-10 Decision on motion for directions, See judgment on application for leave to appeal.
2018-05-10 Judgment of the Court on the application for leave to appeal, The application for leave to appeal from the judgment of the Federal Court of Appeal, Number A-472-16, 2017 FCA 249, dated December 18, 2017, is granted with costs in the cause. The hearing of the appeal will not be expedited.
The appeal will be heard with National Football League, et al. v. Attorney General of Canada (37897), and with Minister of Citizenship and Immigration v. Alexander Vavilov (37748).
The Court is of the view that these appeals provide an opportunity to consider the nature and scope of judicial review of administrative action, as addressed in Dunsmuir v. New Brunswick,  1 S.C.R. 190, 2008 SCC 9, and subsequent cases. To that end, the appellants and respondent are invited to devote a substantial part of their written and oral submissions on the appeal to the question of standard of review, and shall be allowed to file and serve a factum on appeal of at most 45 pages.
d)	that the Registrar set a timetable for serving and filing appeal materials, if leave to appeal is granted to accommodate the expedited hearing date.
3)	The motion for directions setting a timetable for serving and filing appeal materials (if leave to appeal is granted) is referred to the panel to whom the application for leave to appeal is submitted.

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MAE C. DOUGLAS & another vs. JOHN J. HARTY & another.
Interlocutory decree confirming master's report affirmed. Final decree affirmed with costs of appeal. The plaintiffs seek to enjoin the defendants' continued use of a fence built in 1955 upon land claimed by one plaintiff and by the defendants. They also ask to have the ownership of the disputed land "established" for two periods of time, viz. from August 22, 1955, to March 1, 1956, and from that date to the date of filing the bill in equity. A master found that the land "is owned by" one of the plaintiffs, John Tyler Douglas, who acquired title from Mae C. Douglas in 1956. A final decree, among other things, declared the state of the title, ordered the removal of the fence, and awarded damages. The defendants appealed. The Superior Court, in considering equitable relief, may determine title to land. See O'Brien v. Murphy, 189 Mass. 353, 357; Shoer v. Daffe, 337 Mass. 420; Cesarone v. Femino, 340 Mass. 638, 639-640. See also Geragosian v. Union Realty Co. 289 Mass. 104, 109. The master's conclusions were consistent with his subsidiary findings that the boundary was ambiguously described, that there were physical indicia of a boundary on the land, and that predecessors in title of the parties acquiesced in these indications of the boundary. See Methodist Episcopal Soc. in Charlton City v. Akers, 167 Mass. 560, 563; Morrison v. Holder, 214 Mass. 366, 368-370; Fulgenitti v. Cariddi, 292 Mass. 321, 324-325, 327; Swaim, Crocker's Notes on Common Forms (7th ed.) Section 215; Tiffany, Real Property (3d ed.) Sections 653-654; Am. Law of Property, Sections 12.91, 12.11.
JOSEPH HUNT & another vs. ATTLEBORO ICE COMPANY & another.
Exceptions overruled. This is an action of tort for negligence by Janie C. Hunt (the plaintiff) and her husband. The plaintiff fell on the sidewalk of South Main Street, a public way in Attleboro, where an oil hose had been laid across the sidewalk by the defendant Carlson for the delivery of oil from the truck of his employer, the defendant Attleboro Ice Company, to a nearby customer. The plaintiff testified by deposition that she was walking on the sidewalk when "she suddenly fell and she did not know why or how she had fallen." After the fall she saw the hose. A man who was walking six or eight feet behind her saw her fall but did not see her trip over the hose. When he saw her fall she was beyond and "[c]ompletely over the hose." The cause of her fall was not removed from conjecture by an unresponsive part of an answer made by her that "they told me I fell over it." There was no error in directing verdicts for the defendants. Connolly v. Boston Elev. Ry. 309 Mass. 177. Howe v. Boston, 311 Mass. 278. McNeil v. First Natl. Stores, Inc. 339 Mass. 46. Gerstenzang v. Kennedy & Co. Inc. 340 Mass. 174.
SAUL E. MOFFIE vs. NATHAN SHARAF.
matter of evidence in this action of contract for services rendered by the plaintiff as architect in the remodelling of a building owned by the defendant. A finding of liability on the part of the defendant, as distinguished from the bankrupt corporation of which he was treasurer, was clearly warranted by the evidence. Other exceptions have been fully considered. We perceive no reversible error.

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In this medical malpractice case, Husband alleged that Defendants, several physicians, a hospital and others, caused his Wife's death by negligently failing to administer an expensive drug to treat her hypertension. Because the drug needed to be administered indefinitely and could cause deadly symptoms if its administration was interrupted, Wife's treating physicians decided not to administer the drug until Wife's insurer approved it or another source of payment could be found. Wife died before either happened. The jury returned a general verdict for Defendant. Husband then filed a motion for a new trial, which the court granted based on its conclusion that Defendants' expert testimony was inconsistent with the standard of care. At issue on appeal was whether under the circumstances of this case, an expert medical witness is permitted to opine that under the customary standard of care, a physician should consider the health risks to a patient who may be unable to pay for continued treatment. The Supreme Court reversed the district court's order granting a new trial, holding that such testimony is admissible and that, as a matter of law, it could not be said that Defendants' decisions in this case violated the standard of care.
Nebraska Advance Sheets 260 282 nebraska reports occupation tax authorized by L.B. 701 violates the constitutional prohibition against commutation. V. CONCLUSION For the reasons discussed, we conclude that the landowners have not overcome the presumption of constitutionality with respect to the challenged statutes, and we therefore affirm the judgment of the district court. Affirmed. Connolly, J., not participating. Robert Murray, Special Administrator of the Estate of Mary K. Murray, and Robert Murray, individually, appellees, v. UNMC P hysicians, formerly known as University M edical Associates, a corporation, appellant. ___ N.W.2d ___ Filed September 16, 2011. No. S-10-455. 1. Motions for New Trial: Appeal and Error. A motion for new trial is addressed to the discretion of the trial court, whose decision will be upheld in the absence of an abuse of that discretion. 2. Motions for New Trial. The discretion of a trial court in ruling on a motion for new trial is only the power to apply the statutes and legal principles to all facts of the case; a new trial may be granted only where legal cause exists. 3. Negligence: Evidence: Tort-feasors. While the identification of the applicable standard of care is a question of law, the ultimate determination of whether a party deviated from the standard of care and was therefore negligence is a question of fact. To resolve the issue, a finder of fact must determine what conduct the standard of care would require under the particular circumstances presented by the evidence and whether the conduct of the alleged tort-feasor conformed with that standard. Appeal from the District Court for Douglas County: James T. Gleason, Judge. Reversed. Jeffrey A. Nix, Thomas J. Shomaker, and Mary M. Schott, of Sodoro, Daly & Sodoro, P.C., for appellant. Christopher P. Welsh and James R. Welsh, of Welsh & Welsh, P.C., L.L.O., for appellees. Nebraska Advance Sheets murray v. unmc physicians Cite as 282 Neb. 260 261 Heavican, C.J., Connolly, Gerrard, McCormack, and Miller-Lerman, JJ. Gerrard, J. This case involves a failure to provide medical treatment. The treatment at issue is a very expensive drug that must be administered indefinitely. But it also may cause serious and even deadly symptoms if its administration is interrupted. In this case, the patient s treating physicians, wary of those health risks, decided not to administer the drug until the patient s insurer approved it or another source of payment could be found. But, regrettably, the patient died before either happened. The question presented in this appeal is whether under such circumstances, an expert medical witness is permitted to opine that under the customary standard of care, a physician should consider the health risks to a patient who may be unable to pay for continued treatment. We conclude that such testimony is admissible and, therefore, reverse the district court s order granting a new trial. Background This is a medical malpractice case in which Robert Murray, individually and as special administrator of the estate of his wife, Mary K. Murray, alleges that the defendants caused the death of Mary by negligently failing to administer Flolan therapy to treat her pulmonary arterial hypertension. The defend ants were the Nebraska Medical Center, the Board of Regents of the University of Nebraska, UNMC Physicians (UNMC), and several associated individual employees, although UNMC was the only defendant remaining by the time of trial. Pulmonary arterial hypertension is a chronic medical condition in which the blood vessels in the lungs constrict, and the resulting pressure on the heart leads to heart failure. Flolan is a vasodilator that relaxes blood vessels and prevents blood clotting. It is administered by a pump, connected to a port and catheter usually inserted above the collarbone. Flolan is very expensive and shortacting, so patients on Flolan treatment need a constant supply of the drug, because if its administration stops, pulmonary blood pressure rebounds and can be life Nebraska Advance Sheets 262 282 nebraska reports threatening. And because Flolan is a chronic treatment, patients who begin Flolan need to remain on it, essentially, for the rest of their lives it must be administered 24 hours a day and costs approximately $100,000 a year. The parties do not seem to disagree that generally, Flolan therapy is the appropriate course of treatment for chronic pulmonary arterial hypertension. Nor do the parties seem to dispute that there are significant and potentially deadly risks associated with interrupting Flolan treatment. The course of treatment relevant to this case began in late June 2006, as Mary s treating physician, Austin Thompson, M.D., was preparing to treat Mary s pulmonary arterial hypertension with Flolan. On June 29, Mary