A source synchronous I/O system based on high-density silicon carrier interconnects is introduced. Benefiting from the advantages of advanced silicon packaging technologies, the system uses 50 ...μm-pitch μC4s to reduce I/O cell size and fine-pitch interconnects on silicon carrier to achieve record-breaking interconnect density. An I/O architecture is introduced with link redundancy such that any link can be taken out of service for periodic recalibration without interrupting data transmission. A timing recovery system using two phase rotators shared across all bits in a receive bus is presented. To demonstrate these concepts, an I/O chipset using this architecture is fabricated in 45 nm SOI CMOS technology. It includes compact DFE-IIR equalization in the receiver, as well as a new all-CMOS phase rotator. The chipset is mounted to a silicon carrier tile via Pb-free SnAg μ C4 solder bumps. Chip-to-chip communication is achieved over ultra-dense interconnects with pitches of between 8 μm and 22 μm. 8 × 10-Gb/s data is received over distances up to 4 cm with a link energy efficiency of 5.3 pJ/bit from 1 V TX and RX power supplies. 8 × 9-Gb/s data is recovered from a 6-cm link with 16.3 dB loss at 4.5 GHz with an efficiency of 6.1 pJ/bit.
Bright white light has been successfully used for the treatment of depression. There is interest in identifying which spectral colors of light are the most efficient in the treatment of depression. ...It is theorized that green light could decrease the intensity duration of exposure needed. Late Wake Treatment (LWT), sleep deprivation for the last half of one night, is associated with rapid mood improvement which has been sustained by light treatment. Because spectral responsiveness may differ by age, we examined whether green light would provide efficient antidepressant treatment in an elder age group.
We contrasted one hour of bright green light (1,200 Lux) and one hour of dim red light placebo (<10 Lux) in a randomized treatment trial with depressed elders. Participants were observed in their homes with mood scales, wrist actigraphy and light monitoring. On the day prior to beginning treatment, the participants self-administered LWT.
The protocol was completed by 33 subjects who were 59 to 80 years old. Mood improved on average 23% for all subjects, but there were no significant statistical differences between treatment and placebo groups. There were negligible adverse reactions to the bright green light, which was well tolerated.
Bright green light was not shown to have an antidepressant effect in the age group of this study, but a larger trial with brighter green light might be of value.
Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of ...macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.
The incidence of insomnia and depression in the elder population is significant. It is hoped that use of light treatment for this group could provide safe, economic, and effective rapid recovery.
In ...this home-based trial we treated depressed elderly subjects with bright white (8,500 Lux) and dim red (<10 Lux) light for one hour a day at three different times (morning, mid-wake and evening). A placebo response washout was used for the first week. Wake treatment was conducted prior to the initiation of treatment, to explore antidepressant response and the interaction with light treatment. Urine and saliva samples were collected during a 24-hour period both before and after treatment and assayed for aMT6s and melatonin respectively to observe any change in circadian timing. Subjects wore a wrist monitor to record light exposure and wrist activity. Daily log sheets and weekly mood (GDS) and physical symptom (SAFTEE) scales were administered. Each subject was given a SCID interview and each completed a mood questionnaire (SIGH-SAD-SR) before and after treatment. Also, Hamilton Depression Rating (SIGH-SAD version) interviews were conducted by a researcher who was blind to the treatment condition. A control group of healthy, age-matched, volunteers was studied for one day to obtain baseline data for comparison of actigraphy and hormone levels.
Eighty-one volunteers, between 60 and 79 years old, completed the study. Both treatment and placebo groups experienced mood improvement. Average GDS scores improved 5 points, the Hamilton Depression Rating Scale (HDRS) 17 scores (extracted from the self-rated SIGH-SAD-SR) improved 6 points. There were no significant treatment effects or time-by-treatment interactions. No significant adverse reactions were observed in either treatment group. The assays of urine and saliva showed no significant differences between the treatment and placebo groups. The healthy control group was active earlier and slept earlier but received less light than the depressed group at baseline.
Antidepressant response to bright light treatment in this age group was not statistically superior to placebo. Both treatment and placebo groups experienced a clinically significant overall improvement of 16%.
