Tuning the surface reactivity of oxides by peroxide species.

The Mars-van Krevelen mechanism is the foundation for oxide-catalyzed oxidation reactions and relies on spatiotemporally separated redox steps. Herein, we demonstrate the tunability of this separation with peroxide species formed by excessively adsorbed oxygen, thereby modifying the catalytic activity and selectivity of the oxide. Using CuO as an example, we show that a surface layer of peroxide species acts as a promotor to significantly enhance CuO reducibility in favor of H2 oxidation but conversely as an inhibitor to suppress CuO reduction against CO oxidation. Together with atomistic modeling, we identify that this opposite effect of the peroxide on the two oxidation reactions stems from its modification on coordinately unsaturated sites of the oxide surface. By differentiating the chemical functionality between lattice oxygen and peroxide, these results are closely relevant to a wide range of catalytic oxidation reactions using excessively adsorbed oxygen to activate lattice oxygen and tune the activity and selectivity of redox sites.

The heart of VIALE-A: Cardiac complications of hypomethylating agents and venetoclax in acute myeloid leukaemia.

As we commemorate 50 years since the introduction of classical 7 + 3 induction chemotherapy for acute myeloid leukaemia (AML), we also embark upon new territory with the advent of novel targeted therapeutics, including BH3 mimetics. To date, we do not have much large-scale longitudinal data regarding the toxicities of such novel therapies. Johnson et al. perform a comprehensive analysis of cardiac toxicities with hypomethylating agents and venetoclax and offer valuable insight into risk-benefit analysis when considering front-line therapy for AML. Commentary on: Johnson et al. Cardiac events in newly diagnosed acute myeloid leukaemia during treatment with venetoclax + hypomethylating agents. Br J Haematol 2024;204:1232-1237.

Natural history of clonal haematopoiesis seen in real-world haematology settings.

Recursive partitioning of healthy consortia led to the development of the Clonal Hematopoiesis Risk Score (CHRS) for clonal haematopoiesis (CH); however, in the practical setting, most cases of CH are diagnosed after patients present with cytopenias or related symptoms. To address this real-world population, we characterize the clinical trajectories of 94 patients with CH and distinguish CH harbouring canonical DNMT3A/TET2/ASXL1 mutations alone ('sole DTA') versus all other groups ('non-sole DTA'). TET2, rather than DNMT3A, was the most prevalent mutation in the real-world setting. Sole DTA patients did not progress to myeloid neoplasm (MN) in the absence of acquisition of other mutations. Contrastingly, 14 (20.1%) of 67 non-sole DTA patients progressed to MN. CHRS assessment showed a higher frequency of high-risk CH in non-sole DTA (vs. sole DTA) patients and in progressors (vs. non-progressors). RUNX1 mutation conferred the strongest risk for progression to MN (odds ratio [OR] 10.27, 95% CI 2.00-52.69, p = 0.0053). The mean variant allele frequency across all genes was higher in progressors than in non-progressors (36.9% ± 4.62% vs. 24.1% ± 1.67%, p = 0.0064). This analysis in the post-CHRS era underscores the natural history of CH, providing insight into patterns of progression to MN.

Revealing role of epigenetic modifiers and DNA oxidation in cell-autonomous regulation of Cancer stem cells.

