Combination of dual JAK/HDAC inhibitor with regorafenib synergistically reduces tumor growth, metastasis, and regorafenib-induced toxicity in colorectal cancer.

BACKGROUND: Treatment with regorafenib, a multiple-kinase inhibitor, to manage metastatic colorectal cancers (mCRCs) shows a modest improvement in overall survival but is associated with severe toxicities. Thus, to reduce regorafenib-induced toxicity, we used regorafenib at low concentration along with a dual JAK/HDAC small-molecule inhibitor (JAK/HDACi) to leverage the advantages of both JAK and HDAC inhibition to enhance antitumor activity. The therapeutic efficacy and safety of the combination treatment was evaluated with CRC models. METHODS: The cytotoxicity of JAK/HDACi, regorafenib, and their combination were tested with normal colonic and CRC cells exhibiting various genetic backgrounds. Kinomic, ATAC-seq, RNA-seq, cell cycle, and apoptosis analyses were performed to evaluate the cellular functions/molecular alterations affected by the combination. Efficacy of the combination was assessed using patient-derived xenograft (PDX) and experimental metastasis models of CRC. To evaluate the interplay between tumor, its microenvironment, and modulation of immune response, MC38 syngeneic mice were utilized. RESULTS: The combination therapy decreased cell viability; phosphorylation of JAKs, STAT3, EGFR, and other key kinases; and inhibited deacetylation of histone H3K9, H4K8, and alpha tubulin proteins. It induced cell cycle arrest at G0-G1 phase and apoptosis of CRC cells. Whole transcriptomic analysis showed that combination treatment modulated molecules involved in apoptosis, extracellular matrix-receptor interaction, and focal adhesion pathways. It synergistically reduces PDX tumor growth and experimental metastasis, and, in a syngeneic mouse model, the treatment enhances the antitumor immune response as evidenced by higher infiltration of CD45 and cytotoxic cells. Pharmacokinetic studies showed that combination increased the bioavailability of regorafenib. CONCLUSIONS: The combination treatment was more effective than with regorafenib or JAK/HDACi alone, and had minimal toxicity. A clinical trial to evaluate this combination for treatment of mCRCs is warranted.

Effect of Cash Benefits on Health Care Utilization and Health: A Randomized Study.

Importance: Poverty is associated with greater barriers to health care and worse health outcomes, but it remains unclear whether income support can improve health. Objective: To examine the effect of cash benefits on health care utilization and health. Design, Setting, and Participants: The City of Chelsea, Massachusetts, a low-income community near Boston, randomly assigned individuals by lottery to receive cash benefits. Participants' medical records were linked across multiple health systems. Outcomes were assessed during the intervention period from November 24, 2020, to August 31, 2021. Intervention: Cash benefits via debit card of up to $400 per month for 9 months. Main Outcomes and Measures: The primary outcome was emergency department visits. Secondary outcomes included specific types of emergency department visits, outpatient use overall and by specialty, COVID-19 vaccination, and biomarkers such as cholesterol levels. Results: Among 2880 individuals who applied for the lottery, mean age was 45.1 years and 77% were female. The 1746 participants randomized to receive the cash benefits had significantly fewer emergency department visits compared with the control group (217.1 vs 317.5 emergency department visits per 1000 persons; adjusted difference, -87.0 per 1000 persons [95% CI, -160.2 to -13.8]). This included reductions in emergency department visits related to behavioral health (-21.6 visits per 1000 persons [95% CI, -40.2 to -3.1]) and substance use (-12.8 visits per 1000 persons [95% CI, -25.0 to -0.6]) as well as those that resulted in a hospitalization (-27.3 visits per 1000 persons [95% CI, -53.6 to -1.1]). The cash benefit had no statistically significant effect on total outpatient visits (424.3 visits per 1000 persons [95% CI, -118.6 to 967.2]), visits to primary care (-90.4 visits per 1000 persons [95% CI, -308.1 to 127.2]), or outpatient behavioral health (83.5 visits per 1000 persons [95% CI, -182.9 to 349.9]). Outpatient visits to other subspecialties were higher in the cash benefit group compared with the control group (303.1 visits per 1000 persons [95% CI, 32.9 to 573.2]), particularly for individuals without a car. The cash benefit had no statistically significant effect on COVID-19 vaccination, blood pressure, body weight, glycated hemoglobin, or cholesterol level. Conclusions and Relevance: In this randomized study, individuals who received a cash benefit had significantly fewer emergency department visits, including those related to behavioral health and substance use, fewer admissions to the hospital from the emergency department, and increased use of outpatient subspecialty care. Study results suggest that policies that seek to alleviate poverty by providing income support may have important benefits for health and access to care.

