Afebrile status at the time of emergency department visit is associated with delayed antibiotic therapy in patients with sepsis (revised).

OBJECTIVES: To determine whether there is a difference in antibiotic administration time and prognosis in afebrile sepsis patients compared to febrile sepsis patients. METHODS: This was retrospective multicenter observational study. Data collected from three referral hospitals. Data were collected from May 2014 through February 2016 under the SEPSIS-2 criteria and from March 2016 to April 2020 under the newly released SEPSIS-3 criteria. Patients were divided into two groups based on body temperature: afebrile (<37.3 °C) and febrile (≥37.3 °C). The relationship between initial body temperature and 28-day mortality were analyzed using multivariable logistic regression. The subgroup analysis was conducted on patients with complete Hour-1 bundle performance records. RESULTS: We included 4293 patients in this study. Initial body temperatures in 28-day survivors were significantly higher than in 28-day non-survivors (37.5 °C ± 1.2 °C versus 37.1 °C ± 1.2 °C, p < 0.01). Multivariable logistic regression analysis was performed in afebrile and febrile sepsis patients. Adjusted odds ratio of afebrile sepsis patients for 28-day mortality was 1.76 (95% Confidence interval 1.46-2.12). As a result of performing the Hour-1 bundle, the number of patients who received antibiotics within 1 h was smaller in the afebrile sepsis patients (323/2076, 15.6%) than in the febrile sepsis patients (395/2156, 18.3%) (p = 0.02). In the subgroup analysis of patients with complete Hour-1 bundle performance records adjusted odds ratio of afebrile sepsis patients for 28-day mortality was 1.68 (95% Confidence interval 1.34-2.11). The febrile sepsis patients received antibiotics faster than the afebrile sepsis patients (175.5 ± 207.9 versus 209.3 ± 277.9, p < 0.01). CONCLUSIONS: Afebrile sepsis patients were associated with higher 28-day mortality compared to their febrile counterparts and were delayed in receiving antibiotics. This underscores the need for improved early detection and treatment strategies for the afebrile sepsis patients.

The Safety of Aztreonam Versus Ceftazidime in Patients Labeled With Penicillin Allergy: A Cohort Study.

PURPOSE: Penicillin allergy is the most common drug allergy among hospitalized patients. Traditionally, aztreonam is recommended for patients labeled with penicillin allergy (PLWPA) in our institutional empirical antibiotic guidelines. Due to a global aztreonam shortage in December 2022, the antimicrobial stewardship unit recommended ceftazidime as a substitute. There is a paucity of real-world data on the safety profile of ceftazidime in PLWPA. Hence, we evaluated tolerability outcomes of ceftazidime use in PLWPA. METHODS: This retrospective cohort study compared PLWPA in Singapore General Hospital who received aztreonam (October 2022-December 2022) or ceftazidime (December 2022-February 2023). Patients were stratified according to their risk of allergic reaction (AR) based on history of penicillin allergy. The severity of AR was based on the Delphi study grading system. The primary outcome was development of AR after initiation of aztreonam or ceftazidime. The secondary tolerability outcomes include hepatotoxicity and neurotoxicity. FINDINGS: There were 168 patients in the study; 69 were men (41.1%) and the median age was 69 years (interquartile range: 59-76 years). Incidence of AR was statistically similar in both arms: 1 of 102 patients (0.98%) in the aztreonam arm vs 2 of 66 patients (3.03%) in the ceftazidime arm (P = 0.33). The patient in the aztreonam arm was deemed at medium risk of having an AR and developed localized rashes (grade 1). Both patients in the ceftazidime arm were deemed at high risk of AR and developed localized skin reaction (grade 1). Hepatotoxicity was observed in 1 patient prescribed aztreonam. No patients in the ceftazidime arm developed adverse events. IMPLICATIONS: Ceftazidime appears to be better tolerated and cheaper compared with aztreonam in PLWPA, and serves as an antimicrobial stewardship strategy to conserve broader-spectrum antibiotics use.

OTUD7B knockdown inhibits proliferation and autophagy through AKT/mTOR signaling pathway in human prostate cancer cell.

