Mapping the Genetic Landscape of Human Cells.

Seminal yeast studies have established the value of comprehensively mapping genetic interactions (GIs) for inferring gene function. Efforts in human cells using focused gene sets underscore the utility of this approach, but the feasibility of generating large-scale, diverse human GI maps remains unresolved. We developed a CRISPR interference platform for large-scale quantitative mapping of human GIs. We systematically perturbed 222,784 gene pairs in two cancer cell lines. The resultant maps cluster functionally related genes, assigning function to poorly characterized genes, including TMEM261, a new electron transport chain component. Individual GIs pinpoint unexpected relationships between pathways, exemplified by a specific cholesterol biosynthesis intermediate whose accumulation induces deoxynucleotide depletion, causing replicative DNA damage and a synthetic-lethal interaction with the ATR/9-1-1 DNA repair pathway. Our map provides a broad resource, establishes GI maps as a high-resolution tool for dissecting gene function, and serves as a blueprint for mapping the genetic landscape of human cells.

Low incidence of cardiotoxicity in patients with non-Hodgkin lymphoma receiving EPOCH after prior anthracycline exposure.

OBJECTIVE: To describe the incidence of cardiotoxicity in patients with anthracycline exposure who subsequently receive EPOCH for non-Hodgkin lymphoma (NHL). METHODS: We conducted a retrospective cohort study of adults with anthracycline exposure who subsequently received EPOCH for NHL at Memorial Sloan Kettering Cancer Center. The primary outcome was cumulative incidence of arrhythmia, heart failure (HF), left ventricular (LV) dysfunction, or cardiac death. RESULTS: Among 140 patients, most had diffuse large B-cell lymphoma. Inclusive of EPOCH, median cumulative doxorubicin-equivalent dose was 364 mg/m2 ; exposure was 400 mg/m2 or higher in 41%. With median 36-month follow-up, 23 cardiac events were noted in 20 patients. Cumulative incidence of cardiac events at 60 months was 15% (95% confidence interval [CI]: 9%-21%). When limited to LV dysfunction/HF, cumulative incidence at 60 months was 7% (95% CI: 3%-13%), with most events occurring after the first year. Univariate analysis indicated only history of cardiac disease and dyslipidemia to be associated with cardiotoxicity; no other risk factors, including cumulative anthracycline dose, were identified. CONCLUSIONS: In this retrospective cohort, representing the largest experience in this setting with extended follow-up, cumulative incidence of cardiac events was low. Rates of LV dysfunction or HF were particularly low, suggesting infusional administration may mitigate risk despite prior exposure.

Conceptualizing lifer versus destination patients for optimized care delivery.

BACKGROUND: Patients presenting to academic medical centers (AMC) typically receive primary care, specialty care, or both. Resources needed for each type of care vary, requiring different levels of care coordination. We propose a novel method to determine whether a patient primarily receives primary or specialty care to allow for optimization of care coordination. OBJECTIVES: We aimed to define the concepts of a Lifer Patient and Destination Patient and analyze the current state of care utilization in those groups to inform opportunities for improving care coordination. METHODS: Using AMC data for a 36-month study period (FY17-19), we evaluated the number of unique patients by residence zip code. Patients with at least one primary care visit and patients without a primary care visit were classified as Lifer and Destination patients, respectively. Cohen's effect sizes were used to evaluate differences in mean utilization of different care delivery settings. RESULTS: The AMC saw 35,909 Lifer patients and 744,037 Destination patients during the study period. Most patients were white, non-Hispanic females; however, the average age of a Lifer was seventy-two years whereas that of a Destination patient was thirty-eight. On average, a Lifer had three times more ambulatory care visits than a Destination patient. The proportion of Inpatient encounters is similar between the groups. Mean Inpatient length of stay (LOS) is similar between the groups, but Destination patients have more variance in LOS. The rate of admission from the emergency department (ED) for Destination patients is nearly double Lifers'. CONCLUSION: There were differences in ED, ambulatory care, and inpatient utilization between the Lifer and Destination patients. Furthermore, there were incongruities between rate of hospital admissions and LOS between two groups. The Lifer and Destination patient definitions allow for identification of opportunities to tailor care coordination to these unique groups and to allocate resources more efficiently.