BACKGROUND: Breast cancer cells (BCCs) can remain undetected for decades in dormancy. These quiescent cells are similar to cancer stem cells (CSCs); hence their ability to initiate tertiary metastasis. Dormancy can be regulated by components of the tissue microenvironment such as bone marrow mesenchymal stem cells (MSCs) that release exosomes to dedifferentiate BCCs into CSCs. The exosomes cargo includes histone 3, lysine 4 (H3K4) methyltransferases - KMT2B and KMT2D. A less studied mechanism of CSC maintenance is the process of cell-autonomous regulation, leading us to examine the roles for KMT2B and KMT2D in sustaining CSCs, and their potential as drug targets. METHODS: Use of pharmacological inhibitor of H3K4 (WDR5-0103), knockdown (KD) of KMT2B or KMT2D in BCCs, real time PCR, western blot, response to chemotherapy, RNA-seq, and flow cytometry for circulating markers of CSCs and DNA hydroxylases in BC patients. In vivo studies using a dormancy model studied the effects of KMT2B/D to chemotherapy. RESULTS: H3K4 methyltransferases sustain cell autonomous regulation of CSCs, impart chemoresistance, maintain cycling quiescence, and reduce migration and proliferation of BCCs. In vivo studies validated KMT2's role in dormancy and identified these genes as potential drug targets. DNA methylase (DNMT), predicted within a network with KMT2 to regulate CSCs, was determined to sustain circulating CSC-like in the blood of patients. CONCLUSION: H3K4 methyltransferases and DNA methylation mediate cell autonomous regulation to sustain CSC. The findings provide crucial insights into epigenetic regulatory mechanisms underlying BC dormancy with KMT2B and KMT2D as potential therapeutic targets, along with standard care. Stem cell and epigenetic markers in circulating BCCs could monitor treatment response and this could be significant for long BC remission to partly address health disparity.

Telehepatology Satisfaction Is Associated with Ethnicity: The Real-World Experience of a Vulnerable Population with Fatty Liver Disease.

BACKGROUND: Since the coronavirus disease 2019 (COVID-19) pandemic began, telemedicine use has transformed healthcare delivery. Yet there is concern that telemedicine may widen care disparities for vulnerable populations, and patient experience data are limited. AIMS: We aimed to assess patient satisfaction with hepatology-related telemedicine (telehepatology) for delivery of fatty liver disease (FLD) care in a safety-net healthcare system. METHODS: Adult patients with FLD were surveyed regarding satisfaction with telehepatology. Clinical, demographic, resources, and social determinants of health (SDoH) data were collected to identify factors associated with satisfaction through multivariable modeling. RESULTS: From June 2020 to March 2022, 220 participants were enrolled: the median age was 52 years, 37% were men, and 68% were Hispanic. One hundred nineteen (54%) had prior telehepatology experience. Overall, satisfaction was high; 70% reported being somewhat or very satisfied. On univariate analysis, Hispanic ethnicity (versus non-Hispanic, OR 0.34, 95% CI 0.1-0.9, p = 0.03) and limited access to personal cellphone/internet (OR 0.16, 95% CI 0.04-0.6, p = 0.01) were associated with lower satisfaction. On multivariable logistic regression modeling adjusted for pandemic duration, age, sex, severity of liver disease, and coexisting liver disease, Hispanic ethnicity and lack of personal cellphone/internet remained independently associated with lower telehepatology satisfaction (OR 0.24, 95% CI 0.07-0.9, p = 0.03 and OR 0.2, 95% CI 0.04-0.9, p = 0.04, respectively). The association remained statistically significant after inclusion of various SDoH in the multivariable model. CONCLUSIONS: Satisfaction with telehepatology among FLD patients in a safety-net clinical setting was high overall. However, Hispanic ethnicity and lack of personal cellphone/internet were independently associated with lower telehepatology satisfaction. A better understanding of patients' experience with telehepatology is needed to identify reasons for dissatisfaction, and in-person visits should remain an option for patients to ensure equitable care.

Challenges and solutions to superior chimeric antigen receptor-T design and deployment for B-cell lymphomas.

Chimeric antigen receptor-T (CAR-T) therapies represent a major breakthrough in cancer medicine, given the ex vivo-based technology that harnesses the power of one's own immune system. These therapeutics have demonstrated remarkable success for relapsed/refractory B-cell lymphomas. Although more than a decade has passed since the initial introduction of CAR-T therapeutics for patients with leukaemia and lymphoma, there is still significant debate as to where CAR-T therapeutics fit into the management paradigm, as consensus guidelines are limited. Competing interventions deployed in subsequent lines of therapy for aggressive lymphoma include novel targeted agents, bispecific antibodies, and time-honoured stem cell transplant. In this focused review, we discuss the major obstacles to advancing the therapeutic reach for CAR-T products in early lines of therapy. Such barriers include antigen escape, "cold" tumour microenvironments, host inflammation and CAR-T cell exhaustion. We highlight solutions including point-of-care CAR-T manufacturing and early T lymphopheresis. We review the evidence basis for early CAR-T deployment for B-cell lymphomas in light of the recent Food and Drug Administration (FDA) approval of three first-in-class anti-CD3/CD20 bispecific antibodies-mosunetuzumab, epcoritamab and glofitamab. We propose practical recommendations for 2024.