Reduced Cost Sharing and Medication Management Services for COPD: A Randomized Clinical Trial.

Importance: High out-of-pocket costs and improper use of maintenance inhalers contribute to poor outcomes among patients with chronic obstructive pulmonary disease (COPD). There is limited evidence for how addressing these barriers could improve adherence and affect COPD exacerbations, spending, or racial disparities in these outcomes. Objective: To examine the effect of a national program to reduce beneficiary cost sharing for COPD maintenance inhalers and provide medication management services that included education on proper technique for inhaler use. Design, Setting, and Participants: This randomized clinical trial included individuals with COPD. All individuals were enrolled in Medicare Advantage. Data were collected from January 2019 to December 2021, and data were analyzed from January 2023 to May 2024. Intervention: Invitation to enroll in a program that reduced cost sharing for maintenance inhalers to $0 or $10 and provided medication management services. The random assignment of the invitation was used to estimate the effects of the invitation and program enrollment, overall and by race. Main Outcomes and Measures: Inhaler adherence measured as proportion of days covered (PDC), moderate-to-severe exacerbations, short-acting inhaler fills, total spending, and as an exploratory outcome, out-of-pocket spending. Results: Of 19 113 included patients, 55.2% were female; 9.5% were Black, 81.1% were White, and 9.4% were another or unknown race; and the median (IQR) age was 74 (69-80) years. Program enrollment was higher in the invited group (29.4%) than the control group (5.1%). The PDC for maintenance inhalers was higher in the invited group than the control group (32.0% vs 28.4%; adjusted invitation effect, 3.8 percentage points; 95% CI, 3.1-4.5); the adjusted effect of the program (the local average treatment effect) was 15.5 percentage points (95% CI, 12.8-18.1), a 55% relative increase in adherence. Mean (SD) out-of-pocket spending for prescriptions was lower in the invited group ($619.5 [$863.1]) than the control group ($675.0 [$887.3]; adjusted invitation effect, -$49.5; 95% CI, -68.9 to -30.0; adjusted program effect, -$203.0; 95% CI, -282.8 to -123.2), but there was no statistically significant difference in exacerbations, short-acting inhaler fills, or total spending. Among Black individuals, the adjusted invitation effect on maintenance inhaler PDC was 5.5 percentage points (95% CI, 3.3-7.7), and the adjusted program effect was 19.5 percentage points (95% CI, 12.4-26.7). Among White individuals, the adjusted invitation effect was 3.7 percentage points (95% CI, 2.9-4.4), and the adjusted program effect was 15.1 percentage points (95% CI, 12.1-18.1). The difference between the invitation effects by race was not statistically significant (1.8 percentage points; 95% CI, -0.5 to 4.1; P = .13). Conclusions and Relevance: Individuals in Medicare Advantage who received an invitation to enroll in a program that reduced cost sharing for maintenance inhalers and provided medication management services had higher inhaler adherence compared with the control group. The difference in the program's effect on inhaler adherence between Black and White individuals was substantial but not statistically significant. Trial Registration: ClinicalTrials.gov Identifier: NCT05497999.

NH3 line broadening coefficients and intensities measurement and impurities determination in emerging applications: CCUS, Biomethane and H2.

A mid-infrared quantum cascade laser (Mid-IR QCL) coupled with a Single Pass Cell and a Multi Pass Cell, was utilized to measure ammonia (NH3) absorption spectroscopic parameters and determine NH3 impurities toward three emerging applications. We for the first time measured the pressure broadening coefficients perturbed by Air, O2, N2, He, CO2, CH4, and H2 and the line intensities of six NH3 transition lines near 1084.6 cm-1. The measured NH3-He, NH3-Air, and NH3-CO2 broadening coefficients align with HITRAN database, while NH3-H2 coefficients exhibit a maximum discrepancy of 46 %. Deviations between the measured line intensities and HITRAN database are minimal. Nevertheless, the uncertainties of line intensities have been significantly reduced from 20 % in HITRAN to below 3 %. The newly measured line parameters are utilized to address NH3 impurity requirements outlined in CCUS (ISO 27913:2016), Biomethane (EN 16723:2016), and H2 (ISO 14687:2019) standards. Based on the concept of optical gas standard (OGS), the NH3 impurity detection requirements in all three standards have been fulfilled with an uncertainty of 1.35 %. The precision of the NH3-OGS is 800 part per trillion (ppt) with an integration time of 100 s. The repeatability of the NH3-OGS is 130 ppt for a continuous measurement time of 48 min. Notably, the NH3-OGS effectively addresses the highly nonlinear adsorption-desorption dynamics, underscoring the potential of OGS as a calibration-free and SI-traceable metrological gas analysis instrument.