Comparison of venous thromboembolism incidence in newly diagnosed multiple myeloma patients receiving bortezomib, lenalidomide, dexamethasone (RVD) or carfilzomib, lenalidomide, dexamethasone (KRD) with aspirin or rivaroxaban thromboprophylaxis.

Incidence of venous thromboembolism (VTE) varies across different regimens in newly diagnosed multiple myeloma (NDMM) patients. Limited data exist on the use of direct oral anticoagulants as thromboprophylaxis in the setting of haematologic malignancies, specifically multiple myeloma. In this retrospective study of 305 NDMM patients, VTE rates in those treated with carfilzomib, lenalidomide, dexamethasone (KRD) + aspirin (ASA), bortezomib, lenalidomide, dexamethasone (RVD) + ASA, and KRD + rivaroxaban were statistically significant, 16·1%, 4·8%, and 4·8%, respectively. The findings confirm a higher incidence of VTE when using KRD induction compared to RVD induction and reveal that the use of low-dose rivaroxaban thromboprophylaxis can mitigate this risk without an observable increase in bleeding rates.

Selinexor: A First-in-Class Nuclear Export Inhibitor for Management of Multiply Relapsed Multiple Myeloma.

Objective: To review the pharmacology, pharmacokinetics, efficacy, and safety of selinexor for management of relapsed multiple myeloma (MM). Data Sources: A literature search was performed of PubMed and MEDLINE databases (January 1, 2000, to November 14, 2019), abstracts from the American Society of Hematology and the American Society of Clinical Oncology, and ongoing studies from US National Institutes of Health ClinicalTrials.gov. Queries were performed using key words selinexor, SINE, XPO1, and Xpovio.Study Selection/Data Extraction: Human and animal studies related to the pharmacology, pharmacokinetics, efficacy, and safety of selinexor were identified. Data Synthesis: Although numerous advances have been made in MM management, there remains an unmet need for treatment of heavily relapsed/refractory disease. Selinexor is a first-in-class selective inhibitor of nuclear export, which, through inhibition of exportin-1, causes accumulation of tumor suppressor proteins, reduction in oncoproteins, and apoptosis of plasma cells. Selinexor exhibited an overall response in 26% of patients with multiply relapsed MM. Median progression-free survival was 3.7 months, and overall survival was 8.6 months. Common adverse effects include thrombocytopenia, neutropenia, fatigue, and nausea. Ongoing studies are investigating combination therapies utilizing selinexor. Relevance to Patient Care and Clinical Practice: This review describes the efficacy, safety, and clinical applicability of selinexor, a novel agent with potential to meet an unmet need in refractory MM. Conclusion: Selinexor has demonstrated activity in a heavily refractory patient population. Given the adverse effect profile and associated costs, additional studies are needed to further elucidate the appropriate clinical scenario and combinations for selinexor use.

Management of Mantle Cell Lymphoma in the Era of Novel Oral Agents.

Objectives: To discuss (1) recent and emerging data for pharmacological management of untreated and relapsed/refractory (R/R) mantle cell lymphoma (MCL) with agents approved in the United States, (2) important considerations for toxicity monitoring and management, and (3) preliminary data and ongoing studies for agents in MCL-specific clinical trials. Data Sources: PubMed/MEDLINE, EMBASE, Google Scholar, product labeling, National Comprehensive Cancer Network, American Cancer Society, and ClinicalTrials.gov were searched for studies published between January 1, 2017, and January 31, 2020, and key historical trials. Study Selection and Data Extraction: Relevant studies conducted in humans and selected supporting preclinical data were reviewed. Data Synthesis: MCL is a rare but usually aggressive non-Hodgkin lymphoma that most commonly affects the older population. Traditionally, the treatment of MCL has been determined based on transplant eligibility. Newer data suggest that more tolerable frontline therapy may produce outcomes similar to intensive historical induction regimens, possibly precluding fewer patients from autologous stem cell transplant and producing better long-term outcomes in transplant-ineligible patients. In the R/R setting, novel regimens are improving outcomes and changing the landscape of treatment. Relevance to Patient Care and Clinical Practice: This review summarizes and discusses recent and emerging data for management of newly diagnosed and R/R MCL; key supportive care considerations for agents are also discussed. Conclusions: Recent study results are changing management of MCL. Although these data have complicated the picture of regimen selection, increasingly effective and tolerable therapy and additional anticipated data point to a brighter future for patients with MCL.