Prostate cancer (PCa) is the second leading disease of cancer-related death in men around the world, and it is almost impossible to treat advanced PCa. OTUD7B is a member of the deubiquitinase family that undergoes a post-translational transformation process, which is essential for cell stability and signaling and is known to play a critical role in cancer. However, its role in PCa has not been discovered. The aim of the study was to investigate the expression and mechanism of OTUD7B in PCa cells. According to the database, high OTUD7B expression showed a poor prognosis. Therefore, we downregulated OTUD7B using siRNA and confirmed the role of OTUD7B in PC3 prostate cancer cells. OTUD7B knockdown effectively induced apoptosis and inhibited the proliferation in PC3 cells. OTUD7B knockdown inhibited autophagy through AKT/mTOR signaling. We also confirmed the relationship between AKT/mTOR signaling and autophagy through rapamycin, an mTOR inhibitor. Taken together, OTUD7B promotes the proliferation, and autophagy, and inhibits apoptosis of prostate cancer cells via the AKT/mTOR signaling pathway.

Slow G-Quadruplex Conformation Rearrangement and Accessibility Change Induced by Potassium in Human Telomeric Single-Stranded DNA.

The guanine-rich telomeric repeats can form G-quadruplexes (G4s) that alter the accessibility of the single-stranded telomeric overhang. In this study, we investigated the effects of Na+ and K+ on G4 folding and accessibility through cation introduction and exchange. We combined differential scanning calorimetry (DSC), circular dichroism (CD), and single molecule Förster resonance energy transfer (smFRET) to monitor the stability, conformational dynamics, and complementary strand binding accessibility of G4 formed by single-stranded telomeric DNA. Our data showed that G4 formed through heating and slow cooling in K+ solution exhibited fewer conformational dynamics than G4 formed in Na+ solution, which is consistent with the higher thermal stability of G4 in K+. Monitoring cation exchange with real time smFRET at room temperature shows that Na+ and K+ can replace each other in G4. When encountering high K+ at room or body temperature, G4 undergoes a slow conformational rearrangement process which is mostly complete by 2 h. The slow conformational rearrangement ends with a stable G4 that is unable to be unfolded by a complementary strand. This study provides new insights into the accessibility of G4 forming sequences at different time points after introduction to a high K+ environment in cells, which may affect how the nascent telomeric overhang interacts with proteins and telomerase.

Prevalence of functional esophageal disorders and associated clinical characteristics in patients with proton-pump-inhibitor-unresponsive reflux symptoms.

BACKGROUND AND AIM: Patients with proton-pump-inhibitor (PPI)-unresponsive reflux symptoms, often caused by functional esophageal disorders (FED), are frequently encountered in clinical practice. We aimed to investigate the prevalence of FED and its associated clinical characteristics in patients with PPI-unresponsive reflux symptoms. METHODS: We retrospectively identified patients who were evaluated for persistent typical reflux symptoms, despite ≥8 weeks of PPI treatment, at the National Taiwan University Hospital from 2014 to 2023. All patients underwent a comprehensive evaluation comprising validated gastroesophageal reflux disease (GERD) symptom questionnaires, 5-item Brief Symptom Rating Scale (BSRS-5), Pittsburgh Sleep Quality Index (PSQI), esophagogastroduodenoscopy, high-resolution impedance manometry, and 24-h impedance-pH monitoring off PPI therapy. Diagnosis of FED and non-erosive reflux disease (NERD) was based on the Rome IV criteria. RESULTS: We analyzed 190 patients [46.8% male, median age 52 (interquartile range, 42-61) years], of whom 32 (16.8%) had NERD and 158 (83.2%) had FED (57.9% with functional heartburn and 25.3% with reflux hypersensitivity). Patients with FED had a lower body mass index than those with NERD and a higher prevalence of psychological comorbidities and poor sleep quality than healthy volunteers. The severity of reflux symptoms among FED patients was significantly associated with the severity of psychological comorbidities and sleep quality. CONCLUSIONS: A notably high prevalence (83.2%) of FED was observed among patients experiencing PPI-unresponsive reflux symptoms. Patients with FED had a higher level of psychological distress and diminished sleep quality, both of which were associated with reflux symptom severity.

Assessment of efficacy and safety of dose-dense doxorubicin and cyclophosphamide (ddAC) in combination with immunotherapy in early-stage triple-negative breast cancer.

