Efficacy and safety of GST-HG171 in adult patients with mild to moderate COVID-19: a randomised, double-blind, placebo-controlled phase 2/3 trial.

Background: GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C like protease inhibitor that has demonstrated greater potency and efficacy compared to Nirmatrelvir in pre-clinical studies. We aimed to evaluate the efficacy and safety of orally administered GST-HG171 plus Ritonavir in patients with coronavirus disease 2019 (COVID-19) infected with emerging XBB and non-XBB variants. Methods: This randomised, double-blind, placebo-controlled phase 2/3 trial was conducted in 47 sites in China among adult patients with mild-to-moderate COVID-19 with symptoms onset ≤72 h. Eligible patients were randomised 1:1 to receive GST-HG171 (150 mg) plus Ritonavir (100 mg) or corresponding placebo tablets twice daily for 5 days, with stratification factors including the risk level of disease progression and vaccination status. The primary efficacy endpoint was time to sustained recovery of clinical symptoms within 28 days, defined as a score of 0 for 11 COVID-19-related target symptoms for 2 consecutive days, assessed in the modified intention-to-treat (mITT) population. This trial was registered at ClinicalTrials.gov (NCT05656443) and Chinese Clinical Trial Registry (ChiCTR2200067088). Findings: Between Dec 19, 2022, and May 4, 2023, 1525 patients were screened. Among 1246 patients who underwent randomisation, most completed basic (21.2%) or booster (74.9%) COVID-19 immunization, and most had a low risk of disease progression at baseline. 610 of 617 who received GST-HG171 plus Ritonavir and 603 of 610 who received placebo were included in the mITT population. Patients who received GST-HG171 plus Ritonavir showed shortened median time to sustained recovery of clinical symptoms compared to the placebo group (13.0 days [95.45% confidence interval 12.0-15.0] vs. 15.0 days [14.0-15.0], P = 0.031). Consistent results were observed in both SARS-CoV-2 XBB (45.7%, 481/1053 of mITT population) and non-XBB variants (54.3%, 572/1053 of mITT population) subgroups. Incidence of adverse events was similar in the GST-HG171 plus Ritonavir (320/617, 51.9%) and placebo group (298/610, 48.9%). The most common adverse events in both placebo and treatment groups were hypertriglyceridaemia (10.0% vs. 14.7%). No deaths occurred. Interpretation: Treatment with GST-HG171 plus Ritonavir has demonstrated benefits in symptom recovery and viral clearance among low-risk vaccinated adult patients with COVID-19, without apparent safety concerns. As most patients were treated within 2 days after symptom onset in our study, confirming the potential benefits of symptom recovery for patients with a longer duration between symptom onset and treatment initiation will require real-world studies. Funding: Fujian Akeylink Biotechnology Co., Ltd.

Microbial Indoles: Key Regulators of Organ Growth and Metabolic Function.

Gut microbes supporting body growth are known but the mechanisms are less well documented. Using the microbial tryptophan metabolite indole, known to regulate prokaryotic cell division and metabolic stress conditions, we mono-colonized germ-free (GF) mice with indole-producing wild-type Escherichia coli (E. coli) or tryptophanase-encoding tnaA knockout mutant indole-non-producing E. coli. Indole mutant E. coli mice showed multiorgan growth retardation and lower levels of glycogen, cholesterol, triglycerides, and glucose, resulting in an energy deficiency despite increased food intake. Detailed analysis revealed a malfunctioning intestine, enlarged cecum, and reduced numbers of enterochromaffin cells, correlating with a metabolic phenotype consisting of impaired gut motility, diminished digestion, and lower energy harvest. Furthermore, indole mutant mice displayed reduction in serum levels of tricarboxylic acid (TCA) cycle intermediates and lipids. In stark contrast, a massive increase in serum melatonin was observed-frequently associated with accelerated oxidative stress and mitochondrial dysfunction. This observational report discloses functional roles of microbe-derived indoles regulating multiple organ functions and extends our previous report of indole-linked regulation of adult neurogenesis. Since indoles decline by age, these results imply a correlation with age-linked organ decline and levels of indoles. Interestingly, increased levels of indole-3-acetic acid, a known indole metabolite, have been shown to correlate with younger biological age, further supporting a link between biological age and levels of microbe-derived indole metabolites. The results presented in this resource paper will be useful for the future design of food intervention studies to reduce accelerated age-linked organ decline.

