Mathematical modelling of stem and progenitor cell dynamics during ruxolitinib treatment of patients with myeloproliferative neoplasms.

Introduction: The Philadelphia chromosome-negative myeloproliferative neoplasms are a group of slowly progressing haematological malignancies primarily characterised by an overproduction of myeloid blood cells. Patients are treated with various drugs, including the JAK1/2 inhibitor ruxolitinib. Mathematical modelling can help propose and test hypotheses of how the treatment works. Materials and methods: We present an extension of the Cancitis model, which describes the development of myeloproliferative neoplasms and their interactions with inflammation, that explicitly models progenitor cells and can account for treatment with ruxolitinib through effects on the malignant stem cell response to cytokine signalling and the death rate of malignant progenitor cells. The model has been fitted to individual patients' data for the JAK2 V617F variant allele frequency from the COMFORT-II and RESPONSE studies for patients who had substantial reductions (20 percentage points or 90% of the baseline value) in their JAK2 V617F variant allele frequency (n = 24 in total). Results: The model fits very well to the patient data with an average root mean square error of 0.0249 (2.49%) when allowing ruxolitinib treatment to affect both malignant stem and progenitor cells. This average root mean square error is much lower than if allowing ruxolitinib treatment to affect only malignant stem or only malignant progenitor cells (average root mean square errors of 0.138 (13.8%) and 0.0874 (8.74%), respectively). Discussion: Systematic simulation studies and fitting of the model to the patient data suggest that an initial reduction of the malignant cell burden followed by a monotonic increase can be recapitulated by the model assuming that ruxolitinib affects only the death rate of malignant progenitor cells. For patients exhibiting a long-term reduction of the malignant cells, the model predicts that ruxolitinib also affects stem cell parameters, such as the malignant stem cells' response to cytokine signalling.

Administration of teclistamab in four patients with multiple myeloma requiring hemodialysis.

OBJECTIVE: Relapsed/refractory multiple myeloma (MM) has poor outcomes, especially in heavily pretreated patients. Limited data exists on the use of novel therapies in MM patients with renal dysfunction. This case series describes the successful initiation of teclistamab in four patients with heavily pre-treated MM on hemodialysis (HD). DATA SOURCES: The medical records of four adult MM patients on HD who received teclistamab were retrospectively reviewed. DATA SUMMARY: All patients completed teclistamab step-up dosing and received at least one full dose. HD runs were administered irrespective of teclistamab initiation. Patients tolerated therapy well, with only one patient experiencing grade 1 CRS, which was managed with supportive care. CONCLUSIONS: Due to the complexity of this patient population, close monitoring and multidisciplinary care are crucial. This approach is essential for effectively managing MM patients with renal dysfunction and for exploring novel treatment options.

Neutrophil-to-lymphocyte ratio and all-cause mortality with and without myeloproliferative neoplasms-a Danish longitudinal study.

The neutrophil-to-lymphocyte ratio(NLR) is increased in chronic inflammation and myeloproliferative neoplasms (MPN). We hypothesize that NLR is associated with all-cause mortality and mortality by comorbidity burden in the general population and individuals with MPN. We included 835,430 individuals from The Danish General Suburban Population Study, general practitioners, and outpatient clinics. We investigated NLR on mortality stratified by prevalent and incident MPN, essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), comorbidity burden (CCI-score), and the Triple-A risk score using hazard ratio (HR) and 95% confidence interval (95%CI). NLR 1-1.9 was the reference level. During a median follow-up of 11.2 years, 197,802 deaths were recorded. All-cause mortality increased for a stepwise increasing NLR with a HR (95%CI) for NLR ≥ 6 of 2.06(2.03-2.09) for the whole population and 2.93(2.44-3.50) in prevalent MPN. ET, PV, and MF had a HR (95%CI) for NLR ≥ 2 of 2.14(1.71-2.69), 2.19(1.89-2.54), and 2.31(1.91-2.80). Results were similar for incident MPN. Mortality was higher for stepwise increasing NLR and CCI-score(pinteraction < 2×10-16), with a HR for NLR ≥ 6 of 2.23(2.17-2.29), 4.10(4.01-4.20), and 7.69(7.50-7.89), for CCI-score 0, 1-2, or ≥3. The Triple-A risk score demonstrated alignment with NLR. Increasing NLR and comorbidity burden were associated with lower survival in individuals without MPN but were even worse in prevalent and incident MPN, ET, PV, and MF.