PURPOSE: This study aimed to assess safety and efficacy of a modified KEYNOTE 522 protocol, which incorporated pembrolizumab every 6 weeks, allowing for concomitant dose-dense (14 day) doxorubicin and cyclophosphamide (ddAC). By optimizing this dosing, the intention of this modified protocol was to improve pathologic complete response (pCR) rates in a population associated with a poorer prognosis. METHODS: This was a retrospective, single-center, cohort study. Patients were included if they had early stage, triple-negative breast cancer, and received at least one dose of AC. The entire cohort received neoadjuvant chemotherapy including weekly carboplatin and paclitaxel with pembrolizumab every 3 weeks for 12 weeks (4 cycles). The group then received either ddAC with pembrolizumab 400 mg every 6 weeks, or AC with pembrolizumab 200 mg every 3 weeks. The primary objective was pCR rate at time of surgery. RESULTS: This study assessed outcomes in 25 patients over 34 months. The pCR rate in the pembrolizumab, AC 3-week cohort was 64.3% versus 81.8% in the ddAC and 6-week pembrolizumab group. No pembrolizumab-associated grade 3-4 adverse events occurred in the either cohort. Despite seeing an increased incidence of grade 3-4 toxicities in the ddAC arm, this did not result in additional chemotherapy delays or dose reductions. CONCLUSION: This study demonstrated tolerability and a potential for favorable outcomes with this patient population, making this modified KEYNOTE 522 protocol a reasonable treatment approach. Larger, prospective studies are warranted to assess the feasibility of this dosing and true optimization of patient outcomes given the small sample size of this study.

The cost of lung transplantation in the United States: How high is too high?

Objectives: To identify patient and process factors that contribute to the high cost of lung transplantation (LTx) in the perioperative period, which may allow transplant centers to evaluate situations in which transplantation is most cost-effective to inform judicious resource allocation, avoid futile care, and reduce costs. Methods: The MarketScan Research databases were used to identify 582 privately insured patients undergoing single or bilateral LTx between 2013 and 2019. The patients were subdivided into groups by disease etiology using the United Network of Organ Sharing classification system. Multivariable generalized linear models using a gamma distribution with a log link were fit to examine the associations between the etiology of lung disease and costs during the index admission, 3 months before admission, and 3 months after discharge. Results: Our results indicate that the index admission contributed the most to the total transplantation costs compared to the 3 months before admission and after discharge. The regression-adjusted mean index hospitalization cost was 35% higher for patients with pulmonary vascular disease compared to those with obstructive lung disease ($527,156 vs $389,055). The use of extracorporeal membrane oxygenation, mechanical ventilation, and surgical complications in the post-transplantation period were associated with higher costs during the index admission. Surprisingly, age ≥55 was associated with lower costs during the index admission. Conclusions: This analysis identifies pivotal factors influencing the high cost of LTx, emphasizing the significant impact of the index admission, particularly for patients with pulmonary vascular disease. These insights offer transplant centers an opportunity to enhance cost-effectiveness through judicious resource allocation and service bundling, ultimately reducing overall transplantation costs.

Assessment of Embedded vs. Remote Pharmacist vs. Remote Student Pharmacist Outreach on Statin Prescribing.

BACKGROUND: The Statin Use in Persons with Diabetes (SUPD) measure is a Star measure by the Center for Medicare & Medicaid Services. The Duke Population Health Management Office (PHMO) has a team of pharmacists and pharmacy students who conduct targeted outreach to patients at risk of failing statin quality measures. Pharmacy services are embedded in select primary care clinics and other clinics are supported remotely. OBJECTIVE: The primary objective of this review is to compare the initiation rates of recommended statin prescriptions between embedded pharmacist vs remote pharmacist vs remote student pharmacist outreach groups, all of which have different levels of autonomy within pharmacy practice. The secondary objectives are to identify the barriers to the implementation of statin therapy and to assess the statin drugs and intensity of the statins prescribed. METHODS: A single-center, retrospective chart review was performed for SUPD patients with Medicare insurance. SUPD patients included patients 40-75 years of age, diagnosed with type 2 diabetes, and were not dispensed at least one statin medication of any intensity during the 6-month measurement period. The primary outcome was the initiation of recommended statin medications prescribed, or pended for the PCP to prescribe, for qualifying patients by embedded, remote, and remote student pharmacists. Secondary outcomes included the reasons for the non-implementation of statin recommendations, reasons statin therapy was not prescribed to patients contributing to the SUPD measure gap, and statin drug and dose prescribed for appropriateness. RESULTS: A total of 189 patients were included in the evaluation. In this study, 34.9% of the patients filled the prescribed or pended statin prescription and 83.3% of patients filled the prescribed or pended statin prescription at the recommended intensity according to the ACC/AHA guidelines, effectively closing the SUPD measure gap. The initiation rates of recommended statin prescriptions between the embedded pharmacist, remote pharmacist, and remote student pharmacist outreach were numerically different at 36.7%, 28.2%, and 36.7%, respectively, even though not statistically different (p=0.61). CONCLUSION: Remote student pharmacists' performance was equal to that of the embedded pharmacists when comparing the initiation rates of statin medications prescribed or pending the PCP's approval. The most common reason for non-implementation of statin therapy is that the statin was refused by the patient. Atorvastatin and rosuvastatin were the two most commonly prescribed statins.

