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Background: According to past studies, recovery and survival following severe vascular events such as acute myocardial infarction and stroke are negatively impacted by vitamin D deficiency. However, the national estimate on disability-related burden is unclear. We intend to evaluate the prevalence and outcomes of vitamin D deficiency (VDD) among patients with cardiovascular disease (CVD) and cerebrovascular disorder (CeVD). Methods: We performed a cross-sectional study on the Nationwide Inpatient Sample data (2016&ndash, 2017) of adult (&ge, 18 years) hospitalizations. We identified patients with a secondary diagnosis of VDD and a primary diagnosis of CVD and CeVD using the 9th revision of the International Classification of Diseases, clinical modification code (ICD-10-CM) codes. A univariate and mixed-effect multivariable survey logistic regression analysis was performed to evaluate the prevalence, disability, and discharge disposition of patients with CVD and CeVD in the presence of VDD. Results: Among 58,259,589 USA hospitalizations, 3.44%, 2.15%, 0.06%, 1.28%, 11.49%, 1.71%, 0.38%, 0.23%, and 0.08% had primary admission of IHD, acute MI, angina, AFib, CHF, AIS, TIA, ICeH, and SAH, respectively and 1.82% had VDD. The prevalence of hospitalizations due to CHF (14.66% vs. 11.43%), AIS (1.87% vs. 1.71%), and TIA (0.4% vs. 0.38%) was higher among VDD patients as compared with non-VDD patients (p &lt, 0.0001). In a regression analysis, as compare with non-VDD patients, the VDD patients were associated with higher odds of discharge to non-home facilities with an admission diagnosis of CHF (aOR 1.08, 95% CI 1.07&ndash, 1.09), IHD (aOR 1.24, 95% CI 1.21&ndash, 1.28), acute MI (aOR 1.23, 95% CI 1.19&ndash, 1.28), AFib (aOR 1.21, 95% CI 1.16&ndash, 1.27), and TIA (aOR 1.19, 95% CI 1.11&ndash, 1.28). VDD was associated with higher odds of severe or extreme disability among patients hospitalized with AIS (aOR 1.1, 95% CI 1.06&ndash, 1.14), ICeH (aOR 1.22, 95% CI 1.08&ndash, 1.38), TIA (aOR 1.36, 95% CI 1.25&ndash, 1.47), IHD (aOR 1.37, 95% CI 1.33&ndash, 1.41), acute MI (aOR 1.44, 95% CI 1.38&ndash, 1.49), AFib (aOR 1.10, 95% CI 1.06&ndash, 1.15), and CHF (aOR 1.03, 95% CI 1.02&ndash, 1.05) as compared with non-VDD. Conclusions: CVD and CeVD in the presence of VDD increase the disability and discharge to non-home facilities among USA hospitalizations. Future studies should be planned to evaluate the effect of VDD replacement for improving outcomes.