Low intra-operative diagnostic accuracy does not affect postoperative treatment of acute appendicitis.

BACKGROUND: The intra-operative classification of appendicitis defines postoperative treatment. The correct designation can influence patient recovery, complications and hospital costs. Recent research has shown that intra-operative classification criteria varies among surgeons, and is not always the same as the pathologist's report. Classification accuracy can lower costs by preventing unnecessary treatment or sub-optimal interventions. METHODS: During a period of 4 months, N = 133 appendix specimens were received and evaluated by the pathology department of a single teaching hospital. Five surgeons extracted the specimens and one experienced pathologist drew the histopathology reports. A comparison between the surgeons' classifications and the pathologist's was made. Classification accuracy was determined and statistical analyses was performed using chi-square, and p values were obtained. A p < 0.05 was considered significant. RESULTS: A total of N = 133 specimens were obtained, 127 belonged to patients following emergency surgery due to acute abdominal pain; the other six were from elective hemi-colectomies for right colonic adenocarcinomas, and were not included. Of the 127 specimens analyzed, 14 (11%) were negative, 21 (16.5%) were edematous, 81 (63.7%) were phlegmonous and 11 (8.6%) were gangrenous. A total of 18 (14%) perforated appendices were also reported. Surgical accuracy was 60.6% (N = 67) with a statistically significant p < 0.001. Only five patients with incorrect intraoperative classifications received unnecessary or lacked treatment. CONCLUSIONS: An overall accuracy of 60.6% is seen when the surgical classification is compared to the pathological classification. Although the surgeons' accuracy is low when comparing intra-operative versus histopathological classification, this variation in designation does not affect postoperative treatment significantly.

Characteristics and outcomes of patients with hematologic malignancies receiving chemotherapy in the intensive care unit.

BACKGROUND: The objective of this study was to evaluate the short-term and long-term outcomes of adult patients with hematologic malignancies who received chemotherapy in the intensive care unit (ICU). METHODS: This was a retrospective, single-center study comparing the outcomes of patients with hematologic malignancies who received chemotherapy in the ICU with a matched cohort of ICU patients who did not receive chemotherapy. Conditional logistic regression and shared-frailty Cox regression were used to assess short-term (ICU and hospital) mortality and death by 12 months after hospital discharge, respectively. RESULTS: One hundred eighty-one patients with hematologic malignancies received chemotherapy in the ICU. The ICU and hospital mortality rates were 25% and 42% for chemotherapy patients and 22% and 33% for non-chemotherapy patients, respectively. Higher severity of illness scores on ICU admission were significantly associated with higher ICU mortality (odds ratio, 1.07; P < .001) and hospital mortality (odds ratio, 1.05; P ≤ .001). Six-month and 12-month survival estimates posthospital discharge were 58% and 50%, respectively. Compared with the matched cohort of patients who did not receive chemotherapy, those who did receive chemotherapy had a significantly longer length of stay in the ICU (median, 6 vs 3 days; P < .001) and in the hospital (median, 22 vs 14 days; P = .024). In multivariable analysis, the patients who received chemotherapy in the ICU had a trend toward a higher risk of dying by 12 months (hazard ratio, 1.45; P = .08). CONCLUSIONS: Short-term mortality was similar among patients with hematologic malignancies who did and did not receive chemotherapy in the ICU, although patients who received chemotherapy had increased resource utilization. These results may inform ICU triage and goals-of-care discussions with patients and their families regarding outcomes after receiving chemotherapy in the ICU. Cancer 2018;124:3025-36. © 2018 American Cancer Society.

Venetoclax: A First-in-Class Oral BCL-2 Inhibitor for the Management of Lymphoid Malignancies.