Impact of obesity on renal function in elderly Korean adults: a national population-based cohort study.

Background: Obesity is a well-known risk factor for chronic kidney disease and its progression. However, the impact of obesity on the renal function of the elderly population is uncertain. We investigated the association between obesity and renal outcomes in the elderly. Methods: We analyzed 130,504 participants from the Korean National Health Insurance Service-Senior cohort. Obesity was classified according to body mass index (BMI), sex-specific waist circumference (WC), and the presence of metabolic syndrome. The primary outcome was renal function decline, defined as a decline in the estimated glomerular filtration rate (eGFR) of at least 50% from baseline or new-onset end-stage renal disease. Results: During a follow-up period of 559,531.1 person-years (median, 4.3 years), 2,486 participants (19.0%; incidence rate of 4.44 per 1,000 person-years) showed renal function decline. A multivariate Cox proportional hazards model revealed that BMI/WC was not associated with renal function decline. However, the group with metabolic syndrome had a significantly increased risk of renal function decline compared to the group without metabolic syndrome (adjusted hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.13-1.36). Compared with the non-metabolic syndrome group, the adjusted HRs (95% CI) for participants with one through five components were 0.96 (0.84-1.11), 1.10 (0.96-1.27), 1.24 (1.06-1.45), 1.37 (1.12-1.66), and 1.99 (1.42-2.79), respectively (p for trend < 0.001). Conclusion: In elderly Korean adults, metabolic syndrome and the number of its components were associated with a higher risk of renal function decline, but BMI or WC was not significant.

Novel role of LLGL2 silencing in autophagy: reversing epithelial-mesenchymal transition in prostate cancer.

PURPOSE: Prostate cancer (PCa) is a major urological disease that is associated with significant morbidity and mortality in men. LLGL2 is the mammalian homolog of Lgl. It acts as a tumor suppressor in breast and hepatic cancer. However, the role of LLGL2 and the underlying mechanisms in PCa have not yet been elucidated. Here, we investigate the role of LLGL2 in the regulation of epithelial-mesenchymal transition (EMT) in PCa through autophagy in vitro and in vivo. METHODS: PC3 cells were transfected with siLLGL2 or plasmid LLGL2 and autophagy was examined. Invasion, migration, and wound healing were assessed in PC3 cells under autophagy regulation. Tumor growth was evaluated using a shLLGL2 xenograft mouse model. RESULTS: In patients with PCa, LLGL2 levels were higher with defective autophagy and increased EMT. Our results showed that the knockdown of LLGL2 induced autophagy flux by upregulating Vps34 and ATG14L. LLGL2 knockdown inhibits EMT by upregulating E-cadherin and downregulating fibronectin and α-SMA. The pharmacological activation of autophagy by rapamycin suppressed EMT, and these effects were reversed by 3-methyladenine treatment. Interestingly, in a shLLGL2 xenograft mouse model, tumor size and EMT were decreased, which were improved by autophagy induction and worsened by autophagy inhibition. CONCLUSION: Defective expression of LLGL2 leads to attenuation of EMT due to the upregulation of autophagy flux in PCa. Our results suggest that LLGL2 is a novel target for alleviating PCa via the regulation of autophagy.

Pattern Clustering of Symmetric Regional Cerebral Edema on Brain MRI in Patients with Hepatic Encephalopathy.

