Endoscopic assessment of the J pouch in ulcerative colitis: A narrative review.

Patients with ulcerative colitis sometimes need a total colectomy with ileal pouch-anal anastomosis due to medically refractory disease or colitis-associated neoplasia. Up to 50% of patients with ulcerative colitis postoperatively develop pouchitis and the rate of chronic inflammatory pouch conditions requiring pouch excision or diverting ileostomy is reported to be 10%. In order to diagnose and monitor pouchitis, pouchoscopy is essential to assess endoscopic inflammatory findings of the J pouch and to survey neoplasia development, particularly in the remnant distal rectum. However, endoscopic protocols for the evaluation of the pouch may not be standardized worldwide and the reliability of existing disease activity indices for pouchitis has been questioned due to the lack of validation. Recently, reliable endoscopic scoring systems based on an observation of the anatomical location of the J pouch were reported and a significant association between the distribution pattern of endoscopic inflammation (i.e., endoscopic phenotype) and pouch outcomes was also uncovered. In this review, we discuss how to survey the J pouch using pouchoscopy, endoscopic indices for pouchitis disease activity, endoscopic phenotypes and classification, and the pathological mechanisms of pouchitis phenotype in patients with ulcerative colitis.

Brain state dynamics differ between eyes open and eyes closed rest.

The human brain exhibits spatio-temporally complex activity even in the absence of external stimuli, cycling through recurring patterns of activity known as brain states. Thus far, brain state analysis has primarily been restricted to unimodal neuroimaging data sets, resulting in a limited definition of state and a poor understanding of the spatial and temporal relationships between states identified from different modalities. Here, we applied hidden Markov model (HMM) to concurrent electroencephalography-functional magnetic resonance imaging (EEG-fMRI) eyes open (EO) and eyes closed (EC) resting-state data, training models on the EEG and fMRI data separately, and evaluated the models' ability to distinguish dynamics between the two rest conditions. Additionally, we employed a general linear model approach to identify the BOLD correlates of the EEG-defined states to investigate whether the fMRI data could be used to improve the spatial definition of the EEG states. Finally, we performed a sliding window-based analysis on the state time courses to identify slower changes in the temporal dynamics, and then correlated these time courses across modalities. We found that both models could identify expected changes during EC rest compared to EO rest, with the fMRI model identifying changes in the activity and functional connectivity of visual and attention resting-state networks, while the EEG model correctly identified the canonical increase in alpha upon eye closure. In addition, by using the fMRI data, it was possible to infer the spatial properties of the EEG states, resulting in BOLD correlation maps resembling canonical alpha-BOLD correlations. Finally, the sliding window analysis revealed unique fractional occupancy dynamics for states from both models, with a selection of states showing strong temporal correlations across modalities. Overall, this study highlights the efficacy of using HMMs for brain state analysis, confirms that multimodal data can be used to provide more in-depth definitions of state and demonstrates that states defined across different modalities show similar temporal dynamics.

Line manager training and organizational approaches to supporting well-being.

BACKGROUND: Employee mental health and well-being (MH&WB) is critical to the productivity and success of organizations. Training line managers (LMs) in mental health plays an important role in protecting and enhancing employee well-being, but its relationship with other MH&WB practices is under-researched. AIMS: To determine whether organizations offering LM training in mental health differ in the adoption of workplace- (i.e. primary/prevention-focused) and worker-directed (including both secondary/resiliency-focused and tertiary/remedial-focused) interventions to those organizations not offering LM training and to explore changes in the proportions of activities offered over time. METHODS: Secondary analysis of enterprise data from computer-assisted telephone interview surveys. The analysis included data from organizations in England across 4 years (2020: n = 1900; 2021: n = 1551; 2022: n = 1904; 2023: n = 1902). RESULTS: Offering LM training in mental health was associated with organizations' uptake of primary-, secondary-, and tertiary-level MH&WB activities across all 4 years. The proportion of organizations offering primary-, secondary- and tertiary-level interventions increased over time. On average, tertiary-level activities were most adopted (2020: 80%; 2021: 81%; 2022: 84%; 2023: 84%), followed by primary-level activities (2020: 66%; 2021: 72%; 2022: 72%; 2023: 73%) and secondary-level activities (2020: 62%; 2021: 60%; 2022: 61%; 2023: 67%). CONCLUSIONS: Offering LM training in mental health is associated with the adoption of other MH&WB practices by organizations. Suggesting that organizations that are committed to the mental health agenda are more likely to take a holistic approach (including both worker and workplace strategies) to promoting workforce mental health, rather than providing LM training in isolation.