OBJECTIVE: To review the pharmacology, efficacy, and safety of venetoclax for treatment of lymphoid malignancies. DATA SOURCES: A literature search was performed of PubMed and MEDLINE databases (2005 to September 2016), abstracts from the American Society of Hematology and the American Society of Clinical Oncology, and ongoing studies from clinicaltrials.gov. Searches were performed utilizing the following key terms: venetoclax, ABT-199, GDC-199, obatoclax, GX15-070, BCL-2 inhibitor, navitoclax, ABT-263, and Venclexta. STUDY SELECTION/DATA EXTRACTION: Studies of pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of venetoclax in lymphoid malignancies were identified. DATA SYNTHESIS: Recently, treatment of B-cell lymphoproliferative disorders has shifted from conventional cytotoxic chemotherapy to novel small-molecule inhibitors. The advent of recently Food and Drug Administration-approved oral agents ibrutinib and idelalisib has shifted the paradigm of chronic lymphocytic leukemia (CLL) treatment; however, complete remission is uncommon, and the outcome for patients progressing on these treatments remains poor. Attention has been focused on a novel target, the B-cell lymphoma-2 protein (BCL-2), which serves an essential role in regulation of apoptosis. Venetoclax has demonstrated efficacy in multiple subtypes of lymphoid malignancies, including patients with relapsed/refractory CLL harboring deletion 17p, with an overall response rate of nearly 80%. Venetoclax is generally well tolerated, with the significant adverse effect being tumor lysis syndrome, for which there are formal management recommendations. CONCLUSION: Venetoclax has demonstrated promising results in relapsed/refractory lymphoid malignancies, with an acceptable adverse effect profile. As the role of BCL-2 inhibition in various malignancies becomes further elucidated, venetoclax may offer benefit to a myriad other patient populations.

Improving healthcare practice behaviors: an exploratory study identifying effective and ineffective behaviors in healthcare.

PURPOSE: The purpose of this paper is to present the results of exploratory research designed to develop an awareness of healthcare behaviors, with a view toward improving the customer satisfaction with healthcare services. It examines the relationship between healthcare providers and their consumers/patients/clients. DESIGN/METHODOLOGY/APPROACH: The study uses a critical incident methodology, with both effective and ineffective behavioral specimens examined across different provider groups. FINDINGS: The effects of these different behaviors on what Berry (1999) identified as the common core values of service organizations are examined, as those values are required to build a lasting service relationship. Also examined are categories of healthcare practice based on the National Quality Strategy priorities. RESEARCH LIMITATIONS/IMPLICATIONS: The most obvious is the retrospective nature of the method used. How accurate are patient or consumer memories? Are they capable of making valid judgments of healthcare experiences (Berry and Bendapudi, 2003)? While an obvious limitation, such recollections are clearly important as they may be paramount in following the healthcare practitioners' instructions, loyalty for repeat business, making recommendations to others and the like. Further, studies have shown retrospective reports to be accurate and useful (Miller et al., 1997). PRACTICAL IMPLICATIONS: With this information, healthcare educators should be in a better position to improve the training offered in their programs and practitioners to better serve their customers. SOCIAL IMPLICATIONS: The findings would indicate that the human values of excellence, innovation, joy, respect and integrity play a significant role in building a strong service relationship between consumer and healthcare provider. ORIGINALITY/VALUE: Berry (1999) has argued that the overriding importance in building a lasting service business is human values. This exploratory study has shown how critical incident analysis can be used to determine both effective and ineffective practices of different medical providers. It also provides guidelines as to what are effective and ineffective behaviors in healthcare.

What is evolutionary novelty? Process versus character based definitions.

With the rise of EvoDevo, the topic of evolutionary novelty has received renewed attention. Indeed, it has been argued that one of the major contributions of EvoDevo to evolutionary theory is the explanation of phenotypic novelty. Despite such assertions, dispute continues over what exactly a novelty is and whether the term applies to a unique type of evolutionary phenomenon or whether it merely has informal meaning. In a recent special issue of J. Exp. Zool. (Mol. Dev. Evol.) dedicated to novelty, a new definition was introduced, linking novelty exclusively with adaptation and developmental constraint. In our commentary, we discuss how defining novelty in this process oriented manner leads to heightened difficulties with the application of the term and the identification of novelties. At the same time it conceals important implications for evolutionary studies. In contrast, we argue for a character based definition that is independent from adaptive necessities and promotes the integration of evolutionary factors not included in the standard theory. The implications of approaching novelty in this manner take the issue beyond definitional debates.