underwent a heart catheterization to confirm her diagnosis and eligibility for Flolan; in fact, Thompson had already written the Flolan order before the catheterization, pending the results of the catheterization and insurance approval. The catheterization showed pulmonary arterial hypertension, significant heart failure, and reduced blood flow. On July 4, 2006, Mary reported to the medical center with swollen legs and fluid around her heart. She was given diuretics and hospitalized until July 8. She was discharged and was supposed to begin Flolan after port placement the following week. But on July 10, she reported to the emergency room with a rapid heartbeat and shortness of breath. She began to seize, then her heartbeat stopped, and medical efforts failed to resuscitate her. At trial, the parties disputed both the cause of Mary s death and whether UNMC had breached the standard of care. Robert presented expert medical testimony that the proximate cause of Mary s death was pulmonary arterial hypertension. UNMC, on the other hand, presented expert medical testimony that myocarditis, an inflammation of the heart usually caused by viral or bacterial infection, was a contributing factor to Mary s death a conclusion with which Robert s experts disagreed. And Robert presented expert medical testimony that immediate Flolan administration, even a day or two before Mary s death, See Physicians Desk Reference 1181-82 (54th ed. 2000). Nebraska Advance Sheets murray v. unmc physicians Cite as 282 Neb. 260 263 would have prevented her death; UNMC, on the other hand, presented expert medical testimony that Flolan would have made no difference. Specifically, Robert s experts testified that Mary s pulmonary arterial hypertension was acute by June 29, 2006, based on the results of her heart catheterization, and that Flolan can be administered as an emergent treatment for acute pulmonary arterial hypertension. Robert adduced expert medical testimony that UNMC s treatment of Mary fell below the relevant standard of care after June 29, because the medical center should have paid for and provided Flolan by July 4 or 5 in other words, that the standard of care for a patient as sick as Mary was to start Flolan and obtain insurance approval afterward. UNMC s witnesses, on the other hand, testified that Flolan was not effective as an emergent treatment, because it did not work immediately. And they testified that their practice was to wait for insurance approval before beginning Flolan, because most patients are not able to pay for the drug without insurance and it can be more dangerous if treatment is started and then stopped. The UNMC attending physician during Mary s July 2006 hospitalization, James Murphy, M.D., explained that because Flolan treatment can last for years and require hundreds of thousands of dollars, it was important to make sure the treatment was sustainable before commencing. Thompson testified to horror stories about patients who had been forced to discontinue treatment, and he said it would be irresponsible not to have lifelong financial support for the drug, because it could be devastating if discontinued. Thompson said that the standard of care required such a process. And another of UNMC s experts, William Johnson, M.D., explained that the standard of care required finding some source of payment for a patient, but that if insurance was unavailable, it was still usually possible to find some other payment on a compassionate need basis within the 12-week timeframe that Johnson opined was appropriate for treatment of chronic pulmonary arterial hypertension. Robert moved for a directed verdict on the standard of care, arguing that as a matter of law, insurance coverage cannot Nebraska Advance Sheets 264 282 nebraska reports dictate what doctors do. UNMC replied that according to its experts, a continuing source for treatment is something that doctors should consider in determining how treatment is to be administered. Robert s motion was overruled. Robert also asked that the jury be instructed that if the standard of care requires prescription of a drug, it is not a defense to a claim the standard of care has been violated that the drug would not be provided until approved by an insurance carrier. That instruction was refused. The jury returned a general verdict for UNMC. But Robert filed a motion for new trial that the district court granted. The court explained: The evidence offered by [Robert s] expert on the issue of standard of care indicated that after the confirmation of [pulmonary arterial hypertension] by a right heart catheterization, the standard of care required the commencement of FLOLAN therapy. The evidence offered by [UNMC s] expert was basically the same with one major difference. [UNMC s] expert opined that the standard of care required the commencement of FLOLAN therapy after payment approval by the patient s insurance carrier. On cross-examination, [UNMC s] expert conceded that if no outside funds were available to subsidize the treatment to a patient who needed it, then treatment would be provided on a humanitarian basis. The substance of this concession was that the treatment was required by the standard of care regardless of how it was to be paid for. This Court is of the opinion that, as a matter of law, a medical standard of care cannot be tied to or controlled by an insurance company or the need for payment. The bean counters in an insurance office are not physicians. Medicine cannot reach the point where an insurance company determines the medical standard of care for the treatment of a patient. Nor, can we live in a society where the medical care required is not controlled by the physicians treating the patient. The position advanced by [UNMC s] expert tells us that the standard of care is different for those with money than for those without. This is neither moral nor just. It is wrong. Nebraska Advance Sheets murray v. unmc physicians Cite as 282 Neb. 260 265 This Court cannot determine the basis upon which the jury found in favor of [UNMC]. It could have been on the standard of care issue and it could have been on the causation issue. This Court erred in not directing the jury that the standard of care had not been met by [UNMC]. This error taints the entire verdict of the jury and requires a new trial. UNMC appeals from the order granting Robert s motion for new trial. Assignment of Error UNMC assigns that the court erred in granting Robert s motion for new trial. Standard of Review [1,2] A motion for new trial is addressed to the discretion of the trial court, whose decision will be upheld in the absence of an abuse of that discretion. But the discretion of a trial court in ruling on a motion for new trial is only the power to apply the statutes and legal principles to all facts of the case; a new trial may be granted only where legal cause exists. Analysis It is important, from the outset, to carefully note what issues this appeal does not present. This appeal arises against a backdrop of increasing concern about the costs of health care, among health care providers, insurers, government officials, and consumers. That concern has prompted a great deal of discussion, among commentators and in the public arena, about what should be done to control health care costs or to allocate potentially limited resources. As we will explain below, the question presented in this appeal is narrow and does not require us to address the more sweeping issues that are the subject of greater public policy debate. But some discussion of the broader picture will help us clarify what this case is about or, more precisely, what it is not about. See Neb. Rev. Stat. § 25-1315.03 (Reissue 2008). Robinson v. Dustrol, Inc., 281 Neb. 45, 793 N.W.2d 338 (2011). Kant v. Altayar, 270 Neb. 501, 704 N.W.2d 537 (2005). Nebraska Advance Sheets 266 282 nebraska reports In Nebraska, in cases arising (like this one) under the Nebraska Hospital-Medical Liability Act, the standard of reasonable and ordinary care is defined as that which health care providers, in the same community or in similar communities and engaged in the same or similar lines of work, would ordinarily exercise and devote to the benefit of their patients under like circumstances. That standard is consistent with the general common-law rule and is a so-called unitary, or wealthblind, standard of care. In other words, the standard of care is found in the customary practices prevailing among reasonable and prudent physicians and must not be compromised simply because the patient cannot afford to pay. That standard of care, however, developed in a world of fee-for-service medicine and persisted while health insurance still primarily provided firstdollar unlimited coverage. Today, [h]ealth plans and self-insured corporations are placing increasingly stringent controls on health care resources, thereby limiting physicians freedom to practice medicine as they see fit. Clinical guidelines have proliferated from a wide variety of sources: managed care organizations, medical subspecialty societies, malpractice insurers, entrepreneurial guideline-writing firms, and others. Each guideline purports to tell physicians the best way to practice. Yet often they conflict with each other, with traditional practice patterns, and with patients e  xpectations.10 But [b]ecause tort law expects physicians to provide the same standard of care regardless of patients ability to pay, 10 See Neb. Rev. Stat. §§ 44-2801 to 44-2855 (Reissue 2010). § 44-2810. See E. Haavi Morreim, Cost Containment and the Standard of Medical Care, 75 Cal. L. Rev. 1719 (1987). See id. See, also, John A. Siliciano, Wealth, Equity, and the Unitary Medical Malpractice Standard, 77 Va. L. Rev. 439 (1991). See E. Haavi Morreim, Stratified Scarcity: Redefining the Standard of Care, 17 L. Med. & Health Care 356 (1989). E. Haavi Morreim, Medicine Meets Resource Limits: Restructuring the Legal Standard of Care, 59 U. Pitt. L. Rev. 1, 5 (1997). Nebraska Advance Sheets murray v. unmc physicians Cite as 282 Neb. 260 267 and because this standard sometimes encompasses costly technologies no longer readily available for the poorest citizens, physicians are caught in a bind between legal expectations and economic realities. 11 Courts have been accused of being oblivious to the costs of care, essentially requiring physicians to commandeer resources that may belong to other parties, regardless of whether those other parties owe the patient these resources. 