Experience-dependent information routing through the basolateral amygdala shapes behavioral outcomes.

It is well established that the basolateral amygdala (BLA) is an emotional processing hub that governs a diverse repertoire of behaviors. Selective engagement of a heterogeneous cell population in the BLA is thought to contribute to this flexibility in behavioral outcomes. However, whether this process is impacted by previous experiences that influence emotional processing remains unclear. Here we demonstrate that previous positive (enriched environment [EE]) or negative (chronic unpredictable stress [CUS]) experiences differentially influence the activity of populations of BLA principal neurons projecting to either the nucleus accumbens core or bed nucleus of the stria terminalis. Chemogenetic manipulation of these projection-specific neurons can mimic or occlude the effects of CUS and EE on behavioral outcomes to bidirectionally control avoidance behaviors and stress-induced helplessness. These data demonstrate that previous experiences influence the responsiveness of projection-specific BLA principal neurons, biasing information routing through the BLA, to drive divergent behavioral outcomes.

Hypoxic Memory Mediates Prolonged Tumor Intrinsic Type I Interferon Suppression to Promote Breast Cancer Progression.

Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis that is associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIFs). Identification of the long-lasting effects of hypoxia beyond the immediate HIF-induced alterations could provide a better understanding of hypoxia-driven metastasis and potential strategies to circumvent it. Here, we uncovered a hypoxia-induced mechanism that exerts a prolonged effect to promote metastasis. In breast cancer patient-derived circulating tumor cell (CTC) lines and common breast cancer cell lines, hypoxia downregulated tumor intrinsic type I interferon (IFN) signaling and its downstream antigen presentation (AP) machinery in luminal breast cancer cells, via both HIF-dependent and HIF-independent mechanisms. Hypoxia induced durable IFN/AP suppression in certain cell types that was sustained after returning to normoxic conditions, presenting a "hypoxic memory" phenotype. Hypoxic memory of IFN/AP downregulation was established by specific hypoxic priming, and cells with hypoxic memory had an enhanced ability for tumorigenesis and metastasis. Overexpression of IRF3 enhanced IFN signaling and reduced tumor growth in normoxic, but not hypoxic, conditions. The histone deacetylase inhibitor (HDACi) entinostat upregulated IFN targets and erased the hypoxic memory. These results point to a mechanism by which hypoxia facilitates tumor progression through a long-lasting memory that provides advantages for CTCs during the metastatic cascade.

Visuomotor adaptation across the lifespan.

Being able to adapt our movements to changing circumstances allows people to maintain performance across a wide range of tasks throughout life, but it is unclear whether visuomotor learning abilities are fully developed in young children and, if so, whether they remain stable in the elderly. There is limited evidence of changes in motor adaptation ability throughout life, and the findings are inconsistent. Therefore, our goal was to compare visuomotor learning abilities throughout the lifespan. We used a shorter, gamified experimental task and collected data from participants in 5 age groups. Young children (M = 7 years), older children (M = 11 years), young adults (M = 20 years), adults (M = 40 years) and older adults (M = 67 years) adapted to a 45° visuomotor rotation in a centre-out reaching task. Across measures of rate of adaptation, extent of learning, rate of unlearning, generalization, and savings, we found that all groups performed similarly. That is, at least for short bouts of gamified learning, children and older adults perform just as well as young adults.

The inconsistency of p-curve: Testing its reliability using the power pose and HPA debates.

Recent works have called into question whether p-curve can reliably assess the presence of "evidential value" within a set of studies. To examine an as-yet unexplored issue, we examined the method used to identify p-values for inclusion in a p-curve analysis. We developed iterated p-curve analysis (IPA), which calculates and p-curves every permutation for a set of reported p-values, and applied it to the data reported in several published p-curve analyses. Specifically, we investigated two phenomena for which p-curves have been used to evaluate the presence of evidential value: the power pose and the hypothalamic-pituitary-adrenal (HPA) reactivity debates. The iterated p-curve analyses revealed that the p-curve method fails to provide reliable estimates or reproducible conclusions. We conclude that p-curve should not be used to make conclusions regarding the presence or absence of evidence for a specific phenomenon.