Seasonal estimation of groundwater vulnerability.

Index-based methods estimate a fixed value of groundwater vulnerability (GWV); however, the effects of time variations on this estimation have not been comprehensively studied. It is imperative to estimate a time-variant vulnerability that accounts for climatic changes. In this study, we used a Pesticide DRASTICL method separating hydrogeological factors into dynamic and static groups followed by correspondence analysis. The dynamic group is composed of depth and recharge, and the static group is composed of aquifer media, soil media, topography slope, impact of vadose zone, aquifer conductivity and land use. The model results were 42.25-179.89, 33.93-159.81, 34.08-168.74, and 45.56-205.20 for spring, summer, autumn, and winter, respectively. The results showed a moderate correlation between the model predictions and observed nitrogen concentrations with R2 = 0.568 and a high correlation for phosphorus concentrations with R2 = 0.706. Our results suggest that the time-variant GWV model provides a robust yet flexible method for investigating seasonal changes in GWV. This model is an improvement to the standard index-based methods, making them sensitive to climatic changes and portraying a true vulnerability estimation. Finally, the correction of the rating scale value fixes the problem of overestimation in standard models.

A DUAL MTOR/NAD+ ACTING GEROTHERAPY.

The geroscience hypothesis states that a therapy that prevents the underlying aging process should prevent multiple aging related diseases. The mTOR (mechanistic target of rapamycin)/insulin and NAD+ (nicotinamide adenine dinucleotide) pathways are two of the most validated aging pathways. Yet, it's largely unclear how they might talk to each other in aging. In genome-wide CRISPRa screening with a novel class of N-O-Methyl-propanamide-containing compounds we named BIOIO-1001, we identified lipid metabolism centering on SIRT3 as a point of intersection of the mTOR/insulin and NAD+ pathways. In vivo testing indicated that BIOIO-1001 reduced high fat, high sugar diet-induced metabolic derangements, inflammation, and fibrosis, each being characteristic of non-alcoholic steatohepatitis (NASH). An unbiased screen of patient datasets suggested a potential link between the anti-inflammatory and anti-fibrotic effects of BIOIO-1001 in NASH models to those in amyotrophic lateral sclerosis (ALS). Directed experiments subsequently determined that BIOIO-1001 was protective in both sporadic and familial ALS models. Both NASH and ALS have no treatments and suffer from a lack of convenient biomarkers to monitor therapeutic efficacy. A potential strength in considering BIOIO-1001 as a therapy is that the blood biomarker that it modulates, namely plasma triglycerides, can be conveniently used to screen patients for responders. More conceptually, to our knowledge BIOIO-1001 is a first therapy that fits the geroscience hypothesis by acting on multiple core aging pathways and that can alleviate multiple conditions after they have set in.

Watersheds may not recover from drought.

The Millennium Drought (southeastern Australia) provided a natural experiment to challenge the assumption that watershed streamflow always recovers from drought. Seven years after the drought, the runoff (as a fraction of precipitation) had not recovered in 37% of watersheds, and the number of recovered watersheds was not increasing. When recovery did occur, it was not explained by watershed wetness. For those watersheds not recovered, ~80% showed no evidence of recovering soon, suggesting persistence within a low-runoff state. The post-drought precipitation not going to runoff was found to be likely going to increased evapotranspiration per unit of precipitation. These findings show that watersheds can have a finite resilience to disturbances and suggest that hydrological droughts can persist indefinitely after meteorological droughts.

Cardiothoracic Surgery in the Caribbean.