Case Report: First longitudinal study of a patient with CALR positive clonal hematopoiesis of indeterminate potential developing into pre-fibrotic myelofibrosis.

Initial diagnosis of overt myeloproliferative neoplasms (MPNs) represents the juncture during clonal evolution when symptoms or complications prompt an afflicted individual to seek medical attention. In 30-40% of the MPN subgroups essential thrombocythemia (ET) and myelofibrosis (MF), somatic mutations in the calreticulin gene (CALR) are drivers of the disease resulting in constitutive activation of the thrombopoietin receptor (MPL). In the current study, we describe a healthy CALR mutated individual during a 12 year follow-up from initial identification of CALR clonal hematopoiesis of indeterminate potential (CHIP) to the diagnosis of pre-MF. The pre-diagnostic exponential development dynamics of the malignant clone demonstrated close correlation with the platelet counts, neutrophil-to-lymphocyte (NLR) ratio, and inversely correlated to hemoglobin and erythrocyte counts. Backward extrapolation of the growth rate indicated the potential for discovery of the malignant clone many years prior to presentation of overt disease, opening a window of opportunity for early treatment intervention. We did not find any additional mutations associated with MPNs and the current case report provides novel information regarding the development of a driver mutation and the association with blood cell counts prior to clinical manifestation of symptoms suggesting that pre-diagnostic dynamics may supplement future diagnostic criteria for early diagnosis and intervention in MPN patients.

Mutualistic networks emerging from adaptive niche-based interactions.

Mutualistic networks are vital ecological and social systems shaped by adaptation and evolution. They involve bipartite cooperation via the exchange of goods or services between actors of different types. Empirical observations of mutualistic networks across genres and geographic conditions reveal correlated nested and modular patterns. Yet, the underlying mechanism for the network assembly remains unclear. We propose a niche-based adaptive mechanism where both nestedness and modularity emerge simultaneously as complementary facets of an optimal niche structure. Key dynamical properties are revealed at different timescales. Foremost, mutualism can either enhance or reduce the network stability, depending on competition intensity. Moreover, structural adaptations are asymmetric, exhibiting strong hysteresis in response to environmental change. Finally, at the evolutionary timescale we show that the adaptive mechanism plays a crucial role in preserving the distinctive patterns of mutualism under species invasions and extinctions.

Thresholding normally distributed data creates complex networks.

Network data sets are often constructed by some kind of thresholding procedure. The resulting networks frequently possess properties such as heavy-tailed degree distributions, clustering, large connected components, and short average shortest path lengths. These properties are considered typical of complex networks and appear in many contexts, prompting consideration of their universality. Here we introduce a simple model for correlated relational data and study the network ensemble obtained by thresholding it. We find that some, but not all, of the properties associated with complex networks can be seen after thresholding the correlated data, even though the underlying data are not "complex." In particular, we observe heavy-tailed degree distributions, a large numbers of triangles, and short path lengths, while we do not observe nonvanishing clustering or community structure.

A Winding Road to Peace Building: Longitudinal Outcomes of a Peace Intervention for Survivors and Génocidaires of the 1994 Genocide Against the Tutsi in Rwanda.

This longitudinal study examined outcomes of a local peace-building intervention that applied principles of intergroup contact to promote reconciliation between génocidaires and survivors whom they have directly harmed during the 1994 Genocide Against the Tutsi in Rwanda. Individual interviews were conducted with 46 génocidaires and 45 survivors whom they have directly harmed during the genocide at 7-time points over the course of their 22-month participation in three programmatic activities (workshops, cell groups, and cooperative cow raising). One thousand bootstrapped samples generated to measure changes in outcomes indicated that survivors and génocidaires regarded themselves and those who directly impacted them during the genocide more positively after 22 months. Although both survivors and génocidaires experienced significant decline in trauma symptomatology after 22 months, they responded to programmatic activities differently. Cell group interactions sustained some positive outcomes (génocidaires perceived forgiveness by others) after the workshops and further improved others (génocidaires self-forgiveness). Survivors who participated in cell groups and raised cows with génocidaires demonstrated further willingness to reconcile compared to survivors who participated in cell groups alone. Our findings empirically support the benefits of promoting different forms of intergroup interactions long after a period of intense violence and highlight the importance of considering how the trajectories of outcomes can inform program and theory development. HIGHLIGHTS: Survivors and génocidaires in Rwanda benefited from a local intergroup contact intervention (CI). However, génocidaires and survivors they directly harmed benefited differently over 22-months. Preparing survivors and génocidaires with skills to participate in communal life is critical for CI. Highlighting both CI outcomes and trajectories are essential for program and theory development.