Crystalline Si Surface Passivation with Nafion for Bulk Defects Detection with Electron Paramagnetic Resonance.

In monocrystalline Si (c-Si) solar cells, identification and mitigation of bulk defects are crucial to achieving a high photoconversion efficiency. To spectroscopically detect defects in the c-Si bulk, it is desirable to passivate the surface defects. Passivation of the c-Si surface with dielectrics such as Al2O3 and SiNx requires deposition at elevated temperatures, which can influence defects in the bulk. Herein, we report on the passivation of different Czochralski (Cz) Si wafer surfaces by an organic copolymer, Nafion. We test the efficacy of the surface passivation at temperatures ranging from 6 to 473 K to detect bulk defects using electron paramagnetic resonance (EPR) spectroscopy. By comparing with state-of-the-art passivation layers, including Al2O3 and liquid HF/HCl, we found that at room temperature, Nafion can provide comparable passivation of n-type Cz Si with an implied open-circuit voltage (iVoc) of 713 mV and a recombination current prefactor J0 of 5 fA/cm2. For p-type Cz Si, we obtained an iVoc of 682 mV with a J0 of 22.4 fA/cm2. Scanning electron microscopy and photoluminescence reveal that Nafion can also be used to passivate the surface of c-Si solar cell fragments scribed from a solar cell module by using a laser. Consistent with previous studies, analysis of the EPR spectroscopy data confirms that the H-terminated surface is necessary, and fixed negative charge in Nafion is responsible for the field-effect passivation. While the surface passivation quality was maintained for almost 24 h, which is sufficient for spectroscopic measurements, the passivation degraded over longer durations, which can be attributed to surface SiOx growth. These results show that Nafion is a promising room-temperature surface passivation technique to study bulk defects in c-Si.

Accelerated hypofractionated chemoradiation for locally advanced head and neck cancer during COVID 19 pandemic: A tertiary care experience.

PURPOSE: To assess the role of Accelerated Hypofractionated Chemoradiation for Locally Advanced Head & Neck squamous cell cancer (HNSCC) during COVID 19 pandemic. MATERIALS AND METHODS: Previously untreated 20 patients with locally advanced HNSCC (Oral cavity/oropharynx/larynx/hypopharynx) were treated with definitive hypofractionated radiotherapy of 60Gy in 25 fractions with concurrent cisplatin @35 mg/m2 once weekly for 5 weeks from March 2020 to November 2021. The patients were treated on 6MV LINAC with Volumetric modulated arc therapy (VMAT) by the Sequential boost technique and concurrent chemotherapy @35 mg/m2. All the patients received 48Gy in 20 fractions to low-risk volume (CTV LR) in Phase I followed by 12Gy in 5 fractions boost to High-risk volume (CTV HR) in Phase II. The organs at risk (OARs) were contoured and appropriate constraints were given considering the hypofractionated regimen. RESULTS: Out of 20 patients, most of the patients were Stage IV (15;75%) & stage III 20%, out of which (55%) 11 were of the oral cavity, (40%) 8 were of the oropharynx, and (5%) 1 of larynx. All patients were treated with 60Gy/25#/5 weeks with the majority of the patients (17;85%) completing their treatment in less than 45 days. The Median follow-up was of 214 days. The locoregional control at 6 Months was 55%. Maximum acute toxicity was grade 3 mucositis which was observed in 18 (90%) patients. Ryle's tube feeding was needed in 11 (55%) patient. Out of 20 patients, 5 patients did not receive concurrent chemotherapy, and 8 (40%) patients received all 5 cycles of chemotherapy. 7, 35% of the patients could not complete all 5 cycles of concurrent chemotherapy due to grade 3 mucositis. CONCLUSION: During a pandemic crisis with limited manpower & technical resources accelerated hypofractionated radiotherapy with concurrent chemotherapy can be considered a feasible therapeutic option for HNSCC which can significantly reduce the overall Treatment Time (OTT) with comparable local control and manageable toxicities.

Prescription for Cash? Cash Support to Low-Income Families in Maternal and Pediatric Health Care Settings.