INTRODUCTION: Despite being one of the main vacation destinations in the world, health care in the Caribbean faces many difficulties. The challenges involved in these islands' medical care range from low-resource institutions to lack of specialized care. In the field of thoracic and cardiac surgery, many limitations exist, and these include the lack of access to cardiac surgery for many small islands and little governmental funding for minimally invasive approaches in thoracic surgery. METHODS: Literature review was done using PubMed/MEDLINE and Google Scholar databases to identify articles describing the characteristics of thoracic and cardiac surgery departments on Caribbean islands. Articles on the history, current states of practice, and advances in cardiothoracic surgery in the Caribbean were reviewed. RESULTS: Regardless of the middle to high-income profile of the Caribbean, there are significant differences in the speed of technological growth in cardiothoracic surgery from island to island, as well as disparities between the quality of care and resources. Many islands struggle to advance the field of cardiothoracic surgery both through lack of local cardiac surgery centers and limited financial funding for minimally invasive thoracic surgery. CONCLUSIONS: Cardiac and thoracic surgery in the Caribbean depend not only on the support from local government policies and proper distribution of healthcare budgets, but efforts by the surgeons themselves to change and improve institutional cultures. Although resource availability still remains a challenge, the Caribbean remains an important region that deserves special attention with regard to the unmet needs for long-term sustainability of chest surgery.

IVAC With or Without Rituximab for Relapsed or Refractory B-Cell Non-Hodgkin Lymphomas: Real-World Experience in the Modern Era.

INTRODUCTION: Part B of the modified Magrath regimen (IVAC) +/- rituximab (R) is recommended as standalone therapy by national guidelines for management of relapsed/refractory Burkitt lymphoma, and is used in other non-Hodgkin lymphomas (NHL). Activity of IVAC in B-cell NHL, particularly with R, and its toxicity remain incompletely described. PATIENTS AND METHODS: We reviewed patients with relapsed/refractory B-cell NHL treated with IVAC +/- R between 2004 and 2019 at Memorial Sloan Kettering Cancer Center to assess efficacy and toxicity. RESULTS: Among 54 eligible patients (median 2 prior lines of therapy), 76% had diffuse large B-cell lymphoma; 30% had central nervous system involvement at IVAC initiation. Objective response rate was 48%. At median 22-month follow-up, median progression-free and overall survival were 3.1 months and 4.9 months, respectively. Grade ≥ 3 anemia (93%), neutropenia (94%), and thrombocytopenia (100%; all grade 4) were common. Febrile neutropenia occurred in 65% and did not appear to be influenced by use of antimicrobial or granulocyte colony stimulating factor prophylaxis. Mortality was attributed to treatment in 19% of evaluable patients. CONCLUSION: The clinical efficacy and utility of IVAC +/- R remain unclear. However, its profound hematologic toxicity and life-threatening complications despite prophylactic measures warrant careful consideration of alternatives.

Dynamics of minimal residual disease in patients with multiple myeloma on continuous lenalidomide maintenance: a single-arm, single-centre, phase 2 trial.

Background Lenalidomide maintenance improves progression-free survival for patients with multiple myeloma, although its optimal duration is unknown. Clearance of minimal residual disease (MRD) in the bone marrow results in superior outcomes, although its attainment or sustainment does not alter clinical decision-making. Studies that have evaluated MRD serially are limited in length. We therefore aimed to evaluate longitudinal changes in MRD-status (dynamics) and their association with progression-free survival in patients with multiple myeloma. METHODS: In this single-centre, single-arm, phase 2 study, we enrolled patients aged 18 years and older from the Memorial Sloan Kettering Cancer Center (New York, NY, USA) who had newly diagnosed multiple myeloma following unrestricted frontline therapy and an Eastern Cooperative Oncology Group Performance Status of 2 or lower, including patients who started maintenance before study enrolment. All participants received lenalidomide maintenance at 10 mg for 21 days of 28-day cycles until progression or unacceptable toxic effects for up to 5 years on protocol. The primary endpoint was progression-free survival at 60 months per protocol and key secondary endpoints were MRD rates after completion of the 12th, 24th, and 36th cycle of maintenance and the association between progression-free survival and annual measurement of MRD status. MRD was assessed from first-pull bone marrow aspirates at baseline and annually by flow cytometry per International Myeloma Working Group criteria, (limit of detection of at least 1 × 10-5) up to a maximum of 5 years. Patients who completed at least four cycles of treatment were included in the analysis of the primary endpoint, and patients who had completed at least one dose of treatment on protocol were assessable for secondary endpoints. The study was registered at ClinicalTrials.gov, NCT02538198, and is now closed to accrual. FINDINGS: Between Sept 8, 2015, and Jan 25, 2019, 108 patients (100 evaluable for the primary endpoint) were enrolled. Median follow-up was 40·7 months (95% CI 38·7-45·0). At 60 months, progression-free survival was 64% (95% CI 52-79). Median progression-free survival was unreached (95% CI unreached-unreached). MRD dynamics were assessed using 340 MRD assessments done over 5 years for 103 evaluable patients. Patients who sustained MRD negativity for 2 years (n=34) had no recorded disease progression at median 19·8 months (95% CI 15·8-22·3) past the 2-year maintenance landmark. By contrast, patients who lost their MRD-negative responses (n=10) were more likely to progress than those with sustained MRD negativity (HR infinite; p<0·0001) and those with persistent MRD positivity (HR 5·88, 95% CI 1·18-33·33; p=0·015) at the 2-year landmark. Haematological and non-haematological serious adverse events occurred in 19 patients (18%). The most common adverse events of grade 3 or worse were decreased lymphocyte count in 48 (44%) patients and decreased neutrophil count in 47 (44%) patients. One death occurred on study due to sepsis and heart failure and was considered unrelated to the study drug. INTERPRETATION: Serial measurements of MRD allow for dynamic assessment of risk for disease progression. Early intervention should be investigated for patients with loss of MRD negativity. Sustained MRD positivity is not categorically an unfavourable outcome and might portend prolonged stability of low-level disease. FUNDING: Memorial Sloan Kettering and Celgene.

