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Supplementary Tables and Methods

Redacted protocol for supplementary files

Supplementary Figure 4 shows pharmacokinetic parameters for guadecitabine and decitabine in the dose escalation phase

Purpose:Preclinical data indicate that DNA methyltransferase inhibition will circumvent cisplatin resistance in various cancers.Patient and Methods:SPIRE comprised a dose-escalation phase for incurable metastatic solid cancers, followed by a randomized dose expansion phase for neoadjuvant treatment of T2–4a N0 M0 bladder urothelial carcinoma. The primary objective was a recommended phase II dose (RP2D) for guadecitabine combined with gemcitabine and cisplatin. Treatment comprised 21-day gemcitabine and cisplatin cycles (cisplatin 70 mg/m2, i.v., day 8 and gemcitabine 1,000 mg/m2, i.v., days 8 + 15). Guadecitabine was injected subcutaneously on days 1–5, within escalation phase cohorts, and to half of 20 patients in the expansion phase. Registration ID: ISRCTN 16332228.Results:Within the escalation phase, dose-limiting toxicities related predominantly to myelosuppression requiring G-CSF prophylaxis from cohort 2 (guadecitabine 20 mg/m2, days 1–5). The most common grade ≥3 adverse events in 17 patients in the dose-escalation phase were neutropenia (76.5%), thrombocytopenia (64.7%), leukopenia (29.4%), and anemia (29.4%). Addition of guadecitabine to gemcitabine and cisplatin in the expansion phase resulted in similar rates of severe hematologic adverse events, similar cisplatin dose intensity, but modestly reduced gemcitabine dose intensity. Radical treatment options after chemotherapy were not compromised. Pharmacodynamics evaluations indicated guadecitabine maximal target effect at the point of cisplatin administration. Pharmacokinetics were consistent with prior data. No treatment-related deaths occurred.Conclusions:The guadecitabine RP2D was 20 mg/m2, days 1–5, in combination with gemcitabine and cisplatin and required GCSF prophylaxis. Gene promoter methylation pharmacodynamics are optimal with this schedule. Addition of guadecitabine to gemcitabine and cisplatin was tolerable, despite some additional myelosuppression, and warrants further investigation to assess efficacy.

Supplementary Figure 1 shows a schematic of the treatment cycle

Supplementary Figure 2 shows CONSORT diagrams for both phases of the trial

Supplementary Figure 3 shows promotor methylation status for the indicated genes in cfDNA

Trunk support of newly planted Pyrus calhryana saplings (from 57-L [15-gal] containers, 280 cm [9 ft] tall) for 2 years with 2 stakes was compared with the TreeSaver™ Tree Anchoring System (3 rubber support straps anchoring each tree) and with a prototype of Bio-Tie (single-stake system holding each tree in an upright position with a flexible cord allowing for multidirectional movement of each tree). During the first year after installation, the double-staked trees grew taller than those supported with Tree Saver or Bio-Tie systems (P < 0.05). After the trunk supports were removed and the trees were allowed to sway normally in the third year, the differences in growth increase disappeared. The Bio-Tie-supported tree trunks developed significantly more taper than either Tree Saver or the 2 stakes and remained more tapered after the stem supports were removed.

OBJECTIVE—The study aim was to determine if multisystemic therapy (MST), an intensive home-based psychotherapy, could reduce hospital admissions for diabetic ketoacidosis (DKA) in youth with poorly controlled type 1 diabetes over 24 months. Potential cost savings from reductions in admissions were also evaluated. RESEARCH DESIGN AND METHODS—A total of 127 youth were randomly assigned to MST or control groups and also received standard medical care. RESULTS—Youth who received MST had significantly fewer hospital admissions than control subjects (χ2 = 11.77, 4 d.f., n = 127; P = 0.019). MST-treated youth had significantly fewer admissions versus their baseline rate at 6-month (P = 0.004), 12-month (P = 0.021), 18-month (P = 0.046), and 24-month follow-up (P = 0.034). Cost to provide MST was 6,934 USD per youth; however, substantial cost offsets occurred from reductions in DKA admissions. CONCLUSIONS—The study demonstrates the value of intensive behavioral interventions for high-risk youth with diabetes for reducing one of the most serious consequences of medication noncompliance.