Purpose: Metabolic abnormalities in hepatic encephalopathy (HE) cause brain edema or demyelinating disease, resulting in symmetric regional cerebral edema (SRCE) on MRI. This study aimed to investigate the usefulness of the clustering analysis of SRCE in predicting the development of brain failure. Materials and Methods: MR findings and clinical data of 98 consecutive patients with HE were retrospectively analyzed. The correlation between the 12 regions of SRCE was calculated using the phi (Φ) coefficient, and the pattern was classified using hierarchical clustering using the φ2 distance measure and Ward's method. The classified patterns of SRCE were correlated with clinical parameters such as the model for end-stage liver disease (MELD) score and HE grade. Results: Significant associations were found between 22 pairs of regions of interest, including the red nucleus and corpus callosum (Φ = 0.81, p < 0.001), crus cerebri and red nucleus (Φ = 0.72, p < 0.001), and red nucleus and dentate nucleus (Φ = 0.66, p < 0.001). After hierarchical clustering, 24 cases were classified into Group I, 35 into Group II, and 39 into Group III. Group III had a higher MELD score (p = 0.04) and HE grade (p = 0.002) than Group I. Conclusion: Our study demonstrates that the SRCE patterns can be useful in predicting hepatic preservation and the occurrence of cerebral failure in HE.

Demographics of focused ultrasound thalamotomy for essential tremor and trends in deep brain stimulation surgery after its introduction in the USA.

Background: Essential tremor (ET) is a movement disorder that affects 4%-5% of adults >65 years. For patients with medically refractory ET, neurosurgical interventions such as deep brain stimulation (DBS) and unilateral MR-guided focused ultrasound thalamotomy (MRgFUS) are available. In this retrospective cohort study, we examined the demographics of patients with ET who have received MRgFUS and evaluated trends in DBS usage in the USA after the introduction of MRgFUS in 2016. Methods: We used multiple databases to examine the demographics of patients who received DBS and MRgFUS, and trends in DBS. To assess the demographics, we queried the TriNetX database from 2003 to 2022 to identify patients diagnosed with ET and stratify them by DBS or MRgFUS treatment by using Current Procedural Terminology codes. Patient demographics were reported as frequencies and percentages. To examine the trends in DBS for ET, the yearly frequency of DBS procedures done for ET between 2012 and 2019 was extracted from the National Inpatient Sample (NIS) database, and breakpoint analysis was performed. Additionally, the yearly frequency of MRgFUS procedures for ET was obtained from Insightec Exlabate. Results: Most of the patients (88.69%) in the cohort extracted from TriNetX database self-identified as white, followed by black or African American (2.40%) and Asian (0.52%). A higher percentage of black patients received MRgFUS treatment than DBS (4.10% vs 1.88%). According to the NIS database, from 2012 to 2020, 13 525 patients received DBS for ET. Conclusion: This study provides an overview of the characteristics of patients who undergo DBS or MRgFUS. We found notable differences in sex and race among patients who underwent each treatment type. Additionally, until at least the beginning of 2020, the number of DBS procedures for ET was not negatively affected after the introduction of MRgFUS.

Buccal Fat Advancement-Transposition Flap for Reconstruction of Midface Volume Defects.

Background: The buccal fat pad (BFP) has previously been utilized for repair of various defects of the head and neck. Objectives: We explore the utility of a pedicled buccal fat advancement-transposition (BFAT) flap in various forms of midface reconstruction through a variety of surgical approaches and characterize its volume and axial reach in human anatomic specimens. Methods: Ten adult full-head human anatomic specimens were dissected, and a single surgical case demonstrating the use of a BFAT flap is described. Results: Nasolabial, subciliary, and deep plane facelift incisions all provided access to the BFP for use as a BFAT flap. The mean volume of mobilizable fat contained within a BFAT flap accessible through external incision was 7.1 cm3. Once fully mobilized, the externalized BFAT flap had a mean axial reach of 6.9 cm without tension. We also present a case illustrating the successful use of a BFAT flap for volumization of a large midface defect secondary to Mohs micrographic surgical resection of a cutaneous malignancy. Discussion: The BFAT flap, which exhibited substantial volume and reach in this study, can be harvested through multiple dissection windows or pre-existing defects and be used to reconstruct a variety of midface defects.