12 It has been suggested that at a fundamental level, a unitary, wealth-blind standard of care cannot be reconciled with the growth of technology and the stratification of available health care. Custom is increasingly difficult to identify in today s medical marketplace, as resource distinctions produce fragmentation and disintegration.13 It has also been suggested that maintaining a unitary standard of care disadvantages those who may not be able to pay for health care. Physicians remain free, for the most part, to decline to treat those who cannot pay, and an outright refusal to treat an indigent patient, in contrast to a decision to treat in a manner inconsistent with the unitary malpractice standard, rarely creates the threat of liability. 14 So, it has been argued that rather than assume the burden of paying for a patient s treatment, or the potential liability of providing some but not all possible care, the unitary standard makes it more likely that providers will now sidestep the entire problem simply by refusing to accept some, or all, of such patients for treatment. 15 On the other hand, it has been argued that permitting physicians to make medical decisions based on resource scarcity would compromise the fiduciary relationship between patient and physician, creating a conflict of interest because the 11 12 13 14 15 Id. at 4-5. Id. at 4. See James A. Henderson, Jr. & John A. Siliciano, Universal Health Care and the Continued Reliance on Custom in Determining Medical Malpractice, 79 Cornell L. Rev. 1382 (1994). Siliciano, supra note 8 at 457. Id. Nebraska Advance Sheets 268 282 nebraska reports patient s well-being would no longer be the physician s focus.16 The question is how the value judgments inherent in the development of the standard of care might evolve in response to a societal interest in controlling health care costs.17 It has been explained that a physician s initial value judgment, in treating a patient, is made in light of conclusions reached about the likely benefits that services would have had for the plaintiff patient. It involves an evaluation as to whether the serv ices should have been provided given their likely benefits, the risk of iatrogenic harm, and the gravity of the problem experienced by the patient. Normally the value judgment does not involve an explicit consideration of the costs of caring for a patient, although economics are implicitly considered. Physicians do not do everything conceivably possible in caring for a patient they draw what they consider to be reasonable boundary lines. For example, physicians do not order every diagnostic test available for a patient that requests a physical examination, even though doing so might reveal interesting information. Instead, they order tests which are indicated given the age and physical characteristics of the patient.18 A physician s initial value judgment, in other words, is constrained by reason but does not include a societal interest in conserving costs or resources, and certainly does not include weighing the physician s own economic interests.19 In short, the traditional ethical norms of the medical profession and the legal demands of the customary standard of care impose significant restrictions on a physician s ability to consider the costs of treatment, despite significant and increasing 16 17 18 19 See, Maxwell J. Mehlman, The Patient-Physician Relationship in an Era of Scarce Resources: Is There a Duty to Treat?, 25 Conn. L. Rev. 349 (1993); Edward B. Hirshfeld, Should Ethical and Legal Standards for Physicians Be Changed to Accommodate New Models for Rationing Health Care?, 140 U. Pa. L. Rev. 1809 (1992). Hirshfeld, supra note 16. Id. at 1835. See id. See, also, Morreim, supra note 10. Nebraska Advance Sheets murray v. unmc physicians Cite as 282 Neb. 260 269 pressure to contain those costs. Whether the legal standard of care should change to alleviate that conflict, and how it might change, has been the subject of considerable discussion. It has been suggested that the customary standard of care could evolve to permit the denial of marginally beneficial treatment in other words, when high costs would not be justified by minor expected benefits.20 Others have suggested that the standard of care should evolve to consider two separate components: (1) a skill component, addressing the skill with which diagnoses are made and treatment is rendered, that would not vary by a patient s financial circumstances and (2) a resource component, addressing deliberate decisions about how much treatment to give a patient, that would vary so as to not demand more of physicians than is reasonable.21 It has been suggested that physicians should be permitted to rebut the presumption of a unitary standard of care when diminution of care arises by economic necessity instead of negligence.22 And many have suggested that custom should no longer be the benchmark for the standard of care;23 instead, practice standards or guidelines could be promulgated that would settle issues of resource a  llocation.24 All of the concerns discussed above are serious, and they present difficult questions that courts will be required to confront in the future. But we do not confront them here, because under the unique facts of this case, they are not presented. Contrary to the district court s belief, this is not a case in 20 See Mark A. Hall, Rationing Health Care at the Bedside, 69 N.Y.U. L. Rev. 693 (1994). 21 See, Mark A. Hall, Paying for What You Get and Getting What You Pay For: Legal Responses to Consumer-Driven Health Care, 69 Law & Contemp. Probs. 159 (2006); Morreim, supra note 10; Morreim, supra note 9. 22 Morreim, supra note 7. 23 See Morreim, supra note 10. 24 See, Daniel W. Shuman, The Standard of Care in Medical Malpractice Claims, Clinical Practice Guidelines, and Managed Care: Towards a Therapeutic Harmony?, 34 Cal. W. L. Rev. 99 (1997); Hirshfeld, supra note 16; Peter H. Schuck, Malpractice Liability and the Rationing of Care, 59 Tex. L. Rev. 1421 (1981). But see Siliciano, supra note 8. Nebraska Advance Sheets 270 282 nebraska reports which insurance company bean counters overrode the medical judgment of a patient s physicians25 or in which those physicians allowed their medical judgment to be subordinated to a patient s ability to pay for treatment.26 Nor is this a case in which the parties disputed the cost-effectiveness of the treatment at issue.27 Rather, UNMC s evidence was that its decision to wait to begin Flolan treatment was not economic it was a medical decision, based on the health consequences to the patient if the treatment is interrupted.  Whether a medical standard of care can appropriately be premised on such a consideration is a matter of first impression in Nebraska, and the parties have not directed us to (nor are we aware of) any other authority speaking directly to that issue. But as a general matter, we have said that while the identification of the applicable standard of care is a question of law, the ultimate determination of whether a party deviated from the standard of care and was therefore negligent is a question of fact.28 And it is for the finder of fact to resolve that issue by determining what conduct the standard of care would require under the particular circumstances presented by the evidence and whether the conduct of the alleged tort-feasor conformed with that standard.29 Malpractice, as alluded to above, is defined as a health care provider s failure to use the ordinary and reasonable care, skill, and knowledge ordinarily possessed and used under like circumstances by members of his or her profession engaged in a similar practice in his or her or in similar localities.30 The district court granted a new trial based on its conclusion that UNMC s expert testimony was inconsistent with the standard of care. So the question is whether, as a matter of law, UNMC s 25 Compare Long v. Great West Life & Annuity Ins., 957 P.2d 823 (Wyo. 1998). 26 Compare Wickline v. State, 192 Cal. App. 3d 1630, 239 Cal. Rptr. 810 (1986). 27 Compare Helling v. Carey, 83 Wash. 2d 514, 519 P.2d 981 (1974). 28 Wilke v. Woodhouse Ford, 278 Neb. 800, 774 N.W.2d 370 (2009). 29 Id. 30 § 44-2810. Nebraska Advance Sheets murray v. unmc physicians Cite as 282 Neb. 260 271 expert opinion testimony was inconsistent with the standard of care as defined above. The district court determined that it was. But the district court s reasoning was erroneous in three respects. First, the district court understood Johnson s testimony to concede that if no outside funds were available to subsidize the treatment to a patient who needed it, then treatment would be provided on a humanitarian basis. The substance of this concession, the court reasoned, was that the treatment was required by the standard of care regardless of how it was to be paid for. But that is not exactly what Johnson said. The import of Johnson s testimony, as revealed by the record, was that if a patient was unable to obtain insurance coverage for Flolan, it was Johnson s practice to try to work with the patient to find another way for the patient to get the drug on a compassionate need basis. Johnson s testimony in that regard was about his practice, not the general standard of care. Nor did Johnson testify that the drug would be started regardless he simply said that if insurance was unavailable, he would try to find another way for the patient to obtain the medication. Nothing in Johnson s testimony is contrary to his basic opinion that the standard of care requires a doctor to make sure that a payment source is in place before beginning Flolan treatment, because of the risks associated with interruption of treatment. Second, the customary standard of care in this case is defined by statute, and it is not a court s place to contradict the Legislature on a matter of public policy.31 UNMC s witnesses testified that UNMC s treatment of Mary was consistent with the statutory standard of care in other words, that health care providers in the same community or in similar communities and engaged in the same or similar lines of work would ordinarily defer Flolan treatment until payment for a continuous supply had been secured. We cannot depart from the customary standard of care on policy grounds, even if it is subject to criticism, because the standard of care is defined by statute and public policy is declared by the Legislature.32 Robert was, of course, 31 32 See Wilke, supra note 28. See id. Nebraska Advance Sheets 272 282 nebraska reports free to argue and present evidence that UNMC s experts were wrong when they opined about customary practice. But that was a jury question. Finally, and more fundamentally, the district court s concerns about health care policy, while understandable, are misplaced in a situation in which the patient s ability to continue to pay for treatment is still a medical consideration. In other words, even when the standard of care is limited to medical considerations relevant to the welfare of the patient, and not economic considerations relevant to the welfare of the health care provider,33 the standard of care articulated by UNMC s witnesses in this case was still consistent with a medical standard of care. This case does not involve a conflict of interest between the physician and patient there was no evidence, for instance, of a financial incentive for UNMC s physicians to control costs.34 As explained by UNMC s witnesses, the decision to defer Flolan treatment was not based on its financial effect on UNMC, or subordinating Mary s well-being to the interests of other patients, or even considering Mary s own financial interest. Instead, when making its initial value judgment regarding Mary s treatment,35 UNMC s physicians were not weighing the risk to Mary s health against the risk to her pocketbook, or UNMC s budget, or even a general social interest in controlling health care costs. UNMC s physicians were weighing the risk to Mary s health of delaying treatment against the risk to Mary s health of potentially interrupted treatment. Stated another way, this was not a case in which a physician refused to provide beneficial care it was a case in which the physicians determined that the care would not be beneficial if it was later interrupted. In fact, it could be deadly. As explained by Murphy, Thompson, and Johnson, the reason for waiting to begin Flolan until after insurance approval 33 See, e.g., Thompson v. Sun City Community Hosp., Inc., 141 Ariz. 597, 688 P.2d 605 (1984); Wilmington Gen. Hospital v. Manlove, 54 Del. 15, 174 A.2d 135 (1961). Cf. Creighton-Omaha Regional Health Care Corp. v. Douglas County, 202 Neb. 686, 277 N.W.2d 64 (1979). 