Patterns of inpatient acute care and emergency department utilization within one year post-initial amputation among individuals with dysvascular major lower extremity amputation in Ontario, Canada: A population-based retrospective cohort study.

INTRODUCTION: Lower extremity amputation (LEA) is a life altering procedure, with significant negative impacts to patients, care partners, and the overall health system. There are gaps in knowledge with respect to patterns of healthcare utilization following LEA due to dysvascular etiology. OBJECTIVE: To examine inpatient acute and emergency department (ED) healthcare utilization among an incident cohort of individuals with major dysvascular LEA 1 year post-initial amputation; and to identify factors associated with acute care readmissions and ED visits. DESIGN: Retrospective cohort study using population-level administrative data. SETTING: Ontario, Canada. POPULATION: Adults individuals (18 years or older) with a major dysvascular LEA between April 1, 2004 and March 31, 2018. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Acute care hospitalizations and ED visits within one year post-initial discharge. RESULTS: A total of 10,905 individuals with major dysvascular LEA were identified (67.7% male). There were 14,363 acute hospitalizations and 19,660 ED visits within one year post-discharge from initial amputation acute stay. The highest common risk factors across all the models included age of 65 years or older (versus less than 65 years), high comorbidity (versus low), and low and moderate continuity of care (versus high). Sex differences were identified for risk factors for hospitalizations, with differences in the types of comorbidities increasing risk and geographical setting. CONCLUSION: Persons with LEA were generally more at risk for acute hospitalizations and ED visits if higher comorbidity and lower continuity of care. Clinical care efforts might focus on improving transitions from the acute setting such as coordinated and integrated care for sub-populations with LEA who are more at risk.

A national survey of medication utilization for cardiac resuscitation in the emergency department: A survey of emergency medicine pharmacists.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Vasoactive medications are used during advanced cardiac life support (ACLS) to shunt oxygenated blood to vital organs and after return of spontaneous circulation (ROSC) to maintain hemodynamic goals. However, limited evidence exists to support vasoactive medication recommendations in such scenarios, and it is unknown how practices vary among emergency departments across the US. METHODS: A survey questionnaire (15 questions) was electronically distributed to emergency medicine pharmacists (EMPs) in the US through various professional listservs. Demographic information, American Heart Association ACLS algorithm medication use, and use of continuous vasopressor infusions and adjunct medications following ROSC were assessed and are reported descriptively. RESULTS: The survey was distributed to 764 EMPs, with a 23% response rate from a wide geographic distribution and 48% of respondents practicing in academic medical centers. Epinephrine dosing and administration during cardiac arrest were reported by most to be in accordance with ACLS cardiac arrest algorithms. Calcium, magnesium sulfate, and sodium bicarbonate were the most common adjunct intravenous medications given during cardiac arrest. Norepinephrine was the first-choice vasopressor (81%) for post-ROSC hypotension, while epinephrine was preferred less frequently (17%). Antibiotics and sodium bicarbonate were the most frequently administered post-ROSC adjunct medications. CONCLUSION: This survey of a geographically diverse group of EMPs demonstrated high ACLS algorithm adherence for epinephrine during cardiac arrest with frequent additional administration of nonalgorithm medications. Sodium bicarbonate and calcium were the most frequently administered adjunct medications during cardiac arrest, while sodium bicarbonate and antibiotics were the most frequently used adjunct medications following ROSC. Norepinephrine was the most commonly used vasopressor following ROSC.

Structural color in the bacterial domain: The ecogenomics of a 2-dimensional optical phenotype.

Structural color is an optical phenomenon resulting from light interacting with nanostructured materials. Although structural color (SC) is widespread in the tree of life, the underlying genetics and genomics are not well understood. Here, we collected and sequenced a set of 87 structurally colored bacterial isolates and 30 related strains lacking SC. Optical analysis of colonies indicated that diverse bacteria from at least two different phyla (Bacteroidetes and Proteobacteria) can create two-dimensional packing of cells capable of producing SC. A pan-genome-wide association approach was used to identify genes associated with SC. The biosynthesis of uroporphyrin and pterins, as well as carbohydrate utilization and metabolism, was found to be involved. Using this information, we constructed a classifier to predict SC directly from bacterial genome sequences and validated it by cultivating and scoring 100 strains that were not part of the training set. We predicted that SCr is widely distributed within gram-negative bacteria. Analysis of over 13,000 assembled metagenomes suggested that SC is nearly absent from most habitats associated with multicellular organisms except macroalgae and is abundant in marine waters and surface/air interfaces. This work provides a large-scale ecogenomics view of SC in bacteria and identifies microbial pathways and evolutionary relationships that underlie this optical phenomenon.