The emerging therapeutic landscape of relapsed/refractory multiple myeloma.

From a historic lens, treatment for patients with relapsed/refractory multiple myeloma (R/R MM) has advanced significantly since the advent of immunomodulatory agents (IMiDs) in the 1990s, proteasome inhibitors in the 2000s, monoclonal antibodies in the 2010s, and CAR-T treatments in the 2020s. However, the availability of multiple new therapies has also created significant ambiguity regarding therapy selection and sequencing, as consensus guidelines are limited, and cross-trial comparisons of the novel agents are challenging. In this focused review, we discuss the novel Food & Drug Administration (FDA)-approved medications for R/R MM, including the recently approved first-in-class BCMA-directed bispecific antibody teclistamab. We highlight the seminal clinical trials data and discuss optimal sequencing considerations based on the goal of treatment, with an emphasis on the two novel CAR-T cell products. We consider the limited tolerability of certain agents, prospects for our aging population, and financial aspects of these therapies. Finally, we spotlight ongoing trials involving promising agents making their way through the pharmacologic pipeline including the BCMA-directed bispecific antibody elranatamab and the GPRC5D-directed bispecific antibody talquetamab. We summarize our recommendations based on the best available evidence as we enter 2023.

Clinico-Radio-Pathologic Correlation of Leukostasis in Acute Myeloid Leukemia with FLT3 Mutation.

The systemic complications of acute hematologic emergencies account for the high mortality rates seen during inpatient management. Perhaps the most challenging diagnostic entity among all hematologic emergencies is leukostasis. In acute myeloid leukemia, myeloid blasts are often highly adherent to the endothelial vasculature, and high peripheral blood blast count in excess of 100,000 cells per microliter can predispose patients to the pulmonary and neurologic complications, leading to rapid clinical deterioration even before a formal diagnosis of leukostasis is made. The mobilization of the appropriate healthcare personnel in the inpatient setting at inopportune times sometimes poses a major barrier to the successful treatment for patients with leukostasis, and patients often pass away quickly. In this report, we describe clinico-radio-pathologic correlations of leukostasis using pre- and post-mortem analysis in a patient with acute myeloid leukemia (AML) with a FLT3-TKD mutation, and we describe the current literature on best management approaches based on recent evidence.

Understanding Health Economics in Hand Surgery.

Rising health care costs in the United States, besides evolving payment models that place emphasis on value instead of volume, have led to an increasing number of studies evaluating hand surgery from an economic perspective. To better understand such economics-based studies, this review provides a foundational understanding of what value entails by defining its features of quality and cost. Principles of evaluating value through cost-benefit, cost-effectiveness, and cost-utility analyses are discussed. Models of discounting and clinical decision analyses are also discussed. Understanding such concepts and their evaluation in economic analyses will provide greater insight into the economic landscape of hand surgery and improving patient care.

Risk of Dislocation and Revision Following Primary Total Hip Arthroplasty in Patients With Prior Lumbar Fusion With Spinopelvic Fixation.