Policy Points Pregnancy and childhood are periods of heightened economic vulnerability, but current policies for addressing health-related social needs, including screening and referral programs, may be insufficient because of persistent gaps, incomplete follow-up, administrative burden, and limited take-up. To bridge gaps in the social safety net, direct provision of cash transfers to low-income families experiencing health challenges during pregnancy, infancy, and early childhood could provide families with the flexibility and support to enable caregiving, increase access to health care, and improve health outcomes.

Targeting of oncogenic AAA-ATPase TRIP13 reduces progression of pancreatic ductal adenocarcinoma.

Thyroid hormone receptor-interacting protein 13 (TRIP13) is involved in cancer progression, but its role in pancreatic ductal adenocarcinoma (PDAC) is unknown. Thus, we assessed the expression, functional role, and mechanism of action of TRIP13 in PDAC. We further examined the efficacy of TRIP13 inhibitor, DCZ0415, alone or in combination with gemcitabine on malignant phenotypes, tumor progression, and immune response. We found that TRIP13 was overexpressed in human PDACs relative to corresponding normal pancreatic tissues. TRIP13 knockdown or treatment of PDAC cells with DCZ0415 reduced proliferation and colony formation, and induced G2/M cell cycle arrest and apoptosis. Additionally, TRIP13 knockdown or targeting with DCZ0415 reduced the migration and invasion of PDAC cells by increasing E-cadherin and decreasing N-cadherin and vimentin. Pharmacologic targeting or silencing of TRIP13 also resulted in reduce expression of FGFR4 and STAT3 phosphorylation, and downregulation of the Wnt/ß-catenin pathway. In immunocompromised mouse models of PDAC, knockdown of TRIP13 or treatment with DCZ0415 reduced tumor growth and metastasis. In an immunocompetent syngeneic PDAC model, DCZ0415 treatment enhanced the immune response by lowering expression of PD1/PDL1, increasing granzyme B/perforin expression, and facilitating infiltration of CD3/CD4 T-cells. Further, DCZ0415 potentiated the anti-metastatic and anti-tumorigenic activities of gemcitabine by reducing proliferation and angiogenesis and by inducing apoptosis and the immune response. These preclinical findings show that TRIP13 is involved in PDAC progression and targeting of TRIP13 augments the anticancer effect of gemcitabine.

Association Between a State-Level Fat Tax and Fast Food Purchases.

Importance: India faces an increasing obesity problem, including in the Indian state of Kerala in which the fat tax was implemented but was nullified 11 months later. A fat tax, defined as a tax on unhealthy foods, may be associated with changes in food purchases and outcomes for multiple diet-related diseases. Objective: To investigate the association between the state-level fat tax and fast food purchases in Kerala, India. Design, Setting, and Participants: This cohort study analyzed a large-scale credit and debit card transaction data set and aggregated this sample at the account-year-month level of fast food purchases in Kerala state and 9 major cities in other Indian states (Ahmedabad, Bangalore, Bhubaneswar, Chennai, Delhi, Gurgaon, Kolkata, Mumbai, and Surat). Purchase records were obtained for January 1, 2016, to December 31, 2017. The association between the fat tax and fast food purchases was examined using the difference-in-differences method. This analysis was initiated on December 1, 2022. Exposures: The exposure was the fat tax. Kerala was the exposed group, and 9 major Indian cities were the control group. Main Outcomes and Measures: The main outcome was the fast food purchase ratio, defined as the proportion of fast food purchases of the total food purchases. Changes in the fast food purchase ratio were estimated in Kerala across the sample period and then compared with 9 major cities. Results: The sample for analysis included 238 015 credit and debit card accounts, of which 36.7% were in Kerala and 63.3% were in 9 major cities. The cardholders included 191 603 males (80.5%) with a mean (SD) age of 36.6 (12.8) years. During the fat tax implementation (August 2016-June 2017), Kerala's fast food purchase ratio decreased by 3.9 percentage points (ß [SE], -0.039 [0.002]; 95% CI, -0.042 to -0.036), compared with 9 major cities. After the fat tax was nullified, the fast food purchase ratio reduced by 5.6 percentage points (γ [SE], -0.056 [0.002]; 95% CI, -0.059 to -0.052) compared with 9 major cities and using the pretax period as the benchmark. Conclusions and Relevance: Results of this cohort study suggest that the Kerala fat tax was associated with fewer fast food purchases. Food tax policies need to have an elaborate design, and related issues, such as social inequality, nutritional deficiency, and political concerns, need to be evaluated in future studies.