Phase I study, and dosing regimen selection for a pivotal COVID-19 trial of GST-HG171.

This study is aimed to evaluate the safety, tolerability, and pharmacokinetics (PK), as well as to select an appropriate dosing regimen for the pivotal clinical trial of GST-HG171, an orally bioavailable, potent, and selective 3CL protease inhibitor by a randomized, double-blind, and placebo-controlled phase I trial in healthy subjects. We conducted a Ph1 study involving 78 healthy subjects to assess the safety, tolerability, and PK of single ascending doses (150-900 mg) as well as multiple ascending doses (MADs) (150 and 300 mg) of GST-HG171. Additionally, we examined the food effect and drug-drug interaction of GST-HG171 in combination with ritonavir through a MAD regimen of GST-HG171/ritonavir (BID or TID) for 5 days. Throughout the course of these studies, no serious AEs or deaths occurred, and no AEs necessitated study discontinuation. We observed that food had no significant impact on the exposure of GST-HG171. However, the presence of ritonavir substantially increased the exposure of GST-HG171, which facilitated the selection of the GST-HG171/ritonavir dose and regimen (150/100 mg BID) for subsequent phase II/III trials. The selected dose regimen was achieved through concentrations continuously at 6.2-9.9-fold above the levels required for protein-binding adjusted 50% inhibition (IC50) of viral replication in vitro. The combination of 150 mg GST-HG171/100 mg ritonavir demonstrated favorable safety and tolerability profiles. The PK data obtained from GST-HG171/ritonavir administration guided the selection of appropriate dose for a pivotal phase II/III trial currently in progress. (This study has been registered at ClinicalTrials.gov under identifier NCT05668897).

Trends and Predictors of Short Length of Stay Following Transcatheter Aortic Valve Replacement.

BACKGROUND: Minimalist approaches to Transcatheter aortic valve replacement (TAVR) have allowed for improved efficiency in care of patients. We hypothesized that improved efficiencies in care process may have led to increased adoption of a one night length of stay (LOS) in this patient group. OBJECTIVES: The authors aimed to study temporal trends in short length of stay following TAVR. METHODS: This is a nationwide temporal trends study using the 2016-2019 National In Patient Sample (NIS) registry. Short stay was defined as LOS of one night or less. Trends in proportion of patients with short stay were obtained. A multivariate model to identify predictors of short stay was built after adjusting for confounders. Secondary analysis of temporal trends was stratified by presence or absence of major complications (major bleeding requiring transfusion or pacemaker implantation [PPMI]). RESULTS: A total of 217,110 patients were included in the weighted sample. The proportion of patients with short stay significantly increased for those with and without complications (Ptrend < 0.001). The morbidity burden, as defined by the proportion of patients with a Charlson comorbidity index (CCI) score of ≥2 and rate of major complications decreased significantly. On multivariate analysis short stay was predicted by male sex, white ethnicity, Southern/Western regions and lower CCI score. Patients with major bleeding requiring transfusion or PPMI were less likely to have short stay (aOR 0.23 and aOR 0.12, p < 0.001 respectively). CONCLUSION: There is a national trend towards shorter LOS following TAVR. There is a decrease in major post procedural complication rates from 2016 to 2019.

Improved benefit of continuing luspatercept therapy: sub-analysis of patients with lower-risk MDS in the MEDALIST study.

