Mathematical methods of linear programming

Thesis (M.A.)--Boston UniversityA complex modern society has presented its managers with the need to solve a variety of optimization problems. The desire to run a firm in such a way that profit is maximized, to schedule bombing runs to inflict a maximum of damage on an opponent consistent with acceptable losses, or to choose an assignment of available personnel which optimizes efficiency are typical examples. Such problems are called programming problems. The unifying idea here is that the limited resources (e.g. factors of production, planes, or personnel) which are available for use may be combined in a large (generally infinite) number of ways. The object is to choose from these possibilities the combination or combinations which will optimize a measure of the effectiveness of the enterprise. Mathematically, the programming problem is stated. [TRUNCATED

Safety, pharmacokinetics and target engagement of novel RIPK1 inhibitor SAR443060 (DNL747) for neurodegenerative disorders:Randomized, placebo-controlled, double-blind phase I/Ib studies in healthy subjects and patients

RIPK1 is a master regulator of inflammatory signaling and cell death and increased RIPK1 activity is observed in human diseases, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). RIPK1 inhibition has been shown to protect against cell death in a range of preclinical cellular and animal models of diseases. SAR443060 (previously DNL747) is a selective, orally bioavailable, central nervous system (CNS)-penetrant, small-molecule, reversible inhibitor of RIPK1. In three early-stage clinical trials in healthy subjects and patients with AD or ALS (NCT03757325 and NCT03757351), SAR443060 distributed into the cerebrospinal fluid (CSF) after oral administration and demonstrated robust peripheral target engagement as measured by a reduction in phosphorylation of RIPK1 at serine 166 (pRIPK1) in human peripheral blood mononuclear cells compared to baseline. RIPK1 inhibition was generally safe and well-tolerated in healthy volunteers and patients with AD or ALS. Taken together, the distribution into the CSF after oral administration, the peripheral proof-of-mechanism, and the safety profile of RIPK1 inhibition to date, suggest that therapeutic modulation of RIPK1 in the CNS is possible, conferring potential therapeutic promise for AD and ALS, as well as other neurodegenerative conditions. However, SAR443060 development was discontinued due to long-term nonclinical toxicology findings, although these nonclinical toxicology signals were not observed in the short duration dosing in any of the three early-stage clinical trials. The dose-limiting toxicities observed for SAR443060 preclinically have not been reported for other RIPK1-inhibitors, suggesting that these toxicities are compound-specific (related to SAR443060) rather than RIPK1 pathway-specific

Learning from the public:citizens describe the need to improve end-of-life care access, provision and recognition across Europe

Background: Despite ageing populations and increasing cancer deaths, many European countries lack national policies regarding palliative and end-of-life care. The aim of our research was to determine public views regarding end-of-life care in the face of serious illness. Methods: Implementation of a pan-European population-based survey with adults in England, Belgium (Flanders), Germany, Italy, the Netherlands, Portugal and Spain. Three stages of analysis were completed on open-ended question data: (i) inductive analysis to determine a category-code framework; (ii) country-level manifest deductive content analysis; and (iii) thematic analysis to identify cross-country prominent themes. Results: Of the 9344 respondents, 1543 (17%) answered the open-ended question. Two prominent themes were revealed: (i) a need for improved quality of end-of-life and palliative care, and access to this care for patients and families and (ii) the recognition of the importance of death and dying, the cessation of treatments to extend life unnecessarily and the need for holistic care to include comfort and support. Conclusions: Within Europe, the public recognizes the importance of death and dying; they are concerned about the prioritization of quantity of life over quality of life; and they call for improved quality of end-of-life and palliative care for patients, especially for elderly patients, and families. To fulfil the urgent need for a policy response and to advance research and care, we suggest four solutions for European palliative and end-of-life care: institute government-led national strategies; protect regional research funding; consider within-and between-country variance; establish standards for training, education and service delivery

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Ethnic disparities in the incidence, presentation and complications of malignant hypertension

BACKGROUND: The incidence of malignant hypertension has declined after the introduction of antihypertensive agents. However, previous reports have suggested that malignant hypertension may be relatively common in multi-ethnic populations. The aim of this study was to compare ethnic disparities in the incidence, clinical characteristics and complications of malignant hypertension. METHODS: A retrospective cohort study on malignant hypertension in a multi-ethnic population in Amsterdam, the Netherlands, between August 1993 and August 2005. RESULTS: A total of 122 patients with malignant hypertension were included, mean age 44 years (+/- 12), 66% were men and 47% were black. The incidence rate remained approximately 2.6 (+/- 0.9) per 100,000 per year and was higher among blacks. Black individuals had higher systolic blood pressure (234 +/- 23 versus 225 +/- 22, P = 0.03) and more renal dysfunction compared with white individuals (39% with serum creatinine > 300 micromol/l versus 22%, P = 0.04). Hypertension was previously diagnosed in 58% of all patients, 37% received medication, and 23% stopped their drugs before admission. Health insurance was absent in 25% of black and 2% of white patients (P < 0.01). Secondary causes were identified in 40% of white and 10% of black subjects (P < 0.01). After a mean follow-up of 4.0 +/- 3.2 years 10% had died and 19% needed renal replacement therapy. Renal failure was more frequent in black than in white individuals (hazard ratio 2.8; 95% confidence interval 1.1-7.2), but mainly because of higher serum creatinine levels at presentation. CONCLUSION: The incidence of malignant hypertension and related renal complications is higher in black compared with white individuals. These differences may be explained by ethnic disparities in blood pressure control, drug adherence and insurance statu