Dose at posterior-inferior border of symphysis point: A predictor for vaginal stricture in cervical cancer.

PURPOSE: To study the effect of various dose-volume parameters on the severity of vaginal stricture (VS) and the correlation of the latter with the posterior-inferior border of symphysis (PIBS) points in locally advanced cervical cancer patients treated with concurrent chemoradiation and brachytherapy. METHODS AND MATERIALS: A prospective study was done on 45 histologically proven locally advanced cervical cancer patients between January 2020 and March 2021. All of them were treated with concurrent chemoradiation with 6 MV photon linear accelerator to a dose of 45 Gy/25 fractions in 5 weeks. Twenty-three patients were treated with intracavitary brachytherapy with a dose of 7 Gy/fraction/week for three fractions. Twenty-two patients were treated with interstitial brachytherapy, with 6 Gy/fraction for four fractions, each fraction 6 h apart. Grading of VS was done as per Common Terminology Criteria for Adverse Events version 5. RESULTS: The median followup was 21.5 months. About 37.8% of patients had VS with a median duration of 8.0 months (4.0-12 months). About 22.2% had Grade 1, 6.7% had Grade 2, and 8.9% had Grade 3 toxicity. Doses at PIBS and PIBS-2 points had no correlation with vaginal toxicity, however, the dose at PIBS+2 was significantly associated with VS (p = 0.004). The treated length of the vagina at the time of brachytherapy (p = 0.001), initial tumor volume (p = 0.009), and vaginal involvement after completion of external beam radiotherapy (EBRT) (p = 0.01) were also statistically significant with the development of VS of Grade 2 or more. CONCLUSIONS: Dose at PIBS + 2, treated length of the vagina with brachytherapy, initial tumor volume, and post-EBRT vaginal involvement are strong predictors for the severity of VS.

BZW2 Inhibition Reduces Colorectal Cancer Growth and Metastasis.

Because survival of patients with metastatic colorectal cancer remain poor, there is an urgent need to identify potential novel druggable targets that are associated with colorectal cancer progression. One such target, basic leucine zipper and W2 domains 2 (BZW2), is involved in regulation of protein translation, and its overexpression is associated with human malignancy. Thus, we investigated the expression and regulation of BZW2, assessed its role in activation of WNT/ß-catenin signaling, identified its downstream molecules, and demonstrated its involvement in metastasis of colorectal cancer. In human colorectal cancers, high mRNA and protein expression levels of BZW2 were associated with tumor progression. BZW2-knockdown reduced malignant phenotypes, including cell proliferation, invasion, and spheroid and colony formation. BZW2-knockdown also reduced tumor growth and metastasis; conversely, transfection of BZW2 into BZW2 low-expressing colorectal cancer cells promoted malignant features, including tumor growth and metastasis. BZW2 expression was coordinately regulated by microRNA-98, c-Myc, and histone methyltransferase enhancer of zeste homolog 2 (EZH2). RNA sequencing analyses of colorectal cancer cells modulated for BZW2 identified P4HA1 and the long noncoding RNAs, MALAT1 and NEAT1, as its downstream targets. Further, BZW2 activated the Wnt/ß-catenin signaling pathway in colorectal cancers expressing wild-type ß-catenin. In sum, our study suggests the possibility of targeting BZW2 expression by inhibiting EZH2 and/or c-Myc. IMPLICATIONS: FDA-approved small-molecule inhibitors of EZH2 can indirectly target BZW2 and because BZW2 functions as an oncogene, these inhibitors could serve as therapeutic agents for colorectal cancer.

Comparison of 2 different inhaled epoprostenol dosing strategies for acute respiratory distress syndrome in critically ill adults: Weight-based vs fixed-dose administration.