Red blood cell transfusion independence (RBC-TI) is an important goal in treating lower-risk myelodysplastic syndromes with ring sideroblasts. In the phase 3 MEDALIST study, RBC-TI of ≥ 8 weeks was achieved by significantly more luspatercept- versus placebo-treated patients in the first 24 weeks of treatment. In this post hoc analysis, we evaluated RBC transfusion units and visits based on patients' baseline transfusion burden level and the clinical benefit of luspatercept treatment beyond week 25 in initial luspatercept nonresponders (patients who did not achieve RBC-TI ≥ 8 weeks by week 25) but continued luspatercept up to 144 weeks. RBC transfusion burden, erythroid response, serum ferritin levels, and hemoglobin levels relative to baseline were evaluated. Through week 25, fewer RBC transfusion units and visits were observed in luspatercept-treated patients versus placebo, regardless of baseline transfusion burden. This continued through 144 weeks of luspatercept treatment, particularly in patients with low baseline transfusion burden. Sixty-eight patients were initial nonresponders at week 25 but continued treatment; most (81%) received the maximum dose of luspatercept (1.75 mg/kg). Sixteen percent achieved RBC-TI for ≥ 8 weeks during weeks 25-48, 26% had reduced RBC transfusion burden, 10% achieved an erythroid response, 44% had reduced serum ferritin, and hemoglobin levels increased an average of 1.3 g/dL from baseline. These data have implications for clinical practice, as transfusion units and visits are less in luspatercept-treated patients through week 25 regardless of baseline transfusion burden, and continuing luspatercept beyond week 25 can potentially provide additional clinical benefits for initial nonresponders. Trial registration: NCT02631070.

Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial.

PURPOSE: This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430). METHODS: We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m2) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS: Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 (nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 (nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent (nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION: The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

Infectivity of pseudotyped SARS-CoV-2 variants of concern in different human cell types and inhibitory effects of recombinant spike protein and entry-related cellular factors.

Since the report of the first COVID-19 case in 2019, SARS-CoV-2 variants of concern (VOCs) have continued to emerge, manifesting diverse infectivity, evasion of host immunity and pathology. While ACE2 is the predominant receptor of SARS-CoV-2, TMPRSS2, Kim-1, NRP-1, CD147, furin, CD209L, and CD26 have also been implicated as viral entry-related cofactors. To understand the variations in infectivity and pathogenesis of VOCs, we conducted infection analysis in human cells from different organ systems using pseudoviruses of VOCs including Alpha, Beta, Gamma, and Delta. Recombinant spike S1, RBD, ACE2, Kim-1, and NRP-1 proteins were tested for their ability to block infection to dissect their roles in SARS-CoV-2 entry into cells. Compared with wild type SARS-CoV-2 (WT), numerous VOCs had significant increases of infectivity across a wide spectrum of cell types. Recombinant ACE2 protein more effectively inhibited the infection of VOCs including Delta and Omicron (BA.1 and BA.2) than that of WT. Interestingly, recombinant S1, RBD, Kim-1, and NRP-1 proteins inhibited the infection of all pseudoviruses in a manner dependent on the levels of ACE2 expression in different cell types. These results provide insights into the diverse infectivity of SARS-CoV-2 VOCs, which might be helpful for managing the emergence of new VOCs.

Use of Transcarotid Artery Revascularization, Transfemoral Carotid Artery Stenting, and Carotid Endarterectomy in the US From 2015 to 2019.

Importance: A transcarotid artery revascularization (TCAR) device was approved by the US Food and Drug Administration in 2015 for carotid revascularization in patients at high risk for stroke, cranial nerve injury, or major cardiac event. It is unclear how the introduction of TCAR has changed the use of carotid endarterectomy (CEA) and transfemoral carotid artery stenting (TFCAS). Objective: To quantify the temporal changes in the operative approach to carotid revascularization (CEA vs TFCAS vs TCAR), and to identify patient and disease characteristics commonly associated with each approach. Design, Setting, and Participants: This retrospective cohort study obtained data from the Vascular Quality Initiative database from January 1, 2015, to December 31, 2019. Patients with carotid artery stenosis who underwent CEA, TFCAS, or TCAR were included. Data were analyzed from January to April 2022. Exposures: Month and year of surgery as well as patient risk status. Main Outcomes and Measures: Number and proportion of carotid revascularization procedures by operative approach. Results: A total of 108 676 patients (mean [SD] age 56.6 [12.5] years; 66 684 men [61.4%]) were included in the analysis. The most common operative approach overall was CEA (n = 81 508 [75.0%]), followed by TFCAS (n = 15 578 [14.3%]) and TCAR (n = 11 590 [10.7%]). The number of procedures increased over the study period (16 754 in 2015 vs 27 269 in 2019; P < .001). In 2015, CEA was used in 84.9% of all cases, followed by TFCAS (14.4%) and TCAR (0.8%). In 2019, CEA was used in 64.8% of cases, followed by TCAR (21.9%) and TFCAS (13.3%). The proportional use of CEA decreased by 5.0% (95% CI, -7.4% to -2.6%) per year, and TCAR use increased by 5.3% (95% CI, 2.3%-8.3%) per year. Among patients at high risk, the change was greater: CEA use decreased by 7.8% (95% CI, -11.9% to -3.8%) per year, TFCAS decreased by 4.8% (95% CI, -9.5% to -0.14%) per year, and TCAR increased by 12.6% (95% CI, 7.1%-18.1%) per year. Multinomial logistic regression showed that patient risk status was the most important characteristic associated with TCAR compared with CEA (relative risk ratio, 36.10; 95% CI, 29.24-44.66; P < .001) and TFCAS (relative risk ratio, 14.10; 95% CI, 11.86-16.66; P < .001). Linear regression revealed no association between year of surgery and in-hospital myocardial infarction, stroke, or mortality. Conclusions and Relevance: Results of this study indicate that TCAR has become the dominant carotid revascularization approach, surpassing TFCAS and CEA in patients at high risk for stroke, cranial nerve injury, or cardiovascular events. Patient high-risk status was the main characteristic associated with a stenting approach, highlighting the perceived importance of carotid stenting therapies in this patient population.