Background ALRN-6924 is a stabilized, cell-permeating alpha-helical peptide that mimics the p53 tumor suppressor protein to disrupt p53’s interactions with its endogenous inhibitors, MDM2 and MDMX. ALRN-6924 has been evaluated in > 175 cancer patients and demonstrated single-agent activity and a well-tolerated single-agent safety profile. MDM2 amplification is an oncogenic event found in up to 4% of all cancers. Co-amplification of MDM2 and cyclin-dependent kinase 4 (CDK4), which are co-located on chromosome 12q13, provides the rationale for combined use of the MDM2-inhibitor ALRN-6924 and the CDK4/6 inhibitor palbociclib in this population, and is further supported by enhanced combination activity in preclinical models. Methods This trial is designed to enroll 25 patients with solid tumors harboring wild-type p53 and MDM2 amplification or MDM2/CDK4 co-amplifications. Patients have exhausted or are not eligible for other treatment options. ALRN-6924 is given at a dose of 3.1 mg/kg as IV infusion on Days 1, 8 and 15, and palbociclib is given as an oral dose of 100 mg/day on Days 1-21 of every 28-day treatment cycle. The first nine patients enrolled were evaluated for safety and tolerability after completion of one treatment cycle (safety lead-in). Anti-tumor activity is evaluated with imaging every 8 weeks. Results Patient enrollment started in December 2018. As of April 30, 12 patients were enrolled; tumor types include liposarcoma (N = 10), osteosarcoma and glioblastoma (1 of each); 11/12 patients had tumors that were MDM2 and CDK4 co-amplified. The combination was generally well tolerated with transient, self-resolving Grade 3 and 4 neutropenia (N = 7) emerging as the principal but not dose limiting toxicity. Other Grade 3 and 4 adverse events include thrombocytopenia, leukopenia, increased ALT, pulmonary embolism, and fall. An interim analysis of activity and safety (N = 15 patients with ≥2 post baseline CT scans) is scheduled for early September 2019 and the results will be presented. Conclusions The combination of ALRN-6924 and palbociclib at pharmacologically relevant doses is feasible and generally well tolerated. Clinical trial identification NCT02909972. Legal entity responsible for the study Aileron Therapeutics, Inc. Funding Aileron Therapeutics, Inc. Disclosure F. Meric-Bernstam: Honoraria (self): Sumitomo Dainippon Pharma; Dialectica; Advisory / Consultancy: Genentech; Advisory / Consultancy: Inflection Biosciences; Advisory / Consultancy: Pieris; Advisory / Consultancy: Darwin Health; Advisory / Consultancy: Samsung bioepis; Advisory / Consultancy: Aduro; Advisory / Consultancy: Spectrum; Advisory / Consultancy: OrigiMed; Advisory / Consultancy: Debio; Advisory / Consultancy: Xencor; Advisory / Consultancy: Jackson Laboratory; Advisory / Consultancy: Mersana; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Zymeworks; Advisory / Consultancy: Kolon Life Sciences; Advisory / Consultancy: Parexel International; Research grant / Funding (institution): Novartis; AstraZeneca; Taiho; Genentech; Calithera; Debio; Bayer; PUMA; CytoMx; Research grant / Funding (institution): Aileron; Zymeworks; Curis; Pfizer; eFFECTOR; Abbvie; Guardant Health; Daiichi Sankyo; GSK; Travel / Accommodation / Expenses: Taiho; Genentech; Debio; Pfizer. S.G. DuBois: Advisory / Consultancy: Loxo Oncology; Travel / Accommodation / Expenses: Loxo Oncology; Travel / Accommodation / Expenses: Genentech. G.I. Shapiro: Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Merck KGaA/EMD Serono; Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Sierra Oncology; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Pfizer; Research grant / Funding (institution): Array BioPharma; Advisory / Consultancy, Advisory Board: G1 Therapeutics; Advisory / Consultancy, Advisory Board: Roche; Advisory / Consultancy, Advisory Board: Bicycle Therapeutics; Advisory / Consultancy, Advisory Board: Fusion Pharmaceuticals; Advisory / Consultancy, Advisory Board: Astex; Advisory / Consultancy, Advisory Board: Almac; Advisory / Consultancy, Advisory Board: Ipsen; Advisory / Consultancy, Advisory Board: Bayer; Advisory / Consultancy, Advisory Board: Angiex; Advisory / Consultancy, Advisory Board: Daiichi Sankyo; Licensing / Royalties, Compositions and Methods for Predicting Response and Resistance to CDK4/6 Inhibition: Patent pending (work) on palbociclib. M.R. Patel: Research grant / Funding (institution): Aileron Therapeutics, Inc. T. Bauer: Advisory / Consultancy: Ignyta; Guardant Health; Loxo; Pfizer; Moderna Therapeutics; Pfizer; Speaker Bureau / Expert testimony, Speaker’s bureau: Bayer; Research grant / Funding (institution): Daiichi Sankyo; Medpacto; Incyte; Mirati; MedImmune; Abbvie; AstraZeneca; Leap Therapeutics; Research grant / Funding (institution): MabVax; Stemline Therapeutics; Merck; Lilly; GSK; Novartis; Pfizer; Research grant / Funding (institution): Genentech/Roche; Deciphera; Merrimack; Immunogen; Millennium; Ignyta; Calithera; Kolltan; Research grant / Funding (institution): Principa; Peleton, Immunocore; Roche; Aileron; BMS; Amgen; Moderna; Research grant / Funding (institution): Sanofi; Boehrnger Ingelheim; Astellas; Five Prime; Jacobio; top Alliance; Loxo; Janssen; Clovis; Research grant / Funding (institution): Takeda; Karyopharm; Onyx; Phosplatin; Foundation Medicine; ARMO; Travel / Accommodation / Expenses: Astellas; AstraZeneca; Celgene; Clovis; EMD Serono; Genentech; Lilly; Travel / Accommodation / Expenses: Merck; Novartis; Pharmacyclics; Sysmex. D. Pinchasik: Full / Part-time employment, former Aileron employee: Aileron Therapeutics, Inc. A. Annis: Shareholder / Stockholder / Stock options: Aileron Therapeutics, Inc.; Full / Part-time employment: Aileron Therapeutics, Inc. M. Aivado: Shareholder / Stockholder / Stock options: Aileron Therapeutics, Inc.; Full / Part-time employment: Aileron Therapeutics, Inc. V. Vukovic: Full / Part-time employment: Aileron Therapeutics, Inc. All other authors have declared no conflicts of interest.