PURPOSE: Inhaled epoprostenol (iEPO) is a viable, temporizing option for acute respiratory distress syndrome (ARDS), although the optimal iEPO dosing strategy remains inconclusive. The purpose of this study was to evaluate oxygenation and ventilation parameters in a comparison of weight-based and fixed-dose iEPO in adult patients with moderate-to-severe ARDS. METHODS: A retrospective cohort study was conducted at 2 academic medical centers in adult intensive care unit (ICU) patients administered either fixed-dose or weight-based iEPO for moderate-to-severe ARDS. The primary endpoint was the highest recorded change in the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) within 4 hours of baseline. Secondary analyses compared responder rates within 4 hours of initiation, oxygenation and ventilation parameters, in-hospital mortality rates, mechanical ventilation duration, length of stay (ICU and hospital), and tracheostomy rates between the study groups. RESULTS: A total of 294 patients were included, n = 194 with 100 (34.0%) and 194 (66.0%) in the weight-based and fixed-dose iEPO groups, respectively. The mean (SD) change in the highest recorded PaO2/FiO2 value from baseline up to 4 hours after initiation in the fixed-dose and weight-based groups was 81.1 (106.0) and 41.0 (72.5) mm Hg, respectively (P = 0.0015). The responder rate at 4 hours after iEPO initiation was significantly higher in the fixed-dose group (69.9%) than in the weight-based group (30.1%) (P = 0.02). The only predictor of response was fixed-dose administration (odds ratio, 3.28; 95% confidence interval, 1.6-6.7; P = 0.0012). Clinical outcomes were comparable between the groups. CONCLUSION: Fixed-dose iEPO was associated with significantly higher response rates then weight-based iEPO during the first 4 hours of therapy. Fixed-dose iEPO is a more convenient strategy than weight-based approaches.

Incidence of Hypotension Associated With Two Different Vasopressin Discontinuation Strategies in the Recovery Phase of Septic Shock.

Introduction: Safe and effective vasopressor withdrawal strategies during the recovery phase of septic shock lack consensus and are not addressed in clinical practice guidelines. The purpose of this study was to compare the incidence of clinically relevant hypotension associated with different vasopressin (AVP) discontinuation strategies. Methods: This was a single-center, retrospective, cohort study, conducted at a university medical center over a three-year period. Adult patients ≥18 years with septic shock were included in the study. Patients were stratified into two groups; patients incrementally weaned from AVP and patients in which AVP was abruptly discontinued. The primary endpoint was to compare the incidence of clinically relevant hypotension between study groups up to 24 hours following discontinuation. Secondary analyses included the incidence of any hypotensive event up to 24 hours after AVP cessation, intensive care unit and hospital length of stay, and in-hospital mortality. Results: A total of 74 patients (n = 46 AVP wean and n = 28 AVP no-wean) met inclusion criteria and were included in the study. The primary outcome was not statistically different between groups. Clinically relevant hypotension occurred in 24 patients (52.3%) and 16 patients (57.1%) in the AVP wean and AVP no-wean groups, respectively (P = .68). There were no significant differences in any secondary clinical outcome between the two study groups. Conclusion: No differences were found in the incidence of clinically relevant hypotension, length of stay, or mortality between AVP weaning and no-weaning discontinuation strategies. These findings suggest incremental weaning and abrupt withdrawal of AVP are both acceptable discontinuation strategies.

A signature of Prevotella copri and Faecalibacterium prausnitzii depletion, and a link with bacterial glutamate degradation in the Kenyan colorectal cancer patients.

Background: Colorectal cancer (CRC) is the fifth most diagnosed cancer in Sub-Saharan Africa. In Kenya, CRC incidence rates tripled from 1997 to 2017. In the Moi Teaching and Referral Hospital, Moi University, there has been an increase in CRC cases, notably for younger patients. A suggested pathobiology for this increase is gut microbiome dysbiosis. Since, for the Kenyan CRC patient population, microbiome studies are rare, there is a need for a better understanding of how microbiome dysbiosis influences CRC epidemiology in Kenya. In this single-center study, the focus was on profiling the gut microbiome of Kenyan CRC patients and healthy volunteers and evaluating associations between microbiome profiles and the age of CRC patients. Methods: The gut mucosa-associated microbiome of 18 CRC patients and 18 healthy controls were determined by 16S rRNA sequencing and analyzed for alpha and beta diversity, differential abundance, and microbial metabolic profiling. Results: Alpha diversity metrics showed no significant differences, but beta diversity metrics showed dissimilarities in the microbial communities between CRC patients and healthy controls. The most underrepresented species in the CRC group were Prevotella copri (P. copri) and Faecalibacterium prausnitzii (F. prausnitzii), although Bacteroides fragilis (B. fragilis) and Prevotella nigrescens were overrepresented (linear discriminant analysis, LDA score >2, P<0.05). Also, for CRC patients, significant metagenomic functional alterations were evident in microbial glutamate metabolic pathways (L-glutamate degradation VIII was enriched, and L-glutamate and L-glutamine biosynthesis were diminished) (P<0.05, log2 Fold Change >1). Moreover, the microbiome composition was different for patients under 40 years of age compared to older patients (LDA score >2, P<0.05). Conclusions: Microbiome and microbial metabolic profiles of CRC patients are different from those of healthy individuals. CRC microbiome dysbiosis, particularly P. copri and F. prausnitzii depletion and glutamate metabolic alterations, are evident in Kenyan CRC patients.