In 2003, through the Greater Cincinnati Health Council nine health care systems agreed to participate and fund 50% of a two-year project to reduce hospital-acquired infections among patients in intensive care units (ICU) and following surgery (SIP).Hospitals were randomized to either the CR-BSI or SIP project in the first year, adding the alternative project in year 2. Project leaders, often the infection control professionals, implemented evidence-based practices to reduce catheter-related blood stream infections (CR-BSIs; maximal sterile barriers, chlorhexidine) at their hospitals using a collaborative approach. Team leaders entered process information in a secure deidentifled Web-based database.Of the four initial sites randomized to CR-BSI reduction, all reduced central line infections by 50% (CR-BSI, 1.7 to 0.4/1000 line days, p.05). At the project midpoint (3 quarters of 2004), adherence to evidence-based practices increased from 30% to nearly 95%.The direct role of hospital leadership and development of a local community of practice, facilitated cooperation of physicians, problem solving, and success. Use of forcing functions (removal of betadine in kits, creation of an accessory pack and a checklist for line insertion) improved reliability. The appropriate floor for central line infections in ICUs is1 infection /1,000 line days.

Federal law, as currently written, is theoretically capable of redressing widespread sex- and race-based wage discrimination. However, courts are not now applying these laws in ways that will attain that goal. In legal terms, comparable worth does not describe a legal problem or a theory of liability. The problem is sex- and race-based wage discrimination, and the theories of liability are classic employment discrimination theories. Comparable worth studies may be used as part of the proof that wage discrimination exists, and wages based upon the comparable worth of jobs may be ordered as a remedy if plaintiffs prove discrimination. This article discusses several ways to close the gap between courts' current approach and the law's potential to change wage inequities.

It is curious that the question with which, of all others, every participant in local politics finds himself most persistently confronted—and it is a truism that by far the greatest part of our political lives are concerned with local affairs—should be given so little. attention in treatises on American government. I refer to the problem of the relation between national political parties and state and local politics.The problem presents itself under two aspects, in one sense separate, though in reality closely interwoven with each other. There is first the anomaly that local issues seem so far removed from the platforms of the organizations, the national parties, through which the often perplexed and embarrassed voter must express himself in the performance of his ordinary electoral duties in the state or the locality; and there is, secondly, the question faced by every would-be reformer of local government, as to whether the desired reforms can best be brought about through the national party organizations or through separate locally organized groups.

Should the city manager be a leader in the formulation of policy? Is it proper that he should be “in politics”? Or must he remain merely an executive responsible for routine operation only?

Political science is at the parting of the ways. Its foundations have been undermined by the claims of law and jurisprudence, into whose hands it has been deliberately surrendering itself for the past half-century or more, and now its chief strongholds are under fire from the neighboring fields of sociology, economics, and ethics. So severe and so persistent have these attacks become that the time has arrived when the political scientist must decide whether he will allow his subject to be absorbed in any one or all of these various fields, or will attempt to reestablish it as a distinctive discipline. The reasons for this state of things are not difficult to discover. They quite obviously lie in the fact that in the pursuit of their basic problem-the search, namely, for the nature and source of sovereignty-political philosophers have so generally followed two equally futile and fruitless paths: either the path of pure speculation leading to a supernatural or metaphysical theory, or the path of legal analysis, leading ultimately to the juristic theory of the state. Indeed, during these recent years political theory has been so increasingly "under bondage to the lawyers"' that it is little wonder that a reaction has come, and that thinkers in their determination to find the reality behind the formal juristic conception, are now repudiating not only the legal, but even the political, character of the state. The complete history of the juristic theory of the state remains to be written. Its relation on the one hand, however, with the earlier attempts to fix sovereignty in a particular element of the state the so-called "state-organ theories"-and, on the other, with the Austinian doctrine, is sufficiently clear. All of these preceding theories involved, moreover, in their turn, strictly legalistic conceptions, according to which sovereignty was simply a "legal independence free from all external control and a legal