The axial instability of the winding conductor is one of the principal modes of mechanical failure in large power transformers. It is caused by axial compressive forces generated by the electromagnetic interaction of the short-circuit current and the radial leakage flux. It is a buckling type of mechanical instability that occurs under compression. Two possible modes of failure in the layer type coil wound with the continuously transposed cable are identified and analyzed in this paper. The critical design loads leading to instability of the individual strands as well as of the whole cable are separately derived. The actual instability threshold of the coil would be the lesser of the two critical loads. For the through-fault integrity of the transformer design, this threshold must be greater than the peak compressive force on the cable under the worst case short-circuit current.

Glioblastoma (GBM) is the most common brain cancer. Resistance to front-line systemic therapy with temozolomide (TMZ) is correlated with O6-methylguanine-DNA-methyltransferase (MGMT) expression. Second-line treatment with bevacizumab has not improved overall survival. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent that has MGMT-independent cell-kill activity against GBM cell-lines and cancer stem cells in vitro. VAL-083 crosses the blood-brain barrier and showed promise against CNS tumors in prior NCI-sponsored clinical trials. The goal of this clinical trial is to determine appropriate VAL-083 dosing for advancement to Phase III trials as a new treatment for recurrent GBM. METHODS: Patients must have recurrent GBM following surgery, radiation, TMZ and bevacizumab. Phase I: Open-label, single-arm, dose-escalation study. Patients received VAL-083 on days 1,2,3 of a 21-day cycle, until reaching MTD. Phase II: Additional patients enrolled at MTD to further assess safety and outcomes. RESULTS: Phase I: 29 patients were enrolled across 9 dose cohorts (1.5-50 mg/m2/d). 40mg/m2/d was confirmed as MTD. Myelosuppression was mild; no drug-related serious adverse events were reported at doses up to 40mg/m2/d. Dose limiting G4 thrombocytopenia was observed at higher doses. Platelet nadir occurred around day 20 and resolved rapidly and spontaneously. A dose-related survival improvement was observed. Pharmacokinetic analyses show 1-2h plasma terminal half-life; average Cmax 781ng/mL at 40mg/m2/d. Phase II: 14 patients were enrolled at 40mg/m2/d. To date, safety observations in Phase II are consistent with Phase I. CONCLUSIONS: VAL-083 at 40mg/m2/d exhibits a favorable safety profile and dose-related trend toward clinically meaningful improved survival in refractory GBM patient

The authors used gradual ligamentous distraction for closed reduction of nine irreducible dorsal fracture dislocations of the PIP joint. The volar fragment size was equal to or less than 40% in five and more than 50% in four. The average follow up was 18 months. The sequence of treatment required distraction, translation, and joint flexion. Overdistraction by approximately 2 mm was necessary to get sufficient soft tissue lengthening. This allowed adequate joint flexion for concentric joint reduction. Distraction and simultaneous mobilization restored the final range of motion earlier than distraction and subsequent mobilization. The final range of motion of the PIP and DIP joints was from 12 degrees to 91 degrees and 0 to 45 degrees respectively.

Aung Naing1, Jeffrey R. Infante2, Kyriakos P. Papadopoulos3, Karen A. Autio4, Patrick A. Ott5, Deborah J. Wong6, Gerald S. Falchook7, Manish R. Patel2,8 , Shubham Pant9 and Martin Oft10 1 MD Anderson Cancer Center, Houston, TX; 2 Sarah Cannon Research Institute / Tennessee Oncology, PLLC; 3 START Center for Cancer Care, San Antonio, TX; 4 Memorial Sloan-Kettering Cancer Center, New York, NY; 5 Dana-Farber Cancer Institute, Boston, MA; 6 University of California Los Angeles (UCLA), Los Angeles, CA; 7 Sarah Cannon Research Institute at HealthONE, Denver, CO; 8 Florida Cancer Specialists, Sarasota, FL; 9 Oklahoma University, Oklahoma City, OK; 10 ARMO BioSciences, Redwood City CA