Vericiguat suppresses ventricular tachyarrhythmias inducibility in a rabbit myocardial infarction model.

BACKGROUND: The VICTORIA trial demonstrated a significant decrease in cardiovascular events through vericiguat therapy. This study aimed to assess the potential mechanisms responsible for the reduction of cardiovascular events with vericiguat therapy in a rabbit model of myocardial infarction (MI). METHODS: A chronic MI rabbit model was created through coronary artery ligation. Following 4 weeks, the hearts were harvested and Langendorff perfused. Subsequently, electrophysiological examinations and dual voltage-calcium optical mapping studies were conducted at baseline and after administration of vericiguat at a dose of 5 µmol/L. RESULTS: Acute vericiguat therapy demonstrated a significant reduction in premature ventricular beat burden and effectively suppressed ventricular arrhythmic inducibility. The electrophysiological influences of vericiguat therapy included an increased ventricular effective refractory period, prolonged action potential duration, and accelerated intracellular calcium (Cai) homeostasis, leading to the suppression of action potential and Cai alternans. The pacing-induced ventricular arrhythmias exhibited a reentrant pattern, attributed to fixed or functional conduction block in the peri-infarct zone. Vericiguat therapy effectively mitigated the formation of cardiac alternans as well as the development of reentrant impulses, providing additional anti-arrhythmic benefits. CONCLUSIONS: In the MI rabbit model, vericiguat therapy demonstrates anti-ventricular arrhythmia effects. The vericiguat therapy reduces ventricular ectopic beats, inhibiting the initiation of ventricular arrhythmias. Furthermore, the therapy successfully suppresses cardiac alternans, preventing conduction block and, consequently, the formation of reentry circuits.

Nationwide Analysis of Risk Factors Related to Opioid Weaning Following Lumbar Decompression Surgery - A Retrospective Database Study.

BACKGROUND: Opioids are often prescribed for patients who eventually undergo lumbar decompression. Given the potential for opioid-related morbidity and mortality, postoperative weaning is often a goal of surgery. The purpose of this study was to examine the relationship between preoperative opioid use and postoperative complete opioid weaning among lumbar decompression patients. METHODS: We surveyed the IBM Marketscan Databases for patients who underwent lumbar decompression during 2008-2017, had >30 days of opioid use in the year preceding surgery, and consumed a daily average of >0 morphine milligram equivalents in the 3 months preceding surgery. We used multivariable logistic regression and marginal standardization to examine the association between preoperative opioid use duration, average daily dose, and their interactions with complete opioid weaning in the 10-12 months after surgery. RESULTS: Of the 11,114 patients who met inclusion criteria, most (54.7%, n = 6083) had a preoperative average daily dose of 1-20 morphine milligram equivalents. Postoperatively, 6144 patients (55.3%) remained on opioids. For patients with >180 days of preoperative use, the adjusted probability of weaning increased as the preoperative dose decreased. Obesity increased the likelihood of weaning, whereas older age, several comorbidities, female sex, and Medicaid decreased the odds of weaning. CONCLUSIONS: Patients who used opioids for longer preoperatively were less likely to completely wean following surgery. Among patients with >180 days of preoperative use, those with lower preoperative doses were more likely to wean. Weaning was also associated with several clinical and demographic factors. These findings may help shape expectations regarding opioid use following lumbar decompression.

An Antibody-Drug Conjugate for Multiple Myeloma Prepared by Multi-Arm Linkers.

First-line treatment of multiple myeloma, a prevalent blood cancer lacking a cure, using anti-CD38 daratumumab antibody and lenalidomide is often inadequate due to relapse and severe side effects. To enhance drug safety and efficacy, an antibody-drug conjugate, TE-1146, comprising six lenalidomide drug molecules site-specifically conjugated to a reconfigured daratumumab to deliver cytotoxic lenalidomide to tumor cells is developed. TE-1146 is prepared using the HighDAR platform, which employs i) a maleimide-containing "multi-arm linker" to conjugate multiple drug molecules creating a drug bundle, and ii) a designed peptide with a Zn2+-binding cysteine at the C-termini of a reconfigured daratumumab for site-specific drug bundle conjugation. It is shown that TE-1146 remains intact and effectively enters CD38-expressing tumor cells, releasing lenalidomide, leading to enhanced cell-killing effects compared to lenalidomide/daratumumab alone or their combination. This reveals the remarkable potency of lenalidomide once internalized by myeloma cells. TE-1146 precisely delivers lenalidomide to target CD38-overexpressing tumor cells. In contrast, lenalidomide without daratumumab cannot easily enter cells, whereas daratumumab without lenalidomide relies on Fc-dependent effector functions to kill tumor cells.