34 Compare Shea v. Esensten, 622 N.W.2d 130 (Minn. App. 2001). 35 See Hirshfeld, supra note 16. Nebraska Advance Sheets murray v. unmc physicians Cite as 282 Neb. 260 273 had been obtained was out of concern for the health of the patient. That was not meaningfully different from any number of other circumstances in which a health care provider might have to base a treatment decision upon the individual circumstances of a patient. For instance, a physician with concerns about a particular patient s ability to follow instructions, or report for appropriate followup care, might treat the patient s condition differently in the first instance. And a health care provider who is told that a patient cannot afford a particular treatment may recommend a less expensive but still effective treatment, reasoning that a treatment that is actually used is better than one that is not. These are difficult decisions, and there may be room to disagree, but it is hard to say they are unreasonable as a matter of law, or that an expert cannot testify that such considerations are consistent with the customary standard of care. And as noted above, Robert s witnesses were free to disagree with UNMC s witnesses; Robert could (and did) argue that the standard of care required more than UNMC s witnesses said it did. And the evidence might have supported the conclusion that given Mary s deteriorating condition, there was little risk in beginning Flolan even without a payment source in place. (Although we note, for the sake of completeness, that Johnson also testified that Mary s weakening condition militated against beginning Flolan on an emergent basis, because its side effects could have been deadly.) In other words, the jury could have found that in this case, given the facts and testimony, the standard of care required Flolan to be administered immediately. But it was a question for the jury, and there was also competent evidence supporting a conclusion that the standard of care had not been breached. The court erred in concluding that it should have directed a verdict on the standard of care. And for that reason, the court abused its discretion in granting Robert s motion for new trial. UNMC s assignment of error has merit. UNMC s evidence and opinion testimony reflect difficult medical decisions but still medical decisions. Therefore, the scope of our holding is limited. We need not and do not decide whether the standard of care can or should incorporate Nebraska Advance Sheets 274 282 nebraska reports c  onsiderations such as cost control or allocation of limited resources. Although the decision (or lack thereof) of a thirdparty payor contributed to the circumstances of this case, UNMC s decisions were still (according to its evidence) premised entirely upon the medical well-being of its patient. In a perfect world, difficult medical decisions like the one at issue in this case would be unnecessary. But we do not live in a perfect world, and we cannot say as a matter of law that UNMC s decisions in this case violated the standard of care. Conclusion For the foregoing reasons, the district court s order granting Robert s motion for new trial is reversed. R eversed. Wright and Stephan, JJ., not participating. State of Nebraska, appellee, v. Armon M. Dixon, appellant. ___ N.W.2d ___ Filed September 16, 2011. No. S-10-476. 1. Venue: Appeal and Error. An appellate court reviews the denial of a motion to change venue for abuse of discretion. 2. Venue. Under Neb. Rev. Stat. § 29-1301 (Reissue 2008), a change of venue is mandated when a defendant cannot receive a fair and impartial trial in the county where the offense was committed. 3. Venue: Proof. Unless a defendant claims that the pretrial publicity has been so pervasive and prejudicial that a court should presume the partiality of prospective jurors, a change in venue is evaluated under the following factors: These factors are (1) the nature of the publicity, (2) the degree to which the publicity has circulated throughout the community, (3) the degree to which the publicity circulated in areas to which venue could be changed, (4) the length of time between the dissemination of the publicity complained of and the date of the trial, (5) the care exercised and ease encountered in the selection of the jury, (6) the number of challenges exercised during voir dire, (7) the severity of the offenses charged, and (8) the size of the area from which the venire was drawn. 4. Venue: Due Process. Mere exposure to news accounts of a crime does not presumptively deprive a defendant of due process. 5. Venue: Due Process: Proof. To warrant a change of venue, a defendant must show the existence of pervasive misleading pretrial publicity. A defendant must show that publicity has made it impossible to secure a fair and impartial jury.


(B) the cost-of-living adjustment determined under section 1(f)(3) for the calendar year in which the taxable year begins, by substituting "calendar year 2017" for "calendar year 2016" in subparagraph (A)(ii) thereof.
The term "farming business" means the trade or business of farming (within the meaning of section 263A(e)(4)).
The term "farming business" includes the raising, harvesting, or growing of trees to which section 263A(c)(5) applies.
(iv) any other person who acquired such stock by reason of the death of an individual described in clause (i) or (ii) (but only for the 2-year period beginning on the date of the death of such individual).
The term "tax shelter" has the meaning given such term by section 461(i)(3) (determined after application of paragraph (4) thereof). An S corporation shall not be treated as a tax shelter for purposes of this section merely by reason of being required to file a notice of exemption from registration with a State agency described in section 461(i)(3)(A), but only if there is a requirement applicable to all corporations offering securities for sale in the State that to be exempt from such registration the corporation must file such a notice.
(C) at the election of the common parent of an affiliated group (within the meaning of section 1504(a)), all members of such group may be treated as 1 taxpayer for purposes of paragraph (2)(B) if 90 percent or more of the activities of such group involve the performance of services in the same field described in paragraph (2)(A).
(ii) such person meets the gross receipts test of subsection (c) for all prior taxable years.
The Secretary shall prescribe regulations to permit taxpayers to determine amounts referred to in subparagraph (A) using computations or formulas which, based on experience, accurately reflect the amount of income that will not be collected by such person. A taxpayer may adopt, or request consent of the Secretary to change to, a computation or formula that clearly reflects the taxpayer's experience. A request under the preceding sentence shall be approved if such computation or formula clearly reflects the taxpayer's experience.
2017-Subsec. (b)(3). Pub. L. 115–97, §13102(a)(2), amended par. (3) generally. Prior to amendment, text read as follows: "Paragraphs (1) and (2) of subsection (a) shall not apply to any corporation or partnership for any taxable year if, for all prior taxable years beginning after December 31, 1985, such entity (or any predecessor) met the $5,000,000 gross receipts test of subsection (c)."
"(1) In general.-A corporation or partnership meets the $5,000,000 gross receipts test of this subsection for any prior taxable year if the average annual gross receipts of such entity for the 3-taxable-year period ending with such prior taxable year does not exceed $5,000,000."
Subsec. (c)(4). Pub. L. 115–97, §13102(a)(3), added par. (4).
Subsec. (d)(7). Pub. L. 115–97, §13102(a)(4), amended par. (7) generally. Prior to amendment, par. (7) related to coordination with section 481.
2002-Subsec. (d)(5). Pub. L. 107–147 amended heading and text of par. (5) generally. Prior to amendment, text read as follows: "In the case of any person using an accrual method of accounting with respect to amounts to be received for the performance of services by such person, such person shall not be required to accrue any portion of such amounts which (on the basis of experience) will not be collected. This paragraph shall not apply to any amount if interest is required to be paid on such amount or there is any penalty for failure to timely pay such amount."
1988-Subsec. (c)(3)(D). Pub. L. 100–647, §1008(a)(9), added subpar. (D).
Subsec. (d)(2). Pub. L. 100–647, §6032(a), inserted at end "To the extent provided in regulations which shall be prescribed by the Secretary, indirect holdings through a trust shall be taken into account under subparagraph (B)."
Subsec. (d)(2)(B). Pub. L. 100–647, §1008(a)(1)(A), substituted "(or indirectly through 1 or more partnerships, S corporations, or qualified personal service corporations not described in paragraph (2) or (3) of subsection (a))" for "or indirectly".
Subsec. (d)(3). Pub. L. 100–647, §1008(a)(7), inserted sentence at end relating to treatment of S corporation as tax shelter.
Subsec. (d)(4)(C). Pub. L. 100–647, §1008(a)(8), substituted "90 percent or more of" for "substantially all of".