I/sub DDQ/ techniques have been widely used at Intel over the past years to (a) successfully improve outgoing quality of the products by screening defects early in production testing, (b) eliminate or reduce burn in, and (c) improve overall fault grading. Functional (non-scan) I/sub DDQ/ testing has been implemented successfully on a number of products (i960(R), i386/sup TM/EX, and MCS(R) micro-controllers). With more designs implementing scan, the capability to select, grade and implement scan-based I/sub DDQ/ vectors and the resulting contribution to the overall fault coverage can be complicated. Using this I/sub DDQ/ test methodology, we show how to (a) integrate test techniques into the design flow (b) eliminate the need for fault grading, (c) use scan/I/sub DDQ/ to improve fault coverage, and (d) determine the incremental non-scan and scan I/sub DDQ/ coverage impact on the full chip. This paper details the new test technique, methodology, flows, tradeoffs/benefits, implementation, and results for I/sub DDQ/ vector generation, grading, selection and testing of vectors for non-scan and scan-based designs. This technique allows user(s) the option of eliminating comprehensive fault grading resources, and uses existing or new Electronic Design Automation (EDA) tools to achieve desired quality levels prior to design completion, and production testing.

An experimental program involving small turn segment models demonstrated the inter-related effects of thermal aging and mechanical stressing on the integrity of transformer conductor insulation. The experimental data was used to develop mathematical relationships between insulation wear life and the thermal and mechanical parameters which influence it. While modeling limitations preclude the use of these relationships for absolute life predictions without further correlating experiments on larger transformer-like structures, the relationships can be applied on a relative basis to answer questions about loading guides and practices and about effects of different magnitudes and numbers of short-circults. Examples of such applications have been given and discussed.

The two-dimensional plane strain equation of plastic flow in accordance with the Levy-Mises constitutive relation is expressed in terms of stress functions of complex variables. Expressions for the stress, strain rate and velocity are derived for plastic flow in a non linear viscous medium assuming the stress function in the form of both the summation and product of conjugate stress functions. The plastic states are derived, also using a mixed mode solution expressed in terms of non-seperable, independent conjugate complex variables. The analysis of the block indentation associated with a nonlinear viscous (strain rate hardening) material under plane strain condition using the product form solution is performed. The effect of the variation in the strain-rate hardening exponent on the contact stress is investigated. The predicted behavior of the vertical component of the contact stress suggests the possibility of the development of a specially instrumented plane strain block indentation tests, for the rapid determination of the strain-rate sensitivity of the real material. The vertical contact stress and strain-rate obtained from the product of the complex conjugate stress function are compared with those obtained from the summation form of the complex conjugate stream function.

An article based on two papers that are published this month in the Proceedings: paper 4312 S entitled ‘The effect of a back-e.m.f. nonlinearity on responses of a secondorder position control system’ by F. Fallside andM. R. Patel, and paper 4273 S entitled ‘Application of the second method of Lyapunov to the stability of certain position control systems containing a back-e.m.f. nonlinearity’ by F. Fallside and J. O. C. Ezeilo. The papers will be read before a meeting of the Science and General Division on the 9th December 1963 at Savoy Place. Dr. Fallside and Mr. Patel are in the Department of Engineering, University of Cambridge, and Dr. Ezeilo is in the Department of Mathematics, University of Ibadan.

The axial instability of winding conductors is one of the frequent modes of short-circuit failures in power transformers. This paper throws a new light on this failure mode for helical and barrel coils and takes important steps forward in three ways: (i) recognising a new mode of possible failure. (ii) accounting for the dynamic considerations leading to the formula for calculating the mechanical resonance frequency which one must avoid in the design. (iii) calculating the critical strength of winding conductors which should not be exceeded. The conclusions here will help the design engineer to keep the transformer windings stable under short-circuit forces.

In the linearized analysis of control systems containing a d.c. field-excited motor the armature current is assumed constant, allowing motor torque to be taken proportional to field current. Since, in practice, this introduces the complication of current forcing to overcome variations caused by motor back-e.m.f., the question arises of how much armature current forcing, or constancy, is necessary to give desirable system responses. The variation introduces a two-variable (field current, motor speed) non-linearity into the system equation. The paper investigates the effect of the non-linearity on the step function and ramp and frequency responses of an otherwise ideal output-velocity-stabilized second-order position control system. Increase of the non-linearity is initially similar to increased system damping until a heavily non-linear and undesirable type of response is reached; unstable ramp responses can occur. There is, however, a well defined boundary marking the onset of the latter responses; below it responses are comparable with linear, particularly for critical or heavy damping. The range of responses is investigated, together with armature-current behaviour during them. This, together with the boundaries, gives a specification of armature supply requirements for a desirable response. The effects of load viscous friction and field-current saturation are also investigated.