Nanopore tweezers show fractional-nucleotide translocation in sequence-dependent pausing by RNA polymerase.

RNA polymerases (RNAPs) carry out the first step in the central dogma of molecular biology by transcribing DNA into RNA. Despite their importance, much about how RNAPs work remains unclear, in part because the small (3.4 Angstrom) and fast (~40 ms/nt) steps during transcription were difficult to resolve. Here, we used high-resolution nanopore tweezers to observe the motion of single Escherichia coli RNAP molecules as it transcribes DNA ~1,000 times improved temporal resolution, resolving single-nucleotide and fractional-nucleotide steps of individual RNAPs at saturating nucleoside triphosphate concentrations. We analyzed RNAP during processive transcription elongation and sequence-dependent pausing at the yrbL elemental pause sequence. Each time RNAP encounters the yrbL elemental pause sequence, it rapidly interconverts between five translocational states, residing predominantly in a half-translocated state. The kinetics and force-dependence of this half-translocated state indicate it is a functional intermediate between pre- and post-translocated states. Using structural and kinetics data, we show that, in the half-translocated and post-translocated states, sequence-specific protein-DNA interaction occurs between RNAP and a guanine base at the downstream end of the transcription bubble (core recognition element). Kinetic data show that this interaction stabilizes the half-translocated and post-translocated states relative to the pre-translocated state. We develop a kinetic model for RNAP at the yrbL pause and discuss this in the context of key structural features.

Exploring children and young people's experience of participating in citizen science-A qualitative evidence synthesis.

OBJECTIVE: Citizen science with young people is becoming increasingly popular, and understanding their experience is valuable as it can improve research through improved participant motivation/ retention, alongside greater insight. The participants can benefit through opportunities to improve self-efficacy, learning, communication, and relationships. However, studies that explore young people's experience of participating in citizen science have not been synthesised. METHODS: This qualitative thematic synthesis aimed to combine the literature on young citizen scientists' experience of participating in citizen science research studies. Seven databases, Google Scholar and The Journal of Citizen Science Theory and Practice were searched from 2012 to January 2022 and updated in May 2023. The screening included identifying articles by scanning titles and abstracts and, finally, full texts and selecting the articles using inclusion and exclusion criteria. The study findings were synthesised using inductive thematic synthesis (Prospero registration CRD42022299973). RESULTS: Out of 3856 identified articles, 33 studies focusing on the participant experience were included in the synthesis. These papers were coded inductively. The resulting analytical structures were discussed and finalised. The researchers identified three main themes representing aspects of participant experience: relationships, power and personal growth, and three interwoven connecting themes: communication, self-efficacy and decision-making. An illustration of this would be communication bridging relationships and personal growth. As the citizen scientists' communication skills developed through personal growth, their relationships changed both with the project, with the researchers and with wider stakeholders outside the project such as school staff. CONCLUSION: These findings provide a comprehensive understanding of participant experience and how this can be used to inform future citizen science projects to facilitate a positive participant experience.

Quantifying economic vulnerabilities induced by interdependent networks.

Under economic globalization, countries are linked through trade and investments. This economic interdependence creates vulnerabilities. The indirect vulnerability induced by interdependent networks of trade and investments can put a country's economy at risk, but this risk has yet to be systematically quantified and investigated. In this paper, we developed the novel Potential Indirect Vulnerability Index (PIVI) to capture how interdependencies between networks of trade and foreign direct investment (FDI) may induce economic vulnerabilities. The model consisted of three main components: a target country (the importer of goods), an investing country (the exporter of FDI), and the intermediary countries that export commodities to the target country and receive FDI from the investing country, serving as conduits of the vulnerabilities caused indirectly by the investing country. The PIVI quantifies the indirect vulnerabilities based on the product of two fractions: 1) the dependency of the target country on commodities from each intermediary country; and 2) the dependency of each intermediary country on FDI from the investing country. We demonstrated the utility of PIVI by examining the US economy's vulnerability to China using 2019 trade and FDI data. Several Asian countries and a mix of agricultural products and raw materials were identified as conduits through which China could potentially influence the US economy. Vietnam was a sizeable risk because, while it has been a primary source of many US imports, it also received about 30% of its FDI from China. The US policy makers might opt to increase diversity in trade partners or to promote investment in countries such as Vietnam. We also applied the PIVI analysis to critical minerals, identifying cobalt, tungsten, and copper as the most vulnerability-inducing among them. PIVI is a flexible metric than can be aggregated and modified to provide a more nuanced and focused assessment of an economy's vulnerability.