BACKGROUND: The effect of spinopelvic fixation in addition to lumbar spinal fusion (LSF) on dislocation/instability and revision in patients undergoing primary total hip arthroplasty (THA) has not been reported previously. METHODS: The PearlDiver Research Program was used to identify patients aged 30 and above undergoing primary THA who received (1) THA only, (2) THA with prior single-level LSF, (3) THA with prior 2-5 level LSF, or (4) THA with prior LSF with spinopelvic fixation. The incidence of THA revision and dislocation/instability was compared through logistic regression and Chi-squared analysis. All regressions were controlled for age, gender, and Elixhauser Comorbidity Index (ECI). RESULTS: Between 2010 and 2018, 465,558 patients without history of LSF undergoing THA were examined and compared to 180 THA patients with prior spinopelvic fixation, 5,299 with prior single-level LSF, and 1,465 with prior 2-5 level LSF. At 2 years, 7.8% of THA patients with prior spinopelvic fixation, 4.7% of THA patients with prior 2-5 level LSF, 4.2% of THA patients with prior single-level LSF, and 2.2% of THA patients undergoing only THA had a dislocation event or instability (P < .0001). After controlling for length of fusion, pelvic fixation itself was associated with higher independent risk of revision (at 2 years: 2-5 level LSF + spinopelvic fixation: aHR = 3.15, 95% CI 1.77-5.61, P < .0001 vs 2-5 level LSF with no spinopelvic fixation: aOR = 1.39, 95% CI 1.10-1.76, P < .0001). CONCLUSION: At 2 years, spinopelvic fixation in THA patients were associated with a greater than 3.5-fold increase in hip dislocation risk compared to those without LSF, and an over 2-fold increase in THA revision risk compared to those with LSF without spinopelvic fixation. LEVEL OF EVIDENCE: III.

Extramedullary Acute Myeloid Leukemia of the Renal Pelvis: Insights into a Visceral Niche.

Acute myeloid leukemia (AML) is a stem cell malignancy that originates in the bone marrow and involves the peripheral blood. Extramedullary AML is rarer, but it is most commonly associated with the former French-American-British (FAB) subtypes M4 or M5 of AML. AML cells may also home to the central nervous system and other solid organs such as cortical bone and skin. Such target sites of metastasis depend on microenvironmental niche interactions, which have not been fully elucidated to date. Visceral organs usually do not represent a favorable niche for AML stem cell occupancy. Herein, we describe the case of an 80-year-old man with extramedullary AML involvement of the renal pelvis. Hypercalcemia and obstructive uropathy were presenting features. The visceral niche is a rare site of involvement of myeloid malignancy, and hypercalcemia may reflect a mechanism of extramedullary involvement. We propose a treatment paradigm for this uncommon subset of AML based on advanced age and complex karyotype.

The effect of various media and probe angles on the power output of the Cyclo G6 Glaucoma Laser System.

To evaluate the effect of various media and Iridex MicroPulse P3 (MP3) probe angles on the power output from the Cyclo G6 Glaucoma Laser (G6) System. A laser power meter was used to measure the power output (milliwatts, mW) of the Cyclo G6 System. Each of the ten trials consisted of measurements in six different media: no substrate, balanced salt solution (BSS), artificial tears (AT), tetracaine eye drop, lubricating ointment, and lidocaine gel. The output of the MP3 probe was measured at an angle of 90° and 45°, submerged in the respective media. The output was also measured with the probe held at 90° but above the medium. The mean power outputs with the probe being held at 90° to the sensor with no substrate, BSS, AT, tetracaine eye drop, lubricating ointment, and lidocaine gel were 358 ± 16.8 mW, 612 ± 14.2 mW, 613 ± 13.3 mW, 612 ± 14.0 mW, 620 ± 9.9 mW, and 610 ± 12.2 mW, respectively. These values were statistically higher than noncontact and 45° probe angles for each medium. The values between any two media (excluding no substrate) at a 90° probe angle with full contact were not statistically significant. The highest output of the G6 System was obtained with a 90° probe angle, with full contact and any of the coupling media.

BMDExpress 2: enhanced transcriptomic dose-response analysis workflow.