Discovery and preclinical evaluations of GST-HG131, a novel HBV antigen inhibitor for the treatment of chronic hepatitis B infection.

Chronic hepatitis B (CHB) remains a significant health challenge worldwide. The current treatments for CHB achieve less than 10% cure rates, majority of the patients are on therapy for life. Therefore, cure of CHB is a high unmet medical need. HBV surface antigen (HBsAg) loss and seroconversion are considered as the key for the cure. RG7834 is a novel, orally bioavailable small molecule reported to reduce HBV antigens. Based on RG7834 chemistry, we designed and discovered a series of dihydrobenzopyridooxazepine (DBP) series of HBV antigen inhibitors. Extensive SAR studies led us to GST-HG131 with excellent reduction of HBV antigens (both HBsAg and HBeAg) in vitro and in vivo. GST-HG131 improved safety in rat toxicology studies over RG7834. The promising inhibitory activity, together with animal safety enhancement, merited GST-HG131 progressed into clinical development in 2020 (NCT04499443).

Ultrarapid and ultrasensitive detection of SARS-CoV-2 antibodies in COVID-19 patients via a 3D-printed nanomaterial-based biosensing platform.

Rapid detection of antibodies during infection and after vaccination is critical for the control of infectious outbreaks, understanding immune response, and evaluating vaccine efficacy. In this manuscript, we evaluate a simple ultrarapid test for SARS-CoV-2 antibodies in COVID-19 patients, which gives quantitative results (i.e., antibody concentration) in 10-12 s using a previously reported nanomaterial-based three-dimensional (3D)-printed biosensing platform. This platform consists of a micropillar array electrode fabricated via 3D printing of aerosolized gold nanoparticles and coated with nanoflakes of graphene and specific SARS-CoV-2 antigens, including spike S1, S1 receptor-binding domain (RBD) and nucleocapsid (N). The sensor works on the principle of electrochemical transduction, where the change of sensor impedance is realized by the interactions between the viral proteins attached to the sensor electrode surface and the antibodies. The three sensors were used to test samples from 17 COVID-19 patients and 3 patients without COVID-19. Unlike other serological tests, the 3D sensors quantitatively detected antibodies at a concentration as low as picomole within 10-12 s in human plasma samples. We found that the studied COVID-19 patients had higher concentrations of antibodies to spike proteins (RBD and S1) than to the N protein. These results demonstrate the enormous potential of the rapid antibody test platform for understanding patients' immunity, disease epidemiology and vaccine efficacy, and facilitating the control and prevention of infectious epidemics.

Neutralizing antibodies to SARS-CoV-2 variants of concern including Delta and Omicron in subjects receiving mRNA-1273, BNT162b2, and Ad26.COV2.S vaccines.