Prevalence and associated factors of bacterial vaginosis among pregnant women in Hue, Vietnam.

INTRODUCTION: Bacterial vaginosis (BV) is the most frequent vaginal infection affecting women of childbearing age worldwide. It is associated with significant adverse healthcare outcomes, especially during pregnancy. Although screening for BV could reduce potential pregnancy-related obstetric complications, there is no routine screening of pregnant women for BV in Vietnam. We aimed to identify the prevalence of BV among pregnant women and the associated factors in two tertiary hospitals in Hue, Vietnam. METHODOLOGY: This cross-sectional descriptive study included 885 pregnant women in third trimester, who received routine antenatal care in the Hue Central Hospital and Hue University Hospital of Medicine and Pharmacy, Hue city, Thua Thien Hue province, Vietnam. Gram-stained vaginal smears were used for calculating the Nugent score and recording the fungal elements. RESULTS: In total, 435 (49.1%) women had a normal BV score, 352 (39.8%) had intermediate vaginal microbiota, and 98 (11.1%) had BV. Among the 98 women with BV, 71 (72.4%) also had fungal infection. There was a significant association of BV with discharge (p = 0.004) and abnormal cervix (p = 0.014). BV was significantly more frequent among the women who reported previous abortion or miscarriage (p = 0.007). CONCLUSIONS: About a tenth of women in Thua Thien Hue province have BV in the third trimester of pregnancy being associated with previous adverse outcome. Discharge with fishy odour is still a characteristic feature among subtle clinical presentations of BV. Better awareness about this disease and routine test-and-treat management during pregnancy may improve pregnancy outcome.

Seroprevalence of transfusion-transmitted infections among blood donors in Makkah, Saudi Arabia.

INTRODUCTION: Blood donation is vital for healthcare; however, transfusion-transmitted infections (TTIs) pose a serious risk. This study investigated the seroprevalence of TTIs among Saudi blood donors. METHODOLOGY: This retrospective study included male blood donors aged ≥ 18 years who donated blood at Al-Noor Specialist Hospital in Makkah from January 2017 to December 2022. The blood units were screened for hepatitis B surface antigen (HBsAg) and core antibodies (HBc-IgG), hepatitis C antibodies (HCV-Abs), syphilis, HIV-1 antigen/antibody (HIV-1 Ag/Ab), human T-lymphotropic virus 1, 2 (HTLV-1/2), and malaria. RESULTS: There were 40,287 donors with an average age of 44.33 ± 18.12 years, and 62.3% (n = 25103) were Saudis. The overall rate of TTIs seropositivity was 7.4% (n = 2953); HBc-IgG (6.1%; n = 2473) was the most common, followed by HCV-Abs (0.4%; n = 177), and syphilis (0.34%; n = 136). All cases were negative for malaria, whilst HIV and HTLV positive donors were 0.06% (n = 24) and 0.13% (n = 52), respectively. Syphilis was more prevalent among non-Saudis (0.24%; n = 83) than among Saudis (0.1%; n = 53), whereas anti-HBc antibodies seropositivity was significantly higher among Saudi (3.4%; n = 1373) than non-Saudi donors (2.7%; n = 1100). CONCLUSIONS: Hepatitis B virus was the most frequently detected bloodborne pathogen, followed by hepatitis C virus and syphilis. Hepatitis B virus was also more prevalent among Saudi donors, whilst expatriates had higher rates of syphilis. Additional prospective multicenter studies are needed to accurately determine the prevalence of TTIs in Saudi Arabia.

Paradoxes in magnesium transport in Type 1 Bartter's syndrome and Gitelman's syndrome: a modeling analysis.