Resource Loss and Stress Outcomes in a Setting of Chronic Conflict: The Conservation of Resources Theory in the Eastern Congo.

The purpose of this cross-sectional study was to examine conservation of resources (COR) theory in the context of armed conflict in Africa. Specifically, within the setting of ongoing chronic conflict in the eastern Democratic Republic of the Congo (DRC), we tested the COR theory prediction that resource loss contributes to various stress outcomes. A randomly selected sample of 312 adults (125 men, 187 women) from villages in North Kivu, DRC completed orally administered measures of resource loss, daily stressors, and four stress outcomes: depression symptoms, anxiety symptoms, posttraumatic distress, and general distress. Consistent with COR theory, resource loss predicted all four stress outcomes above and beyond the contribution of demographics, relocation experiences, and daily stressors; however, this effect was small, ΔR2 = .02-.06. The most consistent and strongest predictors of stress outcomes were daily stressors, ßs = .42-.62; number of relocation experiences, ßs = .33-.43; and psychosocial resource loss (e.g., loss of hope, meaning or purpose in life, intimacy with friends and family, physical health of family), ßs = .17-.26. Additionally, male sex predicted depression, anxiety, and trauma symptoms, and lower educational status predicted anxiety symptoms and general distress. Our exploratory mediation analysis showed that daily stressors partially mediated all four pairs of associations between psychosocial resource loss and mental health outcomes. We discuss the findings with consideration of research on disasters generally and armed conflicts specifically. We also discuss implications for humanitarian interventions with conflict-affected populations in Africa and beyond.

Caregiver perceptions of environment moderate relationship between neighborhood characteristics and language skills among youth living with perinatal HIV and uninfected youth exposed to HIV in New York City.

Despite the increased recognition of how neighborhood conditions bear on cognitive and academic outcomes, no studies have examined the influences of objective and subjective neighborhood indices on specific areas of cognitive functioning among youth living with perinatal HIV (PHIV). In the United States (US), this is of particular concern as HIV has disproportionately affected African American youth living in economically disadvantaged and racially segregated communities. Thus, based on a longitudinal cohort study of psychosocial and behavioral health outcomes in 340 perinatally HIV-exposed but uninfected (PHEU) and PHIV youth residing in New York City, ages 9-16 years at enrollment, we analyzed data from baseline and multiple follow-up (FU) quantitative interviews with youth and their primary caregivers, from when they were at least 13-years-old (approximately 4-6 years post enrollment). We examined the association between baseline neighborhood indices (2000 US census data and caregiver's perception of neighborhood stressors) and youth receptive language skills (PPVT; Peabody Picture Vocabulary Test) at FU2 and FU3. Census data (percentage of families in neighborhood living below the national poverty rate, median neighborhood household income, and percentage of residents professionally employed) were not independently associated with PPVT scores at both follow-ups. However, in the logistic regression model, the more caregivers perceived their neighborhood as stressful and subjected to violence, the stronger the relationship between census data indicators of low resource neighborhoods and lower PPVT scores for both groups. Findings support "place-based" policies and practices that alleviate caregiver experiences of neighborhood stressors which may contribute to improved cognitive outcomes for youth living with and affected by PHIV.

Stability of entrainment of a continuum of coupled oscillators.

Complex natural and engineered systems are ubiquitous, and their behavior is challenging to characterize and control. We examine the design of the entrainment process for an uncountably infinite collection of coupled phase oscillators that are all subject to the same periodic driving signal. In the absence of coupling, an appropriately designed input can result in each oscillator attaining the frequency of the driving signal, with a phase offset determined by its natural frequency. We consider a special case of interacting oscillators in which the coupling tends to destabilize the phase configuration to which the driving signal would send the collection in the absence of coupling. In this setting, we derive stability results that characterize the trade-off between the effects of driving and coupling, and compare these results to the well-known Kuramoto model of a collection of free-running coupled oscillators.