SARS-CoV-2 vaccines have contributed to the control of COVID-19 in some parts of the world. However, the constant emergence of variants of concern (VOCs) challenges the effectiveness of SARS-CoV-2 vaccines over time. In particular, Omicron contains a high number of mutations in the spike (S) protein gene, on which most vaccines were developed. In this study, we quantitated neutralizing antibodies in vaccine recipients at various times postvaccination using S protein-based pseudoviruses derived from wild type (WT) SARS-CoV-2 and five VOCs including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529). We found that two-dose mRNA-1273 and BNT162b2 vaccines elicited robust neutralizing antibodies against WT, Alpha, Beta, Gamma, and Delta, but wanned after 6 months with a faster decline observed for BNT162b2. Both mRNA-1273 and BNT162b2 elicited weak neutralizing antibodies against Omicron. One dose of Ad26.COV2.S vaccine induced weaker neutralizing antibodies against WT and most VOCs than mRNA-1273 and BNT162b2 did but moderate neutralizing antibodies against Delta and Omicron, which lasted for 6 months. These results support current recommendations of the Centers for Disease Control and Prevention for a booster 5 months after full immunization with an mRNA-based vaccine and the use of an mRNA-based vaccine 2 months after Ad26.COV2.S vaccination.

Low-dose carbon monoxide suppresses metastatic progression of disseminated cancer cells.

Low-dose carbon monoxide (CO) is under investigation in clinical trials to treat non-cancerous diseases and has an excellent safety profile. Due to early detection and cancer awareness, an increasing number of cancer patients are diagnosed at early stages, when potentially curative surgical resection can be done. However, many patients ultimately experience recurrence. Here, we evaluate the therapeutic effect of CO on metastatic cancer progression. We show that 250 ppm CO inhibits the migration of multiple types of cancer cell lines, including breast, pancreatic, colon, prostate, liver, and lung cancer and reduces the ability to adhere to fibronectin. We demonstrate that in mouse models, 250 ppm inhaled CO inhibits lung metastasis of breast cancer and liver metastasis of pancreatic cancer. Moreover, low-dose CO suppresses recurrence and increases survival after surgical removal of primary pancreatic cancer in mice. Mechanistically, low-dose CO blocks transcription of heme importers, leading to diminished intracellular heme levels and a heme-regulated enzyme, cytochrome P4501B1 (CYP1B1). Either supplementing heme or overexpressing CYP1B1 reverses the anti-migration effect of low-dose CO. Taken together, low-dose CO therapy inhibits cell migration, reduces adhesion to fibronectin, prevents disseminated cancer cells from expanding into gross metastases, and improves survival in pre-clinical mouse models of metastasis.

US medical student perspectives on asian american patient inclusion in medical education: a qualitative Study.

BACKGROUND: Asian American (AsAm) representation is lacking in conversations surrounding cultural humility in healthcare. We aimed to investigate US medical student perspectives on AsAm patient inclusion in cultural humility training in medical education. METHODS: This qualitative study analyzed free-text responses to an optional, open-ended question presented at the conclusion of an online survey assessing medical student experiences with and perceptions regarding AsAm patients in their medical education. This survey was distributed to a convenience sample of nine US medical schools. Medical students who completed at least one clinical rotation were eligible to participate in the survey. Qualitative analysis of free-text responses was conducted in an iterative process to generate emergent themes. RESULTS: There was a total of 195 optional free-text responses from 688 participants (28%). Motivation to learn about AsAm population included shared identity and desire to better serve the AsAm population in their local community and future careers. Topics of interest included healthcare-related cultural preferences, healthcare delivery strategies, and health disparities for the AsAm population and other minority patients. Students reported that they drew on personal experiences and some pre-clinical or clinical exposures to learn about AsAm patients. Respondents cited the lack of exposure in the medical school curriculum and clinical experiences as the main challenge to learning about AsAm health and provided suggestions for the delivery of this education in their pre-clinical and clinical education. Respondents emphasized that AsAms are treated as a monolith in medical education and healthcare, despite their heterogeneity. CONCLUSIONS: Medical students identified a need and interest for greater inclusion of AsAm topics in medical education on cultural humility and minority health.

Medicare Beneficiaries In Disadvantaged Neighborhoods Increased Telemedicine Use During The COVID-19 Pandemic.