Pub. L. 100–647, §1008(a)(2), substituted "such group" for "all such members".
Subsec. (d)(8). Pub. L. 100–647, §1008(a)(1)(B), added par. (8).
"(1) In general.-The amendments made by this section [amending this section] shall apply to taxable years ending after the date of the enactment of this Act [Mar. 9, 2002].
"(C) the net amount of the adjustments required to be taken into account by the taxpayer under section 481 of the Internal Revenue Code of 1986 shall be taken into account over a period of 4 years (or if less, the number of taxable years that the taxpayer used the method permitted under section 448(d)(5) of such Code as in effect before the date of the enactment of this Act) beginning with such first taxable year."
Pub. L. 100–647, title VI, §6032(b), Nov. 10, 1988, 102 Stat. 3695 , provided that: "The amendment made by subsection (a) [amending this section] shall apply to taxable years beginning after December 31, 1986."
"(1) In general.-Except as provided in paragraph (2), the amendments made by this section [enacting this section and amending section 461 of this title] shall apply to taxable years beginning after December 31, 1986.
"(2) Election to retain cash method for certain transactions.-A taxpayer may elect not to have the amendments made by this section apply to any loan or lease, or any transaction with a related party (within the meaning of section 267(b) of the Internal Revenue Code of 1954, as in effect before the enactment of this Act), entered into on or before September 25, 1985. Any election under the preceding sentence may be made separately with respect to each transaction.
"(C) used a method of accounting for long-term contracts of accounting [sic] for a substantial part of its income from the performance of engineering services.
"(5) Special rule for paragraphs (2) and (3).-If any loan, lease, contract, or evidence of any transaction to which paragraph (2) or (3) applies is transferred after June 10, 1987, to a person other than a related party (within the meaning of paragraph (2)), paragraph (2) or (3) shall cease to apply on and after the date of such transfer."


text:
The effect of pore morphology and acidity on the selectivity in the hydrogenation of citral was investigated on a series of bifunctional catalysts: Pt-H-SAPO-5, Pt-H-Y zeolite, and Pt-H-MCM-41. The reaction was studied in a batch reactor at 70oC with 10 bar total pressure. The highest selectivity to the unsaturated alcohols of 57% was obtained on the Pt-H-SAPO-5 catalyst at a conversion of 46%. The interplay among a monodimensional pore channel of the H-SAPO-5 support, weak Br?nsted acidity of this silicoaluminophosphate, and large platinum nanoparticles contributed to a high selectivity. The corresponding turn over frequency was 0.036 s-1. Pt-H-MCM-41 showed the highest selectivity to menthol as by product, while Pt-H-Y zeolite demonstrated the highest dehydration rate.
Unsaturated aliphatic alcohols with an allylic double bond are important reactants in fine chemicals synthesis . They can be obtained by the selective hydrogenation of ?, ?-unsaturated aldehydes which is a rather difficult process as the reaction enthalpy for C=C hydrogenation is by 42 kJ/mol higher than that for C=O hydrogenation [2-4]. The hydrogenation catalysts usually contain noble metals as active components. Pt, Pd, Ni, and Ru monometallic catalysts have often been applied in citral hydrogenation [5, 6]. The selectivity depends strongly on the conditions during catalyst preparation as well as on the nature of the support. Silica , titania , carbon , carbon nanotubes [8, 9], polyanilines , zeolites , and mesoporous materials  have been extensively studied in different structures such as thin films, monoliths, and fibers.
Fig. 1. Citral and its derivatives, formed by C=O hydrogenation, C=C hydrogenation, cyclization, dehydration and double bond migration.
Selective hydrogenation of one of the ?, ?, unsaturated aldehydes, citral (3,7-dimethyl-2,6-octadienal), was chosen in this study as a model reaction. Citral is usually a mixture of E- and Z-isomers and it can be hydrogenated towards unsaturated aldehyde (citronellal) or unsaturated alcohols (nerol and geraniol). Subsequent hydrogenation of these products leads to citronellol, and then to dimenthyloctanol, while isomerization of citronellal gives isopulegol (IP).
Metal impregnated zeolites can provide shape selectivity in citral and cinnamaldehyde hydrogenation [13, 14]. Comparison with the current work is limited only to literature data on selective hydrogenation of ?, ?, unsaturated aldehydes on microporous zeolites. Other parameters such as bimetallic effect, reducibility of support and other reaction related parameters are beyond the scope of this study. The influence of geometric constraints in the micropores has been demonstrated in the Pt-BEA zeolite, where selectivity to cinnamylalcohol of 88% was reported [4, 14]. To explain the high selectivity, the authors suggested that diffusion of an aldehyde molecule occurred parallel to the linear channel walls until it reached a Pt cluster. This makes the adsorption via a carbonyl group more probable, resulting in selective hydrogenation to the unsaturated aldehyde. A similar effect was observed on a Ru-LTL zeolite catalyst which has a one-dimensional microporous network with a channel diameter of 0.71 nm. A selectivity to nerol and geraniol of 40% was reported at a citral conversion of 60% at 50oC under 50 bar pressure with 2-propanol as a solvent .
Aluminum-phosphate-based microporous molecular sieves with a one-dimensional framework structure are other potential candidates for selective hydrogenation of ?, ?-unsaturated aldehydes. The nature of their weak acidic properties has been extensively investigated  since their first appearance in the literature [16-18]. H-SAPO-5 has 12-membered rings with an aperture of 0.73 nm in diameter (AFI topology) . On metal-containing H-SAPO-5, the acid as well as the redox properties can be utilized for catalysis. The acidity of H-SAPO-5 can be tuned by changing the Al content resulting in new isomerization routes similar to that reported on Beta and Y zeolites and H-MCM-41 [11, 20].
This paper focuses on the effect of pore morphology and acidity of Pt-H-SAPO-5 and H-SAPO-5 molecular sieves with an AFI structure and their influence on the catalytic performance in citral hydrogenation to unsaturated alcohols (nerol and geraniol). The activity of H-SAPO-5 supported Pt catalyst was investigated and compared with that of Pt-H-Y, and Pt-H-MCM-41, used as reference catalysts. Pt-H-Y exhibits the FAU (faujasite) structure. It has a 3-dimensional pore structure with pores running perpendicular to each other and has a strong acidity. Pt-H-MCM-41 has a one-dimensional framework structure with a weak acidity.
H-SAPO-5 was synthesized according to the procedure by Campelo et al.  with several adjustments. The precursors in the synthesis of H-SAPO-5 were phosphoric acid (Merck, 85 wt.%), hydrated aluminium oxide (Vista, 74.2 wt.% Al2O3, and 25.8 wt.% H2O), fumed silica (Aldrich), tri-n-propylamine (Merck), and distilled water. A gel solution was prepared and poured into a Teflon coated stainless steel autoclave and the synthesis was carried out at 473 K for 24 h under static condition . H-MCM-41 was synthesized using fumed silica (Aldrich), tetramethylammonium silicate (Sachem), sodium silicate (Merck), tetradecyl trimethyl ammonium bromide (CH3(CH2)13N(CH3)3Br, Aldrich), and aluminium isopropoxide (Aldrich) by a method described in . H-Y zeolite was obtained by calcination of NH4-Y (Zeolyst International). The supported platinum catalysts were prepared by impregnation of the corresponding supports with H2PtCl6 (40 wt.%, Degussa) in a rotary evaporator for 24 h.
The acidity of the supports was studied on a ATI Mattson FT-IR spectrometer by pyridine adsorption. A 10 mg/cm2 thin tablet of the catalyst was evacuated at 723 K for 1 h. Pyridine (? 99.5 wt.%) was adsorbed at 373 K for 30 min. The desorption was carried out at 473 K. The amount of adsorbed pyridine was calculated based on the molar extinction coefficient . The BET surface area was measured by nitrogen adsorption at 77 K in an ASAP 2010 instrument (Micromeritics). A desired quantity of catalyst powder (1.0 to 5.0 wt.%) was outgassed at 573 K for 4 h prior to the measurements. XRD data were collected on a Rigaku Geigerflex Max/B diffractometer (40 kV, 40 mA) with Cu K? radiation (using continuous scanning at 0.02o 2 and a counting time of 0.5 s / scan step).
The morphology of the catalysts was determined by transmission electron microscopy (TEM). High resolution transmission electron microscopy (HR-TEM) images/stories/fotki were recorded on a FEI Tecnai TF20 electron microscope operated at 200 kV. The collected powders were grinded and dispersed in ethanol. The suspension was mounted gently to a holey amorphous carbon film on a Ni or Cu grid. The particle size distribution (PSD) was obtained by measuring 100 particles from the TEM micrographs. The mean particle diameter was calculated by the following formula: , where ni is the number of particles with diameter di.
The dispersion, %D, of the metal nanoparticles was measured by CO pulse chemisorption with stoichiometry 1:1. In case of Pt-H-SAPO-5, the dispersion was estimated from the mean particle diameter obtained from the TEM micrographs by the formula: , where C1 is equal to 108 for supported platinum catalysts .