SUMMARY: A new version (version 2) of the genomic dose-response analysis software, BMDExpress, has been created. The software addresses the increasing use of transcriptomic dose-response data in toxicology, drug design, risk assessment and translational research. In this new version, we have implemented additional statistical filtering options (e.g. Williams' trend test), curve fitting models, Linux and Macintosh compatibility and support for additional transcriptomic platforms with up-to-date gene annotations. Furthermore, we have implemented extensive data visualizations, on-the-fly data filtering, and a batch-wise analysis workflow. We have also significantly re-engineered the code base to reflect contemporary software engineering practices and streamline future development. The first version of BMDExpress was developed in 2007 to meet an unmet demand for easy-to-use transcriptomic dose-response analysis software. Since its original release, however, transcriptomic platforms, technologies, pathway annotations and quantitative methods for data analysis have undergone a large change necessitating a significant re-development of BMDExpress. To that end, as of 2016, the National Toxicology Program assumed stewardship of BMDExpress. The result is a modernized and updated BMDExpress 2 that addresses the needs of the growing toxicogenomics user community. AVAILABILITY AND IMPLEMENTATION: BMDExpress 2 is available at https://github.com/auerbachs/BMDExpress-2/releases. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Botulinum Toxin A Improves Symptoms of Gastroparesis.

BACKGROUND AND AIMS: Pyloric injections of botulinum toxin A (BoNT/A) have shown benefit in open-label studies for patients with gastroparesis but not in randomized trials. We sought to examine the effectiveness of BoNT/A injections in a prospective open-label trial of patients with gastroparesis to assess specific symptom improvements over the course of 6 months. We also wanted to determine if specific biochemical measures including creatinine kinase, lactate dehydrogenase, aldolase, and C-reactive protein suggesting muscular injection could be used to predict successful response to pyloric injections of BoNT/A. METHODS: Patients with gastroparesis undergoing pyloric BoNT/A injections for the treatment of symptomatic gastroparesis were enrolled. The patients completed the Gastroparesis Cardinal Symptom Index (GCSI) at the initial encounter and at 1, 3, and 6 months. Blood samples were collected before and 1 h after BoNT/A therapy. RESULTS: We enrolled 34 patients for serum analysis of which 25 patients were available for symptom follow-up. Sixty-four percent of patients had an improvement in symptoms at 1 month. Patients with improved GCSI total score at 1 month had an improvement in most individual symptoms evaluated. For patients that improved at 1 month, this improvement often extended up to 6 months (p = 0.04). Serum measures studied did not correlate with clinical outcomes. CONCLUSIONS: BoNT/A therapy to the pylorus provided symptomatic improvement at 1 month in 64% of patients. For those patients initially responding, the improvement can last out to 6 months. The biochemical markers did not serve to predict the outcome of injections.

Tumor Molecular Testing Guides Anti-PD-1 Therapy and Provides Evidence for Pathogenicity of Mismatch Repair Variants.

Lynch syndrome is characterized by germline abnormalities in mismatch repair (MMR) genes, leading to predisposition to multiple cancers [1]. A second hit to the unaffected allele is required for tumorigenesis. MMR proteins repair incorrectly paired nucleotides and prevent generation of insertions and deletions at microsatellites [2]. Aberrancies in these MMR proteins can be a result of germline mutations or somatic alterations. Defective MMR results in microsatellite instability (MSI) and a high mutational burden [3].The clinical implications of MSI are becoming readily apparent, as presence of MSI leads to the generation of neoantigens, stimulating tumor-associated lymphocytes [4], [5]. This has led to the use of programmed cell death protein 1 blockade for MMR-deficient tumors [6]. The U.S. Food and Drug Administration recently approved pembrolizumab for any advanced solid tumor demonstrating MSI and nivolumab for metastatic MSI colorectal cancer. However, the clinical significance of numerous MMR gene variants remains uncertain. The International Society for Gastrointestinal Hereditary Tumors classification system categorizes 2,360 MMR variants, which can be used to gauge pathogenicity [7]. There are many variants of uncertain significance (VUS; or class 3) for which clinicians are unable to provide recommendations. In this study, we employed the combination of germline testing and tumor mutational assessment to help discern the clinical relevance of VUS and guide immunotherapeutic decisions. KEY POINTS: A clinical dilemma arises when genomic testing yields variants of uncertain significance (VUS).Germline VUS were identified in two patients with gastrointestinal malignancies, but only one patient had a second-hit mutation in a mismatch repair gene leading to mismatch repair deficiency that conferred response to immunotherapy.The combination of germline testing along with tumor mutational assessment can help discern the clinical relevance of VUS and can help guide therapeutic decision-making toward individualized patient care.