Anticipating a growing need for health care during the COVID-19 pandemic, the Centers for Medicare and Medicaid Services expanded telemedicine coverage in the United States on March 6, 2020. In this study we used roughly thirty million Medicare fee-for-service claims to quantify outpatient telemedicine use before and after the Medicare telemedicine coverage waiver and to examine the association of telemedicine use with the Area Deprivation Index, a comprehensive measure of neighborhood socioeconomic disadvantage. Before the waiver, 0.42 percent of patients had at least one outpatient telemedicine visit, with no significant differences between people residing in the most versus the least disadvantaged neighborhoods. With the waiver, 9.97 percent of patients had at least one outpatient telemedicine visit, with the highest odds of utilization seen for people residing in the most disadvantaged neighborhoods. After adjustment, our data suggest that the coverage waiver increased access to telemedicine for all Medicare populations, including people residing in the most disadvantaged neighborhoods, although the odds of use were persistently lower with increasing age. Overall, these findings are encouraging, but they illuminate a need for targeted interventions to improve telemedicine access further.

HJM-561, a Potent, Selective, and Orally Bioavailable EGFR PROTAC that Overcomes Osimertinib-Resistant EGFR Triple Mutations.

The EGFR C797S mutation is the most common on-target resistance mechanism to osimertinib in patients with advanced non-small cell lung cancer (NSCLC). Currently there are no effective treatment options for patients with NSCLC harboring EGFR C797S triple mutants (Del19/T790M/C797S and L858R/T790M/C797S). Herein, we report an orally bioavailable EGFR PROTAC, HJM-561, which selectively degrades the EGFR C797S-containing triple mutants. HJM-561 potently inhibits the proliferation of Del19/T790M/C797S and L858R/T790M/C797S Ba/F3 cells while sparing cells expressing wild-type EGFR. Oral administration of HJM-561 shows robust antitumor activity in EGFR Del19/T790M/C797S-driven Ba/F3 CDX and PDX models that were resistant to osimertinib treatment. Taken together, our results suggest that HJM-561 is a promising therapeutic option for overcoming EGFR triple mutation-mediated drug resistance in NSCLC.

Transcarotid artery revascularization is associated with similar outcomes to carotid endarterectomy regardless of patient risk status.

BACKGROUND: Carotid artery stenting (CAS), including both transfemoral carotid artery stenting (TFCAS) and transcarotid artery revascularization (TCAR), reimbursement has been limited to high-risk patients by the Centers for Medicare & Medicaid Services (CMS) since 2005. We aimed to assess the association of CMS high-risk status with perioperative outcomes for carotid endarterectomy (CEA), TFCAS, and TCAR. METHODS: We performed a retrospective review of all Vascular Quality Initiative patients who underwent carotid revascularization between 2015 and 2020. Patients were stratified by whether they met CMS CAS criteria, and univariable and multivariable logistic regression analyses were performed to assess the association of procedure type (CEA, TFCAS, TCAR) with perioperative outcomes. RESULTS: Of 124,531 individuals who underwent carotid revascularization procedures, 91,687 (73.6%) underwent CEA, 17,247 (13.9%) underwent TFCAS, and 15,597 (12.5%) underwent TCAR. Among patients who met the CMS CAS criteria (ie, high-risk patients), the incidence of perioperative stroke was 2.7% for CEA, 3.4% for TFCAS, and 2.4% for TCAR (P < .001). Among standard-risk patients, the incidence of perioperative stroke was 1.7% for CEA, 2.7% for TFCAS, and 1.8% for TCAR (P < .001). After adjusting for baseline demographic and clinical characteristics, the odds of perioperative stroke were lower for TCAR versus CEA in high-risk patients (adjusted odds ratio [aOR], 0.82; 95% confidence interval [CI], 0.68-0.99) and similar in standard-risk patients (aOR, 1.05; 95% CI, 0.84, 1.31). In contrast, the adjusted odds of perioperative stroke were higher for TFCAS versus CEA in high-risk patients (aOR, 1.23; 95% CI, 1.03-1.46) and standard-risk patients (aOR, 1.60; 95% CI, 1.37-1.86). In both populations, TFCAS and TCAR patients had significantly lower odds of myocardial infarction than CEA patients (both P < .001). CONCLUSIONS: The perioperative risks associated with CEA, TFCAS, and TCAR in high-risk patients support the current CMS criteria, although the risks associated with each revascularization approach in standard-risk patients suggest that distinguishing TCAR from TFCAS may be warranted.