Prior to reaction, the catalysts (300 mg, 1.0-5.0 wt.%)) were reduced in-situ by hydrogen (AGA, 99.999%) at 673 K for 60 min. Then, the reactor, an autoclave (Autoclave Engineers), was cooled to the reaction temperature. A mixture of 0.01 M citral (97 wt.%, Lancaster 5460) in cyclohexane of 200 cm3 was stripped form oxygen and fed to the reactor. The reaction was carried out in the batch mode at 343 K under 10 bar total pressure at a stirring rate of 1500 rpm. Hydrogen was supplied to reach the 10 bar total pressure. Partial pressure of hydrogen in the reactor was 9 bar as calculated from the vapour pressure of cyclohexane at 343 K. Since vigorous stirring and small catalyst particle sizes (< 90 ?m) were applied, the mass transfer resistance could be eliminated . The metal to substrate molar ratio was 20 to 65 in all experiments. Sampling volumes of 1 cm3 were selected for analysis after desired time intervals. The reactants and products were analyzed by a gas chromatograph equipped with a DB-1 capillary column (length: 30 m, internal diameter: 0.25 mm, film thickness: 0.50 ?m). The temperatures of injector and detector were 523 K and 573 K, correspondingly.
The Y zeolite demonstrated the highest concentration of Br?nsted acid sites (Table 1). The acidity of H-MCM-41 and H-SAPO-5 was respectively three and nine time less than that of Y zeolite. The concentration of Lewis acid sites on Y zeolite and H-MCM-41 was considerably higher than that on H-SAPO-5. Introducing metal on the support usually diminishes the number of strongest acid sites . The structure of the micro- and microporous materials, i.e. zeolite Y, H-SAPO-5 and MCM-41 was confirmed by XRD; it remained untagged after Pt loading [27, 28].
Fig. 2. N2 adsorption-desorption isotherms of H-SAPO-5 (?), Pt-H-SAPO-5, Fresh (?) and Spent (?). Pt-H-SAPO-5, Fresh (?) isotherms were shifted by 10 cm3/g STP and H-SAPO-5 isotherms were shifted by 20 cm3/g STP along the Volume Adsorbed axis to obtained well separated isotherms for presentation purposes.
The BET specific surface area of the supports and catalysts are given in Table 1. To be noted, it can be seen that the BET surface area of H-MCM-41 was lower than that of Pt-H-MCM-41, which can be explained by the opening of micropores in the mesoporous material during catalyst preparation; the heat treatment may have opened micropores in the mesoporous material. The specific surface area of the catalysts decreased in the following order: Pt-H-MCM-41 > Pt-H-Y > Pt-H-SAPO-5 (Table 1). The Pt-H-SAPO-5, Pt-H-MCM-41, and Pt-H-Y catalysts have a moderate specific Pt surface area and Pt dispersion in the range of 21 to 29%.
The nitrogen adsorption-desorption isotherms of the H-SAPO-5 support and of the Pt-H-SAPO-5 catalyst are shown in Figure 2.
The initial part of the isotherms corresponds to micropore filling. The subsequent adsorption up to a relative pressure of 0.37 occurs on the outer surface and in the mesopores. An uptake in the adsorption branch of the isotherms in the range of relative pressures between 0.4 and 0.9 corresponds to mesopore filling. Above a relative pressure of 0.9, adsorption takes place mainly on the outer surface and in the macropores which were produced during the pelletizing of the powders [30, 31]. It can be seen that the H-SAPO-5 support has a higher mesopore contribution (0.040 cm3/g) as compared to the Pt-H-SAPO-5 (0.016 cm3/g) catalyst. After Pt deposition, the BET surface area decreased from 220 to 178 m2/g (Table 1). However, the accessibility of the microporous network was not affected by Pt impregnation. The micropore contribution of 124 m2/g remained unchanged after Pt deposition. The mesopore contribution was considerably reduced from 96 to 54 m2/g due to partial pore blockage by Pt agglomerates. The Pt-H-SAPO-5 catalyst has a wide distribution of Pt nanoparticles in the range between 2 and 80 nm (Figure 3 (a), (b), and (c)).
The Pt particle sizes can be combined into four groups: 2-4 nm (small), 5-11 nm (medium), 15-20 nm (large), and 50-80 nm (giant).
The hydrogenation and the dehydration followed by double bond migration routes in citral transformation (Figure 1) can occur simultaneously and their rates determine the selectivity and the deactivation rate of the catalysts. Dehydration products were typically formed via dehydration of isopulegol or menthol followed by double bond isomerization and thus they consisted of C10 cyclic, unsaturated structures, such as 1-methyl-4-propyl-cyclohexene (Figure 1).
Fig. 3. TEM images/stories/fotki of (a) fresh Pt-H-SAPO-5, (b) magnification of fresh Pt-H-SAPO-5, and (c) spent Pt-H-SAPO-5.
Some of the by-products could also be formed by consecutive dehydrogenation to form menthatriene type compounds which have been confirmed by GC-MS analogously to . The presence of gas-phase low molecular weight hydrocarbons was not analyzed. The adsorption of the dehydration products on the walls of the support porous network leads to fast catalyst deactivation. Therefore, the contribution of each route to the overall conversion of citral was evaluated before a detailed activity study on four types of the supported Pt catalysts was carried out (Figure 4).
Fig. 4. Selectivity towards hydrogenation (?) and dehydration and double bond migration (?) over Pt-H-SAPO-5, Pt-H-Y, and Pt-H-MCM-41 at 343 K under 10 bar total pressure in cyclohexane. The initial citral concentration was 0.01 M.
The initial hydrogenation and dehydration rates are listed in Table 2. For easier comparison, the selectivity and concentration profiles in Figures 4 to 8 are normalized to 1 gram of Pt. Citral can be strongly adsorbed on the acid sites . It can be seen that the dehydration selectivity is in line with the acidity of the supports. The dehydration and double bond migration dominates over hydrogenation on the Pt-Y catalyst. Its contribution considerably decreases on the Pt-H-MCM-41 and further on the Pt-H-SAPO-5 catalysts. An increase of the dehydration rate with an increase of Br?nsted acidity was also reported over nickel supported H-MCM-41 and H-Y catalysts .
-aHydrogenation rate is presented in mmol/min/gPt unit (not in mmol/min/gcat) as hydrogenation is controlled by the metal nanoparticles.
bwhere CAL is citronellal, NG is nerol + geraniol, and DH = dehydration and double bond migration products.
It is well known that hydrogenation occurs on the metal sites while dehydration occurs on the acid sites. Therefore, the hydrogenation rates below are given per unit of Pt weight while the dehydration rates are calculated per unit of support weight, hereafter.
The turnover frequency (TOF) after a reaction time of 30 min was in the range of 0.02 to 0.07 s-1. The TOF decreased in the following order: Pt-H-SAPO-5, Pt-H-MCM-41 > Pt-H-Y (Table 2). Interestingly the largest TOF was observed for Pt-H-SAPO-5. The pore size of H-MCM-41 was approximately three times higher that of H-SAPO-5 and H-Y. The initial TOF based on initial hydrogenation rate correlates with the size of nanoparticles; e.g. the smaller the particles, the faster hydrogenation rate.
Full citral conversion over Pt-H-Y and Pt-H-MCM-41 was reached within 25 min (Figure 5). However, complete conversion over Pt-SAPO-5 could not be reached within this reaction time due to the fast catalyst deactivation. The BET surface area of the Pt-H-SAPO-5 catalyst decreased from 178 to 154 m2/g after reaction, mainly due to a decrease in the mesopore surface area from 54 to 36 m2/g. In other words, about one third of the initial mesopore area was not accessible for nitrogen after the reaction. The micropore surface area of the spent Pt-H-SAPO-5 catalyst of 118 m2/g and the micropore volume of 0.054 cm3/g remained relatively unchanged. The Pt-H-SAPO-5 catalyst after the reaction showed a narrow distribution of predominantly spherical nanoparticles in the range from 5 to 11 nm (Figure 3c). Therefore, neither partial pore blocking nor metal sintering can be responsible for such rapid deactivation. Most probably deactivation is caused by decarbonylation of citral and its hydrogenation products, resulting in strongly adsorbed CO and other carbon fragments .
Fig. 5. Citral molar percentage as a function of time over Pt-H-SAPO-5 (?), Pt-H-Y (?), and Pt-H-MCM-41 (?).
Total citral conversion over Pt-H-Y occurred after 10 min with a substantial contribution from the dehydration route. The selectivity to the dehydration products at 50% conversion was 67%. The citral conversion over Pt-H-MCM-41 was 62% after a reaction time of 10 min. Then, the reaction proceeds much slower. The presence of the Br?nsted acid sites was required to achieve high conversion of citral over Ni-H-MCM-41 [11, 33].
Compared with the other micro- and mesoporous support catalysts, activity of Pt-H-SAPO-5 with an H-SAPO-5 support was the highest as shown by the highest TOF and the highest initial hydrogenation rate.
