Treatment of evolving cancers will require dynamic decision support.

Cancer research has traditionally focused on developing new agents, but an underexplored question is that of the dose and frequency of existing drugs. Based on the modus operandi established in the early days of chemotherapies, most drugs are administered according to predetermined schedules that seek to deliver the maximum tolerated dose and are only adjusted for toxicity. However, we believe that the complex, evolving nature of cancer requires a more dynamic and personalized approach. Chronicling the milestones of the field, we show that the impact of schedule choice crucially depends on processes driving treatment response and failure. As such, cancer heterogeneity and evolution dictate that a one-size-fits-all solution is unlikely-instead, each patient should be mapped to the strategy that best matches their current disease characteristics and treatment objectives (i.e. their 'tumorscape'). To achieve this level of personalization, we need mathematical modeling. In this perspective, we propose a five-step 'Adaptive Dosing Adjusted for Personalized Tumorscapes (ADAPT)' paradigm to integrate data and understanding across scales and derive dynamic and personalized schedules. We conclude with promising examples of model-guided schedule personalization and a call to action to address key outstanding challenges surrounding data collection, model development, and integration.

Anatomic Location and Mechanism of Injury Correlating with Prehospital Deaths in Sub-Saharan Africa.

INTRODUCTION: Trauma is a large contributor to morbidity and mortality in developing countries. We sought to determine which anatomic injury locations and mechanisms of injury predispose to prehospital mortality in Malawi to help target preventive and therapeutic interventions. We hypothesized that head injury would result in the highest prehospital mortality. METHODS: This was a retrospective analysis of all trauma patients presenting to Kamuzu Central Hospital in Lilongwe, Malawi, from 2008 to 2015. Independent variables included baseline characteristics, anatomic location of primary injury, mechanism of injury, and severity of secondary injuries. Multivariable logistic regression was used to assess the effect of primary injury location and injury mechanism on prehospital death, after adjusting for confounders. Effect measure modification of the primary injury site/prehospital death relationship by injury mechanism (stratified into intentional and unintentional injury) was assessed. RESULTS: Of 85,806 patients, 701 died in transit (0.8%). Five hundred and five (72%) of these patients sustained a primary head injury. After adjustment, head injury was the anatomic location most associated with prehospital death (OR 11.81 (95% CI 6.96-20.06, p < 0.0001). The mechanisms of injury most associated with prehospital death were gunshot wounds (OR 38.23, 95% CI 17.66-87.78, p < 0.0001) and pedestrian hit by vehicle (OR 2.62, 95% CI 1.92-3.55, p < 0.0001). Among head injury patients, the odds of prehospital mortality were higher with unintentional injuries. CONCLUSIONS: Head injuries are the most common causes of prehospital death in Malawi, while pedestrians hit by vehicles are the most common mechanisms. In a resource-poor setting, preventive measures are critical in averting mortality.

Non reducible inguinal hernias in Malawi: an occupational hazard.

PURPOSE: Inguinal hernias are one of the most common surgical conditions worldwide. Due to limited surgical access in low- and middle-income countries, many hernias present emergently; however, data on the resultant outcome disparities is limited. We, therefore, sought to describe the epidemiology, clinical features, and outcomes of incarcerated inguinal hernias at a tertiary center in Malawi. METHODS: This is a retrospective analysis of the acute care surgery registry at Kamuzu Central Hospital in Lilongwe, Malawi. All patients > 13 years admitted with a non-reducible inguinal hernia from 2013 to 2019 were included. The primary outcome was in-hospital mortality. A Poisson multivariable regression determined factors associated with increased risk of mortality. RESULTS: A total of 297 patients presented with non-reducible inguinal hernias, the majority of which were young (median age 38), male (93.6%), farmers (47.8%). Of the 81% who underwent surgery, 55% were delayed ≥ 24 h. 19.5% of hernias were strangulated. Overall mortality was 5.4%. Increased age (RR 1.06, 95% CI 1.01-1.12), shock index ≥ 1 (RR 4.82, 95% CI 1.45-16.09), and delay ≥ 24 h from presentation to operative intervention (RR 11.24, 95% CI 1.55-81.34) resulted in an increase in relative risk of mortality. CONCLUSION: Non-reducible inguinal hernias largely affect young male farmers in Malawi. Delays to care can limit economic productivity for this rural population, as well as, yield considerable risk of mortality. While specific patient and institutional factors must be further elucidated, increased awareness, public health prioritization, and surgical capacity building is needed to reduce further hernia-related morbidity and mortality.

Effect of in-hospital delays on surgical mortality for emergency general surgery conditions at a tertiary hospital in Malawi.

Background: In sub-Saharan Africa, surgical access is limited by an inadequate surgical workforce, lack of infrastructure and decreased care-seeking by patients. Delays in treatment can result from delayed presentation (pre-hospital), delays in transfer (intrafacility) or after arrival at the treating centre (in-hospital delay; IHD). This study evaluated the effect of IHD on mortality among patients undergoing emergency general surgery and identified factors associated with IHD. Methods: Utilizing Malawi's Kamuzu Central Hospital Emergency General Surgery database, data were collected prospectively from September 2013 to November 2017. Included patients had a diagnosis considered to warrant urgent or emergency intervention for surgery. Bivariable analysis and Poisson regression modelling was done to determine the effect of IHD (more than 24 h) on mortality, and identify factors associated with IHD. Results: Of 764 included patients, 281 (36·8 per cent) had IHDs. After adjustment, IHD (relative risk (RR) 1·68, 95 per cent c.i. 1·01 to 2·78; P = 0·045), generalized peritonitis (RR 4·49, 1·69 to 11·95; P = 0·005) and gastrointestinal perforation (RR 3·73, 1·25 to 11·08; P = 0·018) were associated with a higher risk of mortality. Female sex (RR 1·33, 1·08 to 1·64; P = 0·007), obtaining any laboratory results (RR 1·58, 1·29 to 1·94; P < 0·001) and night-time admission (RR 1·59, 1·32 to 1·90; P < 0·001) were associated with an increased risk of IHD after adjustment. Conclusion: IHDs were associated with increased mortality. Increased staffing levels and operating room availability at tertiary hospitals, especially at night, are needed.

Lectin-binding characteristics of human natural killer cells.

Human natural killer (NK) cells separated initially by density centrifugation of lymphocytes (E+) forming rosettes with sheep red blood cells (SRBC), were further fractionated on gradients of bovine serum albumin (BSA). Low density fractions contained effector cells which displayed high cytotoxicity against the NK-sensitive erythroleukaemic cell line, K562. These low density cells, which expressed receptors for Fc and the monoclonal antibody OKMI, showed enhanced cytotoxicity when treated with lymphoblastoid interferon (IFN-alpha). They also showed an increased response to phytomitogen in comparison with unseparated cells or those recovered from high density fractions. Two lymphocyte subsets one of high and one of low lectin binding capacity were identified in the E+ populations by their reactivity with Lens culinaris agglutinin (LCA). High LCA binding was observed only in low density fractions and was associated with a marked enrichment of NK activity. This property was used to separate the NK active population in E+ cells by fluorescence-activated cell sorting (FACS). These data add a new dimension to the cell surface properties of human NK cells and suggest the presence of LCA-reactive glycoproteins which are either enriched in, or uniquely associated with, cells of the NK subset. The experiments indicate that lectins can serve as useful probes of lymphocyte function and provide the basis for effective cell sorting.