Joint Estimation of Gross Recharge, Groundwater Usage, and Hydraulic Properties within HydroSight.

Groundwater management decisions are often founded upon estimates of aquifer hydraulic properties, recharge and the rate of groundwater usage. Too often hydraulic properties are unavailable, recharge estimates are very uncertain, and usage is unmetered or infrequently metered over only recent years or estimated using numerical groundwater models decoupled from the drivers of drawdown. This paper extends the HydroSight groundwater time-series package ( http://peterson-tim-j.github.io/HydroSight/) to allow the joint estimation of gross recharge, transmissivity, storativity, and daily usage at multiple production bores. A genetic evolutionary scheme was extended from estimating time-series model parameters to also estimating time series of usage that honor metered volumes at each production bore and produces (1) the best fit with the observed hydrograph and (2) plausible estimates of actual evapotranspiration and hence recharge. The reliability of the approach was rigorously tested. Repeated calibration of models for four bores produced estimates of transmissivity, storativity, and mean recharge that varied by a factor of 0.22-0.32, 0.13-0.2, and 0.03-0.48, respectively, when recharge boundary effects were low and the error in monthly, quarterly, and biannual metered usage was generally <10%. Application to the 30 observation bores within the Warrion groundwater management area (Australia), produced a coefficient of efficiency of ≥0.80 at 22 bores and ≥0.90 at 12 bores. The aquifer transmissivity and storativity were reasonably estimated, and were consistent with independent estimates, while mean gross recharge may be slightly overestimated. Overall, the approach allows greater insights from the available data and provides opportunity for the exploration of usage and climatic scenarios.

Developmental finite element analysis of cichlid pharyngeal jaws: Quantifying the generation of a key innovation.

Advances in imaging and modeling facilitate the calculation of biomechanical forces in biological specimens. These factors play a significant role during ontogenetic development of cichlid pharyngeal jaws, a key innovation responsible for one of the most prolific species diversifications in recent times. MicroCT imaging of radiopaque-stained vertebrate embryos were used to accurately capture the spatial relationships of the pharyngeal jaw apparatus in two cichlid species (Haplochromis elegans and Amatitlania nigrofasciata) for the purpose of creating a time series of developmental stages using finite element models, which can be used to assess the effects of biomechanical forces present in a system at multiple points of its ontogeny. Changes in muscle vector orientations, bite forces, force on the neurocranium where cartilage originates, and stress on upper pharyngeal jaws are analyzed in a comparative context. In addition, microCT scanning revealed the presence of previously unreported cement glands in A. nigrofasciata. The data obtained provide an underrepresented dimension of information on physical forces present in developmental processes and assist in interpreting the role of developmental dynamics in evolution.