Impact of Discontinuing Both Hypertonic Saline and Dornase Alfa After Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis.

Rationale Evaluating approaches to reduce treatment burden is a research priority among people with CF (pwCF) on highly effective modulators including elexacaftor/tezacaftor/ivacaftor (ETI). Objective To evaluate the impact of discontinuing both hypertonic saline (HS) and dornase alfa (DA) versus continuing both therapies among a subgroup of participants in the SIMPLIFY study who sequentially participated in trials evaluating the independent clinical effects of discontinuing HS and DA. Methods SIMPLIFY participants ≥12 years old on ETI and comprising a subgroup using both HS and DA at study entry were randomized to the HS or DA trial, and then randomized 1:1 to continue or discontinue the applicable therapy for 6 weeks. After completion of the first trial, eligible participants could enroll in the second trial beginning with a 2-week run in. Study outcomes were compared across the duration of SIMPLIFY participation between a cohort remaining on both therapies during SIMPLIFY versus a cohort that sequentially discontinued both as a result of trial randomizations. Multivariable regression models were used to estimate treatment differences, adjusted for time between trials, trial order, baseline age, sex at birth and percent predicted forced expiratory volume in one second (ppFEV1) at study entry. Results There were 43 participants who discontinued both therapies by the end of SIMPLIFY and 63 who remained on both, with overall average ppFEV1 at study entry 96.7% and average duration of follow up from beginning of the first trial to completion of the second trial 3.9 months, including time between trials. No clinically meaningful difference in the change in ppFEV1 from baseline to completion of the second trial was observed between those who discontinued versus remained on both therapies (difference: 0.22% Off-On, 95% CI: -1.60,2.03). Changes in LCI2.5, patient reported, and safety outcomes were also comparable. Patient reported treatment burden, as measured by a CFQ-R subscale, significantly decreased in those discontinuing both therapies. Conclusions SIMPLIFY participants who sequentially discontinued both HS and DA experienced no meaningful changes in clinical outcomes and reported decreased treatment burden as compared to those who remained on both therapies. These data continue to inform a new era of post-modulator care of pwCF.

Pharmacokinetics of a topical application of moxidectin in bare-nosed wombats (Vombatus ursinus).

Sarcoptic mange is a debilitating disease that affects bare-nosed wombats (Vombatus ursinus). One of the drugs currently used for treatment is moxidectin, as it has a relatively high efficacy against endo and ectoparasites and side effects are uncommon in domestic species, thus it is considered a relatively safe drug to use at the recommended doses. Developing further understanding of the pharmacokinetics of moxidectin will aid in developing treatment regimens for sarcoptic mange in wombats. Here we analyzed the pharmacokinetic parameters of using 100 ml of moxidectin (5 g/l) applied topically. We found that mean peak plasma concentration was 0.50 ng/ml and half-life was 8 days. Moxidectin was excreted in scats with the mean peak concentration of 2461.43 ng/g (on a dry matter basis). Our study has provided the pharmacokinetic parameters of a commonly used treatment for sarcoptic mange in wombats. There were no adverse side effects recorded in the wombats after applying moxidectin topically. This study replicated real-world conditions using topical application on free-living wombats. The relatively low plasma concentration suggests the drug is not accumulating in the blood stream and is excreted via scats.

Comparison of synthesized and acquired high b-value diffusion-weighted MRI for detection of prostate cancer.

BACKGROUND: High b-value diffusion-weighted images (DWI) are used for detection of clinically significant prostate cancer (csPCa). This study qualitatively and quantitatively compares synthesized DWI (sDWI) to acquired (aDWI) for detection of csPCa. METHODS: One hundred fifty-one consecutive patients who underwent prostate MRI and biopsy were included in the study. Axial DWI with b = 0, 500, 1000, and 2000 s/mm2 using a 3T clinical scanner using a 32-channel phased-array body coil were acquired. We retrospectively synthesized DWI for b = 2000 s/mm2 via extrapolation based on mono-exponential decay, using b = 0 and b = 500 s/mm2 (sDWI500) and b = 0, b = 500 s/mm2, and b = 1000 s/mm2 (sDWI1000). Differences in signal intensity between sDWI and aDWI were evaluated within different regions of interest (prostate alone, prostate plus 5 mm, 30 mm and 70 mm margin and full field of view). The maximum DWI value within each ROI was evaluated for prediction of csPCa. Classification accuracy was compared to Restriction Spectrum Imaging restriction score (RSIrs), a previously validated biomarker based on multi-exponential DWI. Discrimination of csPCa was evaluated via area under the receiver operating characteristic curve (AUC). RESULTS: Within the prostate, mean ± standard deviation of percent mean differences between sDWI and aDWI signal were -46 ± 35% for sDWI1000 and -67 ± 24% for sDWI500. AUC for aDWI, sDWI500, sDWI1000, and RSIrs within the prostate 0.62[95% confidence interval: 0.53, 0.71], 0.63[0.54, 0.72], 0.65[0.56, 0.73] and 0.78[0.71, 0.86], respectively. CONCLUSION: sDWI is qualitatively comparable to aDWI within the prostate. However, hyperintense artifacts are introduced with sDWI in the surrounding pelvic tissue that interfere with quantitative cancer detection and might mask metastases. In the prostate, RSIrs yields superior quantitative csPCa detection than sDWI or aDWI.