Type 1 Bartter's syndrome and Gitelman's syndrome are characterized by mutations in two key renal Na+ transporters, Na-K-2Cl cotransporter (NKCC2) and Na-Cl cotransporter (NCC). Since these two transporters play an important role in regulating magnesium (Mg2+) and calcium (Ca2+) transport in the kidney, significant alterations in the transport of these two electrolytes is observed in Type 1 Bartter's syndrome and Gitelman's syndrome. In this study, we used our sex-specific computational models of renal electrolyte transport in rat to understand the complex compensatory mechanisms, in terms of alterations in tubular dimensions and ion transporter activities, that lead to Mg2+ and Ca2+ preservation or wasting in these two genetic disorders. Given the sexual dimorphism in renal transporter pattern, we also assessed how the magnitude of these alterations may differ between males and females. Model simulations showed that in Type 1 Bartter's syndrome, nephron adaptations prevent salt wasting and favor Mg2+ preservation but not Ca2+, whereas in Gitelman's syndrome, those adaptations favor Ca2+ preservation over Mg2+. In addition, our models predicted that the compensatory alterations in tubular dimensions and ion transporter activities are stronger in females than in males.

Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity.

Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic gene across human cancers. Mutant IDH1 (mIDH1) generates the oncometabolite (R)-2-hydroxyglutarate, disrupting enzymes involved in epigenetics and other processes. A hallmark of IDH1-mutant solid tumors is T cell exclusion, whereas mIDH1 inhibition in preclinical models restores antitumor immunity. Here, we define a cell-autonomous mechanism of mIDH1-driven immune evasion. IDH1-mutant solid tumors show selective hypermethylation and silencing of the cytoplasmic double-stranded DNA (dsDNA) sensor CGAS, compromising innate immune signaling. mIDH1 inhibition restores DNA demethylation, derepressing CGAS and transposable element (TE) subclasses. dsDNA produced by TE-reverse transcriptase (TE-RT) activates cGAS, triggering viral mimicry and stimulating antitumor immunity. In summary, we demonstrate that mIDH1 epigenetically suppresses innate immunity and link endogenous RT activity to the mechanism of action of a US Food and Drug Administration-approved oncology drug.

Evaluating Lab-Based Eligibility Criteria by Race/Ethnicity in Clinical Trials of Diffuse Large B-Cell Lymphoma.

Underrepresentation of racial and ethnic subgroups in cancer clinical trials remains a persistent challenge. Restrictive clinical trial eligibility criteria have been shown to exacerbate this problem. We previously identified that up to 24% of patients treated with standard immunochemotherapy (IC) would have been excluded from recent first-line trials in diffuse large B-cell lymphoma (DLBCL) based on 5 lab-based criteria. These ineligible patients had worse clinical outcomes and increased deaths related to lymphoma progression suggesting the potential exclusion of patients who could have benefited most from the novel therapies being evaluated. Utilizing data from the prospectively enrolled Lymphoma Epidemiology Outcomes (LEO) Cohort study, with demographics broadly similar to the U.S. patients diagnosed with lymphoma, we evaluated the impact of laboratory eligibility criteria from recent first-line DLBCL trials across various racial and ethnic backgrounds. There were significant differences in the baseline lab values by race/ethnicity with Black/African American (AA) patients having the lowest mean hemoglobin and highest creatinine clearance. Based on recent clinical trial eligibility criteria, AA and Hispanic patients had higher rates of lab-based ineligibility compared to Non-Hispanic Whites. The largest gap in the clinical outcomes between eligible (ref) and non-eligible patients was noted within AA patients with an overall survival hazard ratio based on POLARIX clinical trial criteria of 4.09, 95% CI: 1.83-9.14. A thoughtful approach to the utility of each criterion and cut offs for eligibility needs to be evaluated in the context of its differential impact across various racial/ethnic groups.

Detection of Noncovalent Protein-Ligand Complexes by IR-MALDESI-MS.

Native mass spectrometry (MS) is a powerful analytical technique to directly probe noncovalent protein-protein and protein-ligand interactions. However, not every MS platform can preserve proteins in their native conformation due to high energy deposition from the utilized ionization source. Most small molecules approved as drugs and in development interact with their targets through noncovalent interactions. Therefore, rapid methods to analyze noncovalent protein-ligand interactions are necessary for the early stages of the drug discovery pipeline. Herein, we describe a method for analyzing noncovalent protein-ligand complexes by IR-MALDESI-MS with analysis times of ∼13 s per sample. Carbonic anhydrase and the kinase domain of Bruton's tyrosine kinase are paired with known noncovalent binders to evaluate the effectiveness of native MS by IR-MALDESI.