Effectiveness of COVID-19 vaccines against severe outcomes in cancer patients: Real-world evidence from self-controlled risk interval and retrospective cohort studies.

BACKGROUND: The effectiveness of COVID-19 vaccines is generally reduced in cancer patients compared to the general population. However, there are only a few studies that compare the relative risk of breakthrough infections and severe COVID-19 outcomes in fully vaccinated cancer patients versus their unvaccinated counterparts. METHODS: To assess the effectiveness of COVID-19 vaccines in cancer patients, we employed (1) a self-controlled risk interval (SCRI) design, and (2) a retrospective matched cohort design. A SCRI design was used to compare the risk of breakthrough infection in vaccinated cancer patients during the period immediately following vaccination ("control window") and the period in which immunity is achieved ("exposure windows"). The retrospective matched cohort design was used to compare the risk of severe COVID-19 outcomes between vaccinated and unvaccinated cancer patients. For both studies, data were extracted from the Korea Disease Control and Prevention Agency-COVID-19-National Health Insurance Service cohort, including demographics, medical history, and vaccination records of all individuals confirmed with COVID-19. We used conditional Poisson regression to calculate the incidence rate ratio (IRR) for breakthrough infection and Cox regression to estimate the hazard ratio (HR) for severe outcomes. RESULTS: Of 14,448 cancer patients diagnosed with COVID-19 between October 2020 and December 2021, a total of 217 and 3996 cancer patients were included in the SCRI and cohort study respectively. While the risk of breakthrough infections, measured by the incidence rate in the control and exposure windows, did not show statistically significant difference in vaccinated cancer patients (IRR=0.88, 95% CI: 0.64-1.22), the risk of severe COVID-19 outcomes was significantly lower in vaccinated cancer patients compared to those unvaccinated (HR=0.27, 95% CI: 0.22-0.34). CONCLUSION: COVID-19 vaccines significantly reduce the risk of severe outcomes in cancer patients, though their efficacy against breakthrough infections is less evident.

Disparities in the treatment of movement disorders using deep brain stimulation.

OBJECTIVE: Deep brain stimulation (DBS) is a well-established treatment for Parkinson's disease (PD) and essential tremor (ET). Although the prevalence of PD and ET can vary by sex and race, little is known about the accessibility of neurosurgical treatments for these conditions. In this nationwide study, the authors aimed to characterize trends in the use of DBS for the treatment of PD and ET and to identify disparities in the neurosurgical treatment of these diseases based on ethnic, racial, sex, insurance, income, hospital, and geographic factors. METHODS: Using the dates January 1, 2012, to December 31, 2019, the authors queried the National Inpatient Sample database for all discharges with an ICD-9 or ICD-10 diagnosis of PD or ET. Among these discharges, the DBS rates were reported for each subgroup of race, ethnicity, and sex. To develop national estimates, all analyses were weighted. RESULTS: Among 2,517,639 discharges with PD, 29,820 (1.2%) received DBS, and among 652,935 discharges with ET, 11,885 (1.8%) received DBS. Amid the PD cases, Black patients (n = 405 [0.2%], OR 0.16, 95% CI 0.12-0.20) were less likely than White patients (n = 23,975 [1.2%]) to receive DBS treatment, as were Hispanic patients (n = 1965 [1.1%], OR 0.76, 95% CI 0.65-0.88), whereas Asian/Pacific Islander patients (n = 855 [1.5%]) did not statistically differ from White patients. Amid the ET cases, Black (n = 230 [0.8%], OR 0.39, 95% CI 0.27-0.56), Hispanic (n = 215 [1.0%], OR 0.39, 95% CI 0.28-0.55), and Asian/Pacific Islander (n = 55 [1.0%], OR 0.51, 95% CI 0.28-0.93) patients were less likely than White patients (n = 10,440 [1.9%]) to receive DBS. Females were less likely than males to receive DBS for PD (OR 0.69, p < 0.0001) or ET (OR 0.70, p < 0.0001). CONCLUSIONS: The authors describe significant racial and sex-based differences in the utilization of DBS for the treatment of PD and ET. Further research is required to ascertain the causes of these disparities, as well as any differences in access to specialty neurosurgical care and referral for neuromodulation approaches.