What Is the Carbon Footprint of Adult Spinal Deformity Surgery?

Background/Objectives: While the economic cost of adult spinal deformity (ASD) surgery has been studied extensively, its environmental impact is unknown. The aim of this study is to determine the carbon footprint (CF) associated with ASD surgery. Methods: ASD patients who underwent > four levels of corrective surgery between 2017 and 2021 were included. The open group included a posterior-only, single-stage technique, while the minimally invasive surgery (MIS) group was defined as the use of lateral interbody fusion and percutaneous posterior screw fixation. The two groups were propensity-score matched to adjust for baseline demographic, surgical, and radiographic characteristics. Data on all disposables and reusable instruments, anesthetic gas, and non-gas medications used during surgery were collected from medical records. The CF of transporting, using, and disposing of each product and the footprint of energy use in operating rooms were calculated. The CF produced was evaluated using the carbon dioxide equivalent (CO2e), which is relative to the amount of CO2 with an equivalent global warming potential. Results: Of the 175 eligible patients, 15 pairs (65 ± 9 years, 47% female) were properly matched and analyzed for all variables. The average CF generated per case was 147.7 ± 37.3 kg-CO2e, of which 54% was attributable to energy used to sterilize reusable instruments, followed by anesthetic gas released into the environment (17%) and operating room air conditioning (15%). Conclusions: The CF generated during ASD surgery should be reduced using a multidisciplinary approach, taking into account that different surgical procedures have different impacts on carbon emission sources.

Discovery of Monovalent Direct Degraders of BRD4 that Act via the Recruitment of DCAF11.

Targeted protein degradation (TPD) using the ubiquitin proteasome system (UPS) is a rapidly growing drug discovery modality to eliminate pathogenic proteins. Strategies for TPD have focused on heterobifunctional degraders that often suffer from poor drug-like properties, and molecular glues that rely on serendipitous discovery. Monovalent "direct" degraders represent an alternative approach, in which small molecules bind to a target protein and induce degradation of that protein through the recruitment of an E3 ligase complex. Using an ultra-high throughput cell-based screening platform, degraders of the bromodomain extraterminal protein BRD4 were identified and optimized to yield a lead compound, PLX-3618. In this paper, we demonstrate that PLX-3618 elicited UPS-mediated selective degradation of BRD4, resulting in potent antitumor activity in vitro and in vivo. Characterization of the degradation mechanism identified DCAF11 as the E3 ligase required for PLX-3618-mediated degradation of BRD4. Protein-protein interaction studies verified a BRD4:PLX-3618:DCAF11 ternary complex, and mutational studies provided further insights into the DCAF11-mediated degradation mechanism. Collectively, these results demonstrate the discovery and characterization of a novel small molecule that selectively degrades BRD4 through the recruitment of the E3 substrate receptor, DCAF11, and promotes potent antitumor activity in vivo.

Anterior cruciate ligament primary repair revision rates are increased in skeletally mature patients under the age of 21 compared to reconstruction, while adults (>21 years) show no significant difference: A systematic review and meta-analysis.