Financial Impact of Incentive Spirometry.

Despite largely unproven clinical effectiveness, incentive spirometry (IS) is widely used in an effort to reduce postoperative pulmonary complications. The objective of the study is to evaluate the financial impact of implementing IS. The amount of time nurses and RTs spend each day doing IS-related activities was assessed utilizing an online survey distributed to the relevant national nursing and respiratory therapists (RT) societies along with questionnaire that was prospectively collected every day for 4 weeks at a single 10-bed cardiothoracic surgery step-down unit. Cost of RT time to teach IS use to patients and cost of nurse time spent reeducating and reminding patients to use IS were used to calculate IS implementation cost estimates per patient. Per-patient cost of IS implementation ranged from $65.30 to $240.96 for a mean 9-day step-down stay. For the 566 patients who stayed in the 10-bed step-down in 2016, the total estimated cost of implementing IS ranged from $36 959.80 to $136 383.36. Using national survey workload data, per-patient cost of IS implementation costed $107.36 (95% confidence interval [CI], $97.88-$116.98) for a hospital stay of 4.5 days. For the 9.7 million inpatient surgeries performed annually in the United States, the total annual cost of implementing postoperative IS is estimated to be $1.04 billion (95% CI, $949.4 million-$1.13 billion). The cost of implementing IS is substantial. Further efficacy studies are necessary to determine whether the cost is justifiable.

The RNA-binding protein Musashi 1 stabilizes the oncotachykinin 1 mRNA in breast cancer cells to promote cell growth.

Substance P and its truncated receptor exert oncogenic effects. The high production of substance P in breast cancer cells (BCCs) is caused by the enhancement of tachykinin (TAC)1 translation by cytosolic factor. In vitro translational studies and mRNA stabilization analyses indicate that BCCs contain the factor needed to increase TAC1 translation and to stabilize the mRNA. Prediction of protein folding, RNA-shift analysis, and proteomic analysis identified a 40 kDa molecule that interacts with the noncoding exon 7. Western blot analysis and RNA supershift identified Musashi 1 (Msi1) as the binding protein. Ectopic expression of TAC1 in nontumorigenic breast cells (BCs) indicates that TAC1 regulates its stability by increasing Msi1. Using a reporter gene system, we showed that Msi1 competes with microRNA (miR)130a and -206 for the 3' UTR of exon 7/TAC1. In the absence of Msi1 and miR130a and -206, reporter gene activity decreased, indicating that Msi1 expression limits TAC1 expression. Tumor growth was significantly decreased when nude BALB/c mice were injected with Msi1-knockdown BCCs. In summary, the RNA-binding protein Msi1 competes with miR130a and -206 for interaction with TAC1 mRNA, to stabilize and increase its translation. Consequently, these interactions increase tumor growth.

A Unique Case of Bilateral Microphthalmia That May Be Related to 14q32.33.

A 2-day-old Hispanic boy was transferred to us with concerns of a small left eye. The pregnancy was uncomplicated, and both parents are healthy. Examination showed a left orbit that appeared to be empty with conjunctival tissue. The right eye had a 7 mm clear cornea, and retinal exam showed areas of thin or absent tissue and no visible optic nerve. MRI revealed a hypoplastic left orbit with an orbital cyst. The anterior-posterior diameter of the right globe was 14 mm and the left globe was 4 mm. Genetic microanalysis showed genetic abnormalities (845 kb gain) on chromosome 14 at q32.33. A diagnosis of bilateral microphthalmia with an orbital cyst was made. This is an isolated case of bilateral microphthalmia possibly associated with 14q32-33.