Vancomycin With Concomitant Piperacillin/Tazobactam vs. Cefepime or Meropenem Associated Acute Kidney Injury in General Ward Patients: A Multicenter Propensity Score-Matched Study.

Background: Concurrent administration of vancomycin and piperacillin/tazobactam (VAN+PTZ) may increase the risk of acute kidney injury (AKI) in hospitalized patients. Comprehensive characterization of VAN+PTZ associated AKI and recovery patterns remains lacking in previous reports. Objective: To compare the incidence of AKI associated with VAN+PTZ compared to either cefepime (CEF) or meropenem (MER) with VAN in adult general ward patients. Methods: A multicenter, retrospective, propensity score cohort study was conducted in non-critically ill adult patients. Included patients were concurrently administered VAN+PTZ or VAN+CEF/MER. Patients developing AKI ≤48 hours following combination therapy were excluded. The primary endpoint was to compare the incidence of AKI between study groups. Multivariable Cox regression modeling in predicting AKI was also conducted. Results: A total of 3199 patients met inclusion criteria and were evaluated. The incidence of AKI in VAN+PTZ and VAN+CEF/MER groups were 16.4% and 8.7%, respectively (P < .001). The onset to AKI was 1.8 days earlier with VAN+PTZ compared to VAN+CEF/MER (P < .001). Multivariable prediction model showed concomitant VAN+PTZ was identified as an independent risk factor of developing AKI (HR 2.34, 1.82-3.01, P < .001). The VAN+PTZ group experienced significantly higher rates of severe AKI (stage II or III) compared to the VAN+CEF/MER group (P = .002). No differences in the AKI recovery patterns were found between study groups. Conclusions: Concomitant VAN+PTZ in adult general ward patients was independently associated with an increased risk of AKI overall. More severe AKI was also associated with VAN+PTZ.

COVID-19 Time of Intubation Mortality Evaluation (C-TIME): A system for predicting mortality of patients with COVID-19 pneumonia at the time they require mechanical ventilation.

BACKGROUND: An accurate system to predict mortality in patients requiring intubation for COVID-19 could help to inform consent, frame family expectations and assist end-of-life decisions. RESEARCH OBJECTIVE: To develop and validate a mortality prediction system called C-TIME (COVID-19 Time of Intubation Mortality Evaluation) using variables available before intubation, determine its discriminant accuracy, and compare it to acute physiology and chronic health evaluation (APACHE IVa) and sequential organ failure assessment (SOFA). METHODS: A retrospective cohort was set in 18 medical-surgical ICUs, enrolling consecutive adults, positive by SARS-CoV 2 RNA by reverse transcriptase polymerase chain reaction or positive rapid antigen test, and undergoing endotracheal intubation. All were followed until hospital discharge or death. The combined outcome was hospital mortality or terminal extubation with hospice discharge. Twenty-five clinical and laboratory variables available 48 hours prior to intubation were entered into multiple logistic regression (MLR) and the resulting model was used to predict mortality of validation cohort patients. Area under the receiver operating curve (AUROC) was calculated for C-TIME, APACHE IVa and SOFA. RESULTS: The median age of the 2,440 study patients was 66 years; 61.6 percent were men, and 50.5 percent were Hispanic, Native American or African American. Age, gender, COPD, minimum mean arterial pressure, Glasgow Coma scale score, and PaO2/FiO2 ratio, maximum creatinine and bilirubin, receiving factor Xa inhibitors, days receiving non-invasive respiratory support and days receiving corticosteroids prior to intubation were significantly associated with the outcome variable. The validation cohort comprised 1,179 patients. C-TIME had the highest AUROC of 0.75 (95%CI 0.72-0.79), vs 0.67 (0.64-0.71) and 0.59 (0.55-0.62) for APACHE and SOFA, respectively (Chi2 P<0.0001). CONCLUSIONS: C-TIME is the only mortality prediction score specifically developed and validated for COVID-19 patients who require mechanical ventilation. It has acceptable discriminant accuracy and goodness-of-fit to assist decision-making just prior to intubation. The C-TIME mortality prediction calculator can be freely accessed on-line at https://phoenixmed.arizona.edu/ctime.