PURPOSE: To evaluate the impact of age as a risk factor on the revision rates of anterior cruciate ligament (ACL) primary repair (ACLPR), dynamic intraligamentary stabilization (DIS) and bridge-enhanced ACL restoration (BEAR) compared to ACL reconstruction (ACLR). METHODS: A systematic literature search was performed for comparative studies comparing outcomes for ACLPR, DIS or BEAR to ACLR. A random-effects meta-analysis was performed to assess nondifferentiated and age-differentiated (skeletally mature patients ≤21 and >21 years) ACL revision and reoperation risk, as well as results for subjective outcomes. Methodological study quality was assessed using the Risk of Bias Tool 2.0c and Methodological Index for Nonrandomized Studies tools. RESULTS: A total of 12 studies (n = 1277) were included. ACLR demonstrated a lower nonage-stratified revision risk at 2 years versus ACLPR, DIS and BEAR, but a similar revision risk at 5 years when compared to DIS. However, an age-stratified analysis demonstrated a significantly increased ACLPR revision risk as compared to ACLR in skeletally mature patients ≤21 years of age (risk ratios [RR], 6.33; 95% confidence interval [CI], 1.18-33.87, p = 0.03), while adults (>21 years) showed no significant difference between groups (RR, 1.48; 95% CI, 0.25-8.91, n.s.). Furthermore, DIS reoperation rates were significantly higher than respective ACLR rates (RR, 2.22; 95% CI, 1.35-3.65, p = 0.002), whereas BEAR (RR, 1.07; 95% CI, 0.41-2.75, n.s.) and ACLPR (RR, 0.81; 95% CI, 0.21-3.09, n.s.) showed no differences. IKDC scores were equivalent for all techniques. However, ACLPR exhibited significantly better FJS (mean difference, 11.93; 95% CI, 6.36-17.51, p < 0.0001) and Knee injury and Osteoarthritis Outcome Score Symptoms (mean difference, 3.01; 95% CI, 0.42-5.60, p = 0.02), along with a lower Tegner activity reduction. CONCLUSIONS: ACLPR in skeletally mature patients ≤21 years of age is associated with up to a six-fold risk increase for ACL revision surgery compared to ACLR; however, adults (>21 years) present no significant difference. Based on the current data, age emerges as a crucial risk factor and should be considered when deciding on the appropriate treatment option in proximal ACL tears. LEVEL OF EVIDENCE: Level III.

Perioperative Infection Prophylaxis with Vancomycin is a Significant Risk Factor for Deep Surgical Site Infection in Spine Surgery.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: The purpose of this study was to compare the efficacy of cefazolin versus vancomycin for perioperative infection prophylaxis. SUMMARY OF BACKGROUND DATA: The relative efficacy of cefazolin alternatives for perioperative infection prophylaxis is poorly understood. METHODS: This study was a single-center multi-surgeon retrospective review of all patients undergoing primary spine surgery from an institutional registry. Postoperative infection was defined by the combination of three criteria: irrigation and debridement within 3 months of the index procedure, clinical suspicion for infection, and positive intraoperative cultures. Microbiology records for all infections were reviewed to assess the infectious organism and organism susceptibilities. Univariate and multivariate analyses were performed. RESULTS: A total of 10,122 patients met inclusion criteria. The overall incidence of infection was 0.78%, with an incidence of 0.73% in patients who received cefazolin and 2.03% in patients who received vancomycin (OR 2.83, 95% CI 1.35-5.91, P-0.004). Use of IV vancomycin (OR 2.83, 95% CI 1.35-5.91, P=0.006), BMI (MD 1.56, 95% CI 0.32-2.79, P=0.014), presence of a fusion (OR 1.62, 95% CI 1.04-2.52, P=0.033), and operative time (MD 42.04, 95% CI 16.88-67.21, P=0.001) were significant risk factors in the univariate analysis. In the multivariate analysis, only non-cefazolin antibiotics (OR 2.48, 95% CI 1.18-5.22, P=0.017) and BMI (MD 1.56, 95% CI 0.32-2.79, P=0.026) remained significant independent risk factors. Neither IV antibiotic regimen nor topical vancomycin significantly impacted Gram type, organism type, or antibiotic resistance (P>0.05). The most common reason for antibiosis with vancomycin was a penicillin allergy (75.0%). CONCLUSIONS: Prophylactic antibiosis with IV vancomycin leads to a 2.5-times higher risk of infection compared to IV cefazolin in primary spine surgery. We recommend the routine use of IV cefazolin for infection prophylaxis, and caution against the elective use of alternative regimens like IV vancomycin unless clinically warranted.

Conditional Risk and Predictive Factors Associated With Late Toxicity in Patients With Prostate Cancer Treated With External Beam Radiation Therapy Alone in the Randomized Trial RTOG 0126.

PURPOSE: The objective of this study was to characterize the conditional risk of developing grade 2+ urinary or gastrointestinal (GI) toxicity for patients treated with external beam radiation therapy in Radiation Therapy Oncology Group 0126. A secondary objective was to analyze baseline patient and treatment characteristics and determine their relevance in predicting toxicity both at the time of trial enrollment and at later points of follow-up. METHODS AND MATERIALS: One thousand five hundred thirty-two patients with localized prostate