In citral hydrogenation one of the most important issues regarding catalyst development is to compare chemoselective hydrogenation, i.e. hydrogenation of carbonyl and ethylenic functionalities, respectively. This was performed here in two ways, i.e. by calculating the ratio of the initial rates for formation of nerol and geraniol to that of citronellal , and by reporting selectivities. The ratio between the initial formation rates of nerol and geraniol to citronellal decreased in the following order: Pt-H-SAPO-5 (2.0) > Pt-H-MCM-41 (0.4) > Pt-H-Y (0), indicating that Pt-H-SAPO-5 was five fold more active in the hydrogenation of carbonyl bond than Pt-H-MCM-41, which was the second most active catalyst for hydrogenation of the carbonyl bond. The selectivities towards the main hydrogenation products, nerol and geraniol, citronellal, citronellol, 3,7-dimethyloctanal, 3,7-dimethyloctanol, isopulegol, menthol and towards the dehydration products, are listed in Tables 2 and 3. It should be noted that the sum of the selectivities of the seven main products is often less than 100% due to formation of small amounts of other isomerization by-products, e.g. neomenthol, isomenthol and menthones, which selectivities were not included in further consideration.
Fig. 7. (a) Molar percentage of isopulegol, and (b) molar percentage of menthol in a 300 min prolonged citral hydrogenation over Pt-H-SAPO-5 (?), Pt-H-Y (?), Pt-H-MCM-41 (?), and Pt-SiO2 (?).
Comparison of the formation of various products from hydrogenation and cyclisation is depicted in Figures 6 and 7. In the absence of steric limitations and strong acid sites, the supported Pt catalysts are selective in C=C hydrogenation . Hydrogenation of the conjugated C=C bond to citronellal was the main route over Pt-H-MCM-41. The selectivity to the unsaturated alcohols was below 5%. The selectivity towards the undesired dehydration and double bond migration products was 18% over Pt-H-MCM-41 at full conversion of citral.
The most selective catalyst towards nerol and geraniol from the four studied catalysts was the bifunctional Pt-H-SAPO-5, giving nerol and geraniol with a selectivity towards 57% at a citral conversion level of 46% (Table 3). This value was higher than that previously reported on a monodimensional LTL zeolite . The overall kinetics for citral hydrogenation over Pt-H-SAPO-5 is shown in Figure 8a, in which an exceptionally high formation rates for nerol and geraniol compared to those for the citronellal and 3,7-dimethyloctanal generation are clearly visible. Furthermore, citronellol was hydrogenated rapidly to 3,7-dimethyloctanol. An increase of selectivity to the unsaturated alcohols with the increase of citral conversion over Pt-SAPO-5 (Figure 8b) occurred up to about 46% conversion, thereafter selectivity decreased due to consecutive hydrogenation. This curve shape is exceptional, since a typical selectivity curve for a consecutive reaction is similar to that of Pt-H-MCM-41 (Figure 8b), in which the selectivity of an intermediate product started to decrease with increasing conversion. An increasing selectivity to the unsaturated alcohols as a function of conversion has been previously reported for citral  and for cinnamaldehyde . This exceptionally selectivity increase on the conversion can be caused by multicentred adsorption where the steric constrains induced by the H-SAPO-5 monodimensional pores influence the number of sites available for adsorption of carbonyl and carbon double bond on Pt-H-SAPO-5 .
The steric limitations of the citral molecule with a molecular diameter of 0.58 nm  confined in the monodimensional pores of Pt-H-SAPO-5 with a diameter of 0.73 nm, could induce an end-on C=O adsorption mode . As a result, the selectivity to citronellal over Pt-H-SAPO-5 was below 7 % (Figure 9) while a substantial amount of isomerization products (isopulegol) were also produced on the acid sites.
Hydrogenation of the isolated C=C bond rather than of the C=O bond occurred in the second hydrogenation step over Pt-H-MCM-41 catalyst (Figure 6 and Figure 9). As a result, a low selectivity to citronellol and a moderate selectivity to 3,7-dimethyloctanal were observed at larger reaction times. 3,7-dimethyloctanol was formed either via hydrogenation of citronellal or via hydrogenation of nerol and geraniol to citronellol. At longer reaction times, citronellol and 3,7-dimethyloctanal were further hydrogenated on the supported Pt catalysts towards 3,7-dimethyloctanol (Fig. 8a). Thus, if reaction time allows, hydrogenation on the supported Pt catalysts always proceeds towards the fully hydrogenated products in the absence of steric limitations. The highest selectivity to 3,7-dimethyloctanol of 34% was observed on the micro(meso)porous Pt-H-MCM-41 catalyst. It is also possible to stop the reaction after the second hydrogenation step (citronellol) using Ni as an active metal [37, 38].
However, not all citral was hydrogenated towards citronellol over the bifunctional Pt-H-MCM-41 and Pt-H-Y catalysts. The product of the first hydrogenation step, citronellal, was isomerized to isopulegol on the acid sites and further hydrogenated to menthol (Figure 7b) at longer reaction times [38-41]. Pt-H-MCM-41 catalyst was the most selective one to menthol with 18% selectivity at a citral conversion of 25% (Table 3). Unlike Ni-H-MCM-41, platinum supported H-MCM-41 was less selective to cyclization route and menthol at long reaction times  due to the fast subsequent hydrogenation of citronellol to 3,7-dimethyloctanol. The most acidic catalyst (Pt-H-Y) was also not selective in cyclization route due to considerable conversion of citral towards dehydration products (e.g. menthatrienes) which were the main products with a selectivity of 67% at full citral conversion (Table 2). The highest selectivity to menthol was 7%. The selectivity to isopulegol over the Pt-H-SAPO-5 catalyst was below 2%.
Hydrogenation of citral was investigated on a series of bifunctional catalysts: Pt-H-Y zeolite, Pt-SAPO-5, as well as on a supported Pt-MCM-41 catalyst. The initial reaction rate in terms of TOF was the highest on the mesoporous Pt-H-MCM-41 catalyst, followed by the microporous Pt-H-SAPO-5, and finally the microporous Pt-H-Y. The acid site concentration decreased in the reversed order. In this way, the H-Y support showed the highest activity in dehydration and double bond migration, which was due to its highest concentration of Br?nsted acid sites. H-SAPO-5 was the most selective support for hydrogenation towards the unsaturated alcohols with selectivity of 57% at the conversion level of 46%. A unique combination of a monosized pore diameter, weak Br?nsted acidity, and a large Pt particle size contributed to a high selectivity. However, rapid deactivation occurred on this support due to adsorption of the dehydration products and partial pore blocking. Pt-H-MCM-41 was the most selective catalyst for the formation of menthol. However, on this catalyst, the parallel dehydrogenation reaction still consumed 18% of citral, while the deactivation rate was less pronounced as compared with H-SAPO-5. Further reducing the size of platinum nanoparticles is required to fully explore the benefit of using unidimensional pore of microporous zeolites such as H-SAPO-5 in selective hydrogenation.
The financial support by the Dutch Technology Foundation (STW, project no. EPC.6359), Shell, Akzo Nobel Chemicals, Schering-Plough, DSM, Bronkhorst, TNO, and the Finnish Centre of Excellence Programme (2000–2011) of the Academy of Finland are gratefully acknowledged. Authors are grateful to Mr. Markku Reunanen for MS analysis at ?bo Akademi University and Dr. Ugo Lafont from Delft University of Technology for the TEM measurements.
Fig. 6. (a) Molar percentage of nerol and geraniol, (b) molar percentage of citronellal, (c) molar percentage of citronellol, (d) molar percentage of 3,7-dimethyloctanal, and (e) molar percentage of 3,7-dimethyloctanol in citral hydrogenation over Pt-H-SAPO-5 (?), Pt-H-Y (?), Pt-H-MCM-41 (?), and Pt-SiO2 (?).
Fig. 9. Selectivity of main citral derivatives as a function of conversion over a) Pt-H-SAPO-5 and b) Pt-H-MCM-41: nerol and geraniol (?), citronellal (O), citronellol (?), 3-7, dimethyloctanal (?), and 3-7, dimethyloctanol (?).
awhere X is conversion, CAL = citronellal, NG = nerol + geraniol, COL = citronellol, DMAL = 3,7-dimethyloctanal, DMOL = 3,7-dimethyloctanol, IP = isopulegol, and MT = menthol. ? is the total selectivity for the main products excluding other menthols such as isomenthol and neomenthol.
bthe experiment was carried out until conversion of 87%.