ARID1A-deficient bladder cancer is dependent on PI3K signaling and sensitive to EZH2 and PI3K inhibitors.

Metastatic urothelial carcinoma is generally incurable with current systemic therapies. Chromatin modifiers are frequently mutated in bladder cancer, with ARID1A-inactivating mutations present in about 20% of tumors. EZH2, a histone methyltransferase, acts as an oncogene that functionally opposes ARID1A. In addition, PI3K signaling is activated in more than 20% of bladder cancers. Using a combination of in vitro and in vivo data, including patient-derived xenografts, we show that ARID1A-mutant tumors were more sensitive to EZH2 inhibition than ARID1A WT tumors. Mechanistic studies revealed that (a) ARID1A deficiency results in a dependency on PI3K/AKT/mTOR signaling via upregulation of a noncanonical PI3K regulatory subunit, PIK3R3, and downregulation of MAPK signaling and (b) EZH2 inhibitor sensitivity is due to upregulation of PIK3IP1, a protein inhibitor of PI3K signaling. We show that PIK3IP1 inhibited PI3K signaling by inducing proteasomal degradation of PIK3R3. Furthermore, ARID1A-deficient bladder cancer was sensitive to combination therapies with EZH2 and PI3K inhibitors in a synergistic manner. Thus, our studies suggest that bladder cancers with ARID1A mutations can be treated with inhibitors of EZH2 and/or PI3K and revealed mechanistic insights into the role of noncanonical PI3K constituents in bladder cancer biology.

The Underuse of Medicare's Prevention and Coordination Codes in Primary Care : A Cross-Sectional and Modeling Study.

BACKGROUND: Efforts to better support primary care include the addition of primary care-focused billing codes to the Medicare Physician Fee Schedule (MPFS). OBJECTIVE: To examine potential and actual use by primary care physicians (PCPs) of the prevention and coordination codes that have been added to the MPFS. DESIGN: Cross-sectional and modeling study. SETTING: Nationally representative claims and survey data. PARTICIPANTS: Medicare patients. MEASUREMENTS: Frequency of use and estimated Medicare revenue involving 34 billing codes representing prevention and coordination services for which PCPs could but do not necessarily bill. RESULTS: Eligibility among Medicare patients for each service ranged from 8.8% to 100%. Among eligible patients, the median use of billing codes was 2.3%, even though PCPs provided code-appropriate services to more patients, for example, to 5.0% to 60.6% of patients eligible for prevention services. If a PCP provided and billed all prevention and coordination services to half of all eligible patients, the PCP could add to the practice's annual revenue $124 435 (interquartile range [IQR], $30 654 to $226 813) for prevention services and $86 082 (IQR, $18 011 to $154 152) for coordination services. LIMITATION: Service provision based on survey questions may not reflect all billing requirements; revenues do not incorporate the compliance, billing, and opportunity costs that may be incurred when using these codes. CONCLUSION: Primary care physicians forego considerable amounts of revenue because they infrequently use billing codes for prevention and coordination services despite having eligible patients and providing code-appropriate services to some of those patients. Therefore, creating additional billing codes for distinct activities in the MPFS may not be an effective strategy for supporting primary care. PRIMARY FUNDING SOURCE: National Institute on Aging.

Extending growth inhibition during area-selective atomic layer deposition of Al2O3 on aminosilane-functionalized SiO2.

During area-selective atomic layer deposition (ALD) based on growth inhibitors, nucleation eventually occurs as the metal precursor reacts with the surface through secondary pathways. We show that ALD of Al2O3 on functionalized SiO2 can be significantly delayed by using a lower reactivity, heteroleptic precursor at well below the saturation dose.

Water conservation through plumbing and nudging.

In this paper, we investigate two solutions to urban water security challenges: plumbing and nudging. Using anonymized monthly billing data from 1.5 million accounts in Singapore over ten years, our staggered difference-in-differences estimates show that a nationwide Home Improvement Programme that improves the efficiency of plumbing reduces residential water consumption by 3.5%. This effect persists over a decade and is robust across population subgroups. Efficiency improvements could enhance the efficacy of other conservation polices and mitigate the effects of excessive heat, rainfall and air pollution. The savings from efficiency improvements on utility bills are small, but the increase in housing value exceeds the private cost of the Home Improvement Programme. However, an evaluation of a nationwide peer-comparison nudging programme finds no evidence of reduced water consumption. Overall, we show that plumbing improvements generate long-lasting effects on water conservation.