Automatic Mechanical Ventilation vs Manual Bag Ventilation During CPR: A Pilot Randomized Controlled Trial.

BACKGROUND: There is insufficient evidence supporting the theory that mechanical ventilation can replace the manual ventilation method during CPR. RESEARCH QUESTION: Is using automatic mechanical ventilation (MV) feasible and comparable to the manual ventilation method during CPR? STUDY DESIGN AND METHODS: This pilot randomized controlled trial compared MV and manual bag ventilation (BV) during CPR after out-of-hospital cardiac arrest (OHCA). Patients with medical OHCA arriving at the ED were randomly assigned to two groups: an MV group using a mechanical ventilator and a BV group using a bag valve mask. Primary outcome was any return of spontaneous circulation (ROSC). Secondary outcomes were changes of arterial blood gas analysis results during CPR. Tidal volume, minute volume, and peak airway pressure were also analyzed. RESULTS: A total of 60 patients were enrolled, and 30 patients were randomly assigned to each group. There were no statistically significant differences in basic characteristics of OHCA patients between the two groups. The rate of any return of spontaneous circulation was 56.7% in the MV group and 43.3% in the BV group, indicating no significant (P = .439) difference between the two groups. There were also no statistically significant differences in changes of PH, Pco2, Po2, bicarbonate, or lactate levels during CPR between the two groups (P values = .798, 0.249, .515, .876, and .878, respectively). Significantly lower tidal volume (P < .001) and minute volume (P = .009) were observed in the MV group. INTERPRETATION: In this pilot trial, the use of MV instead of BV during CPR was feasible and could serve as a viable alternative. A multicenter randomized controlled trial is needed to create sufficient evidence for ventilation guidelines during CPR. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT05550454; URL: www. CLINICALTRIALS: gov.

5-Methoxytryptophan enhances the sensitivity of sorafenib on the inhibition of proliferation and metastasis for lung cancer cells.

BACKGROUND: Lung cancer is a leading cause of cancer-related mortality worldwide, and effective therapies are limited. Lung cancer is a leading cause of cancer-related mortality worldwide with limited effective therapy. Sorafenib is a multi-tyrosine kinase inhibitor frequently used to treat numerous types of malignant tumors. However, it has been demonstrated that sorafenib showed moderate antitumor activity and is associated with several side effects in lung cancer, which restricted its clinical application. This study aimed to examine the antitumor effect of the combination treatment of sorafenib and 5-methoxytryptophan (5-MTP) on cell growth and metastasis of Lewis lung carcinoma (LLC) cells. METHOD: The anticancer effect of the combination treatment of sorafenib and 5-MTP was determined through cytotoxicity assay and colony forming assays. The mechanism was elucidated using flow cytometry and western blotting. Wound healing and Transwell assays were conducted to evaluate the impact of the combination treatment on migration and invasion abilities. An in vivo model was employed to analyze the effect of the combination treatment on the tumorigenic ability of LLC cells. RESULT: Our results demonstrated that the sorafenib and 5-MTP combination synergistically reduced viability and proliferation compared to sorafenib or 5-MTP treatment alone. Reduction of cyclin D1 expression was observed in the sorafenib alone or combination treatments, leading to cell cycle arrest. Furthermore, the sorafenib-5-MTP combination significantly increased the inhibitory effect on migration and invasion of LLC cells compared to the single treatments. The combination also significantly downregulated vimentin and MMP9 levels, contributing to the inhibition of metastasis. The reduction of phosphorylated Akt and STAT3 expression may further contribute to the inhibitory effect on proliferation and metastasis. In vivo, the sorafenib-5-MTP combination further reduced tumor growth and metastasis compared to the treatment of sorafenib alone. CONCLUSIONS: In conclusion, our data indicate that 5-MTP sensitizes the antitumor activity of sorafenib in LLC cells in vitro and in vivo, suggesting that sorafenib-5-MTP has the potential to serve as a therapeutic option for patients with lung cancer.