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The consolidated lawsuits subject to the settlement allege that Insys violated the False Claims Act and Anti-Kickback Statute in connection with its marketing of Subsys, a sub-lingual spray form of the powerful opioid fentanyl. The Food and Drug Administration has approved Subsys for, and only for, the treatment of persistent breakthrough pain in adult cancer patients who are already receiving, and tolerant to, around-the-clock opioid therapy. The government’s complaint alleges that Insys provided kickbacks in the form of arrangements disguised as otherwise permissible activities. Specifically, it alleges that Insys instituted a sham speaker program, paying thousands of dollars in fees to practitioners for speeches “attended only by the prescriber’s own office staff, by close friends who attended multiple presentations, or by people who were not medical professionals and had no legitimate reason for attending.” Many of these speeches were held at restaurants and did not include any substantive presentation. Insys also allegedly provided jobs for prescribers’ friends and relatives, visits to strip clubs, and lavish meals and entertainment.
According to the government, Insys improperly targeted Subsys to patients who did not have cancer. Among other allegations, it notes that most of the physicians that Insys paid through its speaker program were not oncologists. The government also alleges that Insys lied to payors, including Medicare, to induce payment for such off-label prescriptions, and that its deceptive statements were material to the government’s reimbursement decisions.
The relator in the consolidated cases filed claims on behalf of 28 states and the District of Columbia. On the same day that the Insys settlement was announced, six of those states plus Colorado filed an intervenor complaint alleging violations of their respective state false claims acts, other state statutes and common law. Those claims are separate and apart from the ones resolved by the settlement-in-principle.
The allegations against Insys have also given rise to a number of criminal actions against former officers and employees. The same day that the settlement was announced, a former district sales manager, Jeffrey Pearlman, pled guilty in a Connecticut federal court to conspiracy to defraud the United States in connection with the alleged scheme. See Plea Agreement, United States v. Pearlman, 17-CR-27-MPS (D. Conn. Aug. 8, 2018), ECF No. 147. Currently, there are four additional pending criminal actions against a total of 14 other defendants related to the case. Those cases are United States v. Freedman et al., 18-CR-217-KMW (S.D.N.Y. filed Mar. 14, 2018); United States v. Patel, 17-CR-114-VPC (D. Nev. filed Dec. 6, 2017); United States v. Clough, 17- CR-37 JL (D.N.H. filed Mar. 22, 2017); and United States v. Babich et al., 16- CR -10343-ADB (D. Mass. filed Dec. 6, 2016). These criminal cases show a continuing commitment to the principles set forth in the DOJ’s 2015 Yates Memorandum, which called for increased accountability for individuals responsible for corporate wrongdoing.
The five consolidated lawsuits subject to the settlement-in-principle are United States, et al., ex rel. Guzman v. Insys Therapeutics, Inc., et al., 13-cv-5861; United States ex rel. Andersson v. Insys Therapeutics, Inc., 14-cv-9179; United States ex rel. John Doe and ABC, LLC v. Insys Therapeutics, Inc., et al., 14-cv-3488; United States ex rel. Erickson and Lueken v. Insys Therapeutics, Inc., 16-cv-2956; and United States ex rel. Jane Doe, et al. v. Insys Therapeutics, et al., 16-cv-7937.

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At the Laboratory for Microbial and Environmental Genomics, we examine how microorganisms affect environmental health and human health. We are especially interested in how microbes evolve in response to ecosystem change. After all, the sum of the metabolic and evolutionary potential stored in the microbial community defines microorganisms as nature’s first responders.
Two primary areas of research are 1) assessing the intrinsic biodegradation of plastic debris in marine environments and 2) quantifying the prevalence of antibiotic resistance genes in urbanized estuaries. These two project are led by graduate students Lee Pinnell and James Tallman, respectively. Both students have received funding awards from Texas Sea Grant’s Grants-In-Aid of Research Program. Additionally, our plastic research is funded by Texas Research Development Fund and the Texas General Land Office Coastal Management Program. Although these projects are in the initiation stage, study sites have been selected and we will begin collecting data Spring 2016. Please check back in the near future to learn more about these exciting research projects.
More developed research projects include the analysis of multiple Vibrio genomes. The genus occurs naturally in marine environments and is frequently associated with disease in humans. However, these bacteria are not obligate parasites and pathogenicity is widely regarded as a consequence of genes that play a role in the marine environment but afford cross protection in a human host. More exploratory research projects include 1) the antimicrobial analysis of novel amino acid surfactants (an interdisciplinary project coordinated with Dr. Feri Billiot and led by undergraduate student Devin Lovato) and 2) the evaluation of laser-induced plasma to sterilize food and medical tools (an interdisciplinary project coordinated with Dr. Magesh Thiyagarajan).
The abstracts below give a detailed description of current research. We will be showcasing these projects and more at the upcoming 2016 ASLO Ocean Sciences Meeting in New Orleans, LA.
A critical problem in the prevention and treatment of infectious disease is the ability to differentiate virulent from avirulent bacterial strains. The distinction is commonly based on the presence or absence of specific virulence-associated genes. Alternately, serotypic or phylogenetic typing can differentiate virulent from avirulent strains. When these approaches fail, more discriminatory analysis is needed. Pandemic Vibiro parahaemolyticus, distinguishable by genotyping (thermostable direct hemolysin or tdh), serotyping (O3:K6) and multilocus sequence typing (ST3), is regarded as a highly virulent clonal complex. We have previously shown, through population genetics and cytotoxicity testing, that some pandemic strains isolated from environmental sources are avirulent. To investigate the basis for attenuation, we sequenced the draft genomes of 10 pandemic V. parahaemolyticus isolates originating from environmental (N = 7) and clinical sources (N = 3). Genomic comparison of these 10 draft genomes, and the pandemic type strain (RIMD2210633), revealed a large core genome (5,158,719 bp) and a much smaller accessory genome (141,403 bp). The accessory genome was largely comprised of hypothetical proteins; however, several genes encoded phage-related proteins. Phylogenetic analysis, based on 2,902 single nucleotide polymorphisms in the core genome, did not reveal a discernable pattern. Current efforts are focused on the identification of insertions, deletions and point mutations that may alter protein expression or protein function. Preliminary results show the virulence-associated vacB gene (VP1890) is a pseudogene in attenuated strains. This gene encodes a 741 amino acid exoribonuclease homologous to exoribonucleases known to modulate virulence in Salmonella enterica and Helicobacter pylori. The correlation between attenuation and the absence of this gene, suggests that VP1890 plays an important role in human pathogenesis.
Vibrio parahaemolyticus [Vp] is a Gram-negative bacterium indigenous to marine coastal waters. Vp is also the causative agent of a mild to severe gastroenteritis associated with the consumption of raw or undercooked seafood. The majority of infections are caused by a genetically distinct ecotype commonly referred to as the pandemic clonal complex. However, localized outbreaks associated with non-pandemic ecotypes are frequently reported. In the East Pacific, two such ecotypes, identified as ST65 and ST417 by multilocus sequence typing, have been associated with outbreaks in Peru, Chile and the United States. In this study, we sequenced and assembled draft genomes from 4 clinical isolates (ST65: 3328, 3355; ST417: 3646, 3631) that were positive for both the thermostable direct hemolysin (tdh) and thermostable direct-related hemolysin (trh). When compared with the pandemic type strain (V. parahaemolyticus RIMD2210633), each of these isolates harbored more than 400 Kb of novel genetic material. Proteins encoded by this novel genetic material include CcdA-CcdB toxin-antitoxin systems, an efflux pump belonging to the multidrug and toxic efflux (MATE) family, and a repeats-in-toxin (RTX) gene cluster. These features share significant homology and synteny with virulence-associated features found in clinical V. vulnificus and Escherichia coli strains. We hypothesize that these features contribute to a pathogenic phenotype. The identification and characterization of multiple clinical ecotypes could improve efforts aimed at preventing V. parahaemolyticus infections. Further, a greater understanding of the species’ biogeography may lead to a more effective public health response.
Vibrio parahaemolyticus [Vp] is a Gram-negative bacterium and a natural inhabitant of coastal marine ecosystems worldwide. Vp is also a coincidental pathogen of humans. Virulent strains are commonly identified by the presence of the thermostable direct (tdh) or tdh-related (trh) hemolysin genes. However, virulence is multifaceted and many clinical Vp isolates do not carry tdh or trh. In this study, we sequenced and assembled the draft genome of a tdh– and trh-negative environmental isolate (805) shown previously to be highly virulent in zebrafish. To investigate potential mechanisms of virulence, we compared 805 to the clinical V. parahaemolyticus type strain (RIMD2210633). Pairwise comparison revealed the presence of multiple genomic regions including an IncF conjugative pilus (1.3 Kb) and a colicin V plasmid (1.49 Kb). These features are homologous to genomic regions present in clinical V. vulnificus and V. cholerae strains. Genome comparison also revealed the presence of five toxin-antitoxin systems. Isolate 805 likely attained these new features through the lateral acquisition of mobile genomic material – a hypothesis supported by the aberrant GC content of these regions. Colicin V plasmids are a diverse group of IncF plasmids found in invasive bacterial strains. Similarly, an abundance of toxin-antitoxin systems have been linked to virulence in Gram-negative bacteria. Current efforts are focused on characterizing 142 coding features present in 805 but absent from the type strain.

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