In this letter, the integration of CMOS-compatible thru-Si via (TSV) interconnects with deep-trench decoupling capacitors is demonstrated. Reliability test is performed with a 65-nm CMOS test chip on ...top of a 3-D Si interposer chip that contains 10 000 TSV interconnects. Multilayer stacking is also demonstrated, and capacitance density of 280 nF/mm 2 is achieved with two-layer Si interposer chip stacks.
Abstract 3747
Ponatinib is a potent, oral, pan-BCR-ABL inhibitor with activity against native and mutant forms of BCR-ABL, including the tyrosine kinase inhibitor (TKI)-resistant T315I mutant. The ...efficacy and safety of ponatinib (45 mg orally QD) were evaluated in a phase 2, international, open-label clinical trial (PACE). These multivariate analyses explored the impact of dose intensity and several prognostic and predictive factors on clinical responses, adverse events (AEs), and laboratory changes.
Enrolled patients were resistant or intolerant (R/I) to dasatinib or nilotinib, or had the T315I BCR-ABL mutation at baseline. A total of 267 chronic phase (CP), 83 accelerated phase (AP), and 94 blast phase (BP) CML/Ph+ ALL patients were assigned to 1 of 6 cohorts according to disease phase (CP-, AP-, or BP-CML/Ph+ ALL), R/I to dasatinib or nilotinib, and presence of T315I. Three CP-CML and 2 AP-CML patients were treated, but not assigned to a cohort (post-imatinib, did not have T315I at baseline); these patients were excluded from efficacy analyses and included in safety analyses. For the purposes of the efficacy multivariate analyses, AP-CML, BP-CML, and Ph+ ALL patients were combined. The baseline covariates analyzed were age, time since diagnosis, number of prior TKIs, presence or absence of the T315I mutation, neutrophil and platelet counts, and weight. The primary efficacy outcome analyzed was major cytogenetic response (MCyR) in CP-CML and major hematologic response (MaHR) for all other patients. The safety outcomes analyzed were the following AEs: pancreatitis, elevated lipase, alanine aminotransferase (ALT) increase, aspartate aminotransferase (AST) increase, rash, neutropenia, thrombocytopenia, arthralgia, and hypertriglyceridemia. The impact on neutrophils, platelets, bilirubin, ALT, AST, creatinine, lipase, and triglycerides was also examined. Binary event outcomes were analyzed using logistic regression models. Data values over time were analyzed using linear mixed effects models. Laboratory values were log-transformed. Data as of 27 April 2012 were used in these analyses.
Median baseline characteristics of the CP-CML R/I and T315I cohorts, respectively, were: 61 vs 51 yrs of age, 8 vs 5 yrs since initial diagnosis, 3 vs 2 prior TKIs. The median dose intensity for the CP-CML R/I and T315I cohorts was 30 and 39 mg/day, respectively. In general, other baseline characteristics were balanced between these 2 cohorts. Multivariate analysis found statistically significant associations between MCyR and increasing dose intensity (mg/day) (p<0.0001) and decreasing age (p=0.046) in CP-CML. Despite the finding that CP-CML patients with the T315I mutation had a higher response rate than those without the T315I mutation (MCyR 70% vs 49%), presence of T315I was not a significant prognostic factor for response after adjusting for other covariates (p>0.2). This was likely because patients with T315I received a greater dose intensity, were younger, and were previously treated with fewer TKIs.
The probability of achieving MaHR in patients with AP-CML, BP-CML, and Ph+ ALL increased with increasing dose intensity (p<0.001) and with higher numbers of baseline platelets (p=0.0046). As in CP-CML, similar trends in baseline characteristics were observed, and the presence of the T315I mutation was not a significant prognostic factor for MaHR.
In all patients, the probability of AEs (pancreatitis, lipase increase, ALT and AST increase, thrombocytopenia, neutropenia, arthralgia, and rash) increased with increasing dose intensity. Hypertriglyceridemia was trend level associated with dose intensity (p=0.054). Presence of T315I was associated with a lower risk of thrombocytopenia (p<0.0001) and neutropenia (p=0.005) after adjustment for dose intensity and the other factors. In general, younger age, less time since diagnosis, and fewer prior TKIs were associated with a lower probability of AEs.
These findings suggest that dose intensity and factors related to extent of disease and prior treatment were most predictive of effectiveness and tolerance of ponatinib. T315I was not a significant prognostic factor for efficacy or safety after adjustment for other factors, with the exception of thrombocytopenia and neutropenia; patients with T315I had lower predicted rates of these AEs after adjustment for dose intensity and other factors in the reduced models.
Off Label Use: Ponatinib - non FDA approved (experimental) compound. Cortes:Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding. Kim:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pinilla-Ibarz:Novartis : Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis and Bristol Myers-Squibb: Honoraria. Nicolini:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers-Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Research Funding; ARIAD: Research Funding; Deciphera: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:Bristol Myers-Squibb and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Dorer:ARIAD: Employment, Equity Ownership. Knickerbocker:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hochhaus:ARIAD, Novartis, Bristol Myers-Squibb, Pfizer, and MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:Novartis: Consultancy; Bristol Myers-Squibb: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding. Kantarjian:Pfizer: Research Funding; ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding.
Special Problems of Insurance Companies Knickerbocker, Daniel C.; Groom, Theodore R.; Jacobus, John H. ...
The Business lawyer,
10/1975, Volume:
31
Journal Article
Peer reviewed
LIFE-INSURANCE COMPANIES DIFFER FROM OTHER CORPORATE EMPLOYERS BECAUSE OF THE NATURE OF THE BUSINESS LIFE COMPANIES DO, THE WAY THEY DO IT, AND THE LEGAL MILIEU IN WHICH THEY DO IT. ITS MAJOR PROBLEM ...WITH RESPECT TO ERISA IS THE MULTIPLE SERVICES PROBLEM. IT IS CLEAR THAT THERE IS NO WAY TO INSULATE THE BOARD-OF-DIRECTORS OF A LIFE COMPANY FROM FULL FIDUCIARY RESPONSIBILITY UNDER ERISA WITH RESPECT TO THE MANAGEMENT OF PLAN ASSETS. SINCE A LIFE COMPANY IS OFTEN ONE OF SEVERAL FUND MANAGERS FOR A SINGLE PLAN, IT ALSO FACES THE PROBLEM OF CO-FIDUCIARY LIABILITY. ALSO, SINCE SOME LIFE COMPANIES ALLOT PARTICIPATIONS IN LARGE MORTGAGES AND PRIVATELY PLACED LOANS TO BOTH GENERAL AND SEPARATE ACCOUNTS, THIS NOT ONLY CREATES A POTENTIAL FOR A CONFLICT OF INTEREST BUT ALSO A VIOLATION OF FIDUCIARY PRINCIPLE. ALSO, WITH RESPECT TO ACCOUNTING METHODS, IT IS NOT POSSIBLE TO WALL OFF PARTICULAR CONTRACTS TO PREVENT THEIR BEARING THEIR SHARE OF ALLOCATED EXPENSES.
Who Are Fiduciaries? Bartlett, Marshall; Cummings, Frank; Knickerbocker, Daniel C. ...
The Business lawyer,
10/1975, Volume:
31
Journal Article
Peer reviewed
UNDER THE STATUTORY DEFINITION, FIDUCIARIES INCLUDE OFFICERS AND DIRECTORS OF A PLAN, MEMBERS OF A PLAN'S INVESTMENT COMMITTEE AND PERSONS WHO SELECT THESE INDIVIDUALS. THUS THE DEFINITION INCLUDES ...PERSONS WHO HAVE AUTHORITY AND RESPONSIBILITY WITH RESPECT TO A PLAN, REGARDLESS OF THEIR FORMAL TITLE. THE EMPLOYING CORPORATION IS CLEARLY A FIDUCIARY. THE BOARD-OF-DIRECTORS ARE FIDUCIARIES AS TO THEIR APPOINTING AND REMOVING FUNCTIONS, BUT NOT INSOFAR AS ESTABLISHING A PLAN. OTHER POTENTIAL FIDUCIARIES ARE THE DIRECTORS OF OTHER FIDUCIARIES, SUCH AS OF A BANK ACTING AS TRUSTEE, OR OF AN INVESTMENT ADVISOR. THERE IS GREAT VALUE IN BEING A NAMED FIDUCIARY IN THAT HIS LIABILITY CAN BE LIMITED BY ALLOCATING HIS RESPONSIBILITIES, OR BY DELEGATION. HOWEVER, THE ALLOCATION OR DELEGATION HAS TO BE PRUDENT, AND HE MUST CONTINUE TO MONITOR.
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