Immune checkpoint-targeted antibodies: a room for dose and schedule optimization?

Anti-CTLA-4 and anti-PD-1/PD-L1 immune checkpoint inhibitors are therapeutic monoclonal antibodies that do not target cancer cells but are designed to reactivate or promote antitumor immunity. Dosing and scheduling of these biologics were established according to conventional drug development models, even though the determination of a maximum tolerated dose in the clinic could only be defined for anti-CTLA-4. Given the pharmacology of these monoclonal antibodies, their high interpatient pharmacokinetic variability, the actual clinical benefit as monotherapy that is observed only in a specific subset of patients, and the substantial cost of these treatments, a number of questions arise regarding the selected dose and the dosing interval. This review aims to outline the development of these immunotherapies and considers optimization options that could be used in clinical practice.

Hiring schedule optimization at the Surrey fire department

PurposeThe Surrey (British Columbia, Canada) fire department has an annual cycle for hiring full-time firefighters. This paper optimizes the timing of the annual hiring period. A key issue is handling workplace absences, which can be covered by overtime cost or full-time hires.Design/methodology/approachShort-term and long-term absences patterns are analyzed according to season and age cohorts of the firefighters. These are then used in both an explanatory and time series model to predict future absences. The hiring schedule is optimized based on these predictions and additional constraints.FindingsThe current practice fares well in the analysis. For the time period studied, moving to earlier hiring dates appears beneficial. This analysis is robust with respect to various assumptions.Originality/valueThis is a case study where analytic techniques and machine learning are applied to an organizational practice that is not commonly analyzed. In this case, the previous method was not much worse than the optimized solution. The techniques used are quite general and can be applied to various organizational decision problems.

Fast and exact audit scheduling optimization

This article is concerned with the cost and time-effective scheduling of financial auditors with integer linear programming. The schedule optimization considers 13 different constraints, staff scarcity, frequent alterations of the input data with the need to minimize the changes in the generated schedule, and scaling issues. The delivered implementation reduced the time to the first schedule from 3 man-days to 1 h and the schedule update time from 1 man-day to 4 min.

Rhesus macaques compensate for reproductive delay following ecological adversity early in life

Adversity early in life can shape the reproductive potential of individuals through negative effects on health and lifespan. However, long-lived populations with multiple reproductive events may present alternative life history strategies to optimize reproductive schedules and compensate for shorter lifespans when experiencing adversities early in life. Here, we quantify the effects of major hurricanes and density-dependence as sources of early-life ecological adversity on the mean age-specific fertility, reproductive pace, and lifetime reproductive success (LRS) of Cayo Santiago rhesus macaque females, and explored demographic mechanisms for reproductive schedule optimization later in life. Females experiencing major hurricanes early in life exhibit a delayed reproductive debut, but maintain inter-birth intervals and show a higher mean fertility during prime reproductive ages relative to females experiencing no hurricanes. Increasing density at birth is associated to a decrease in mean fertility and LRS. When combined, our study reveals that early-life ecological adversities predict a delay-overshoot pattern in mean age-specific fertility that supports the maintenance of LRS. In contrast to predictive adaptive response models of accelerated reproduction, the long-lived Cayo Santiago population presents a novel reproductive strategy where females who experience major natural disasters early in life ultimately overcome their initial reproductive penalty with no overall negative fitness outcomes. Such strategy suggests that investing more energy into development and maintenance at younger ages allows long-lived females experiencing early-life ecological adversity to reproduce at a mean rate equivalent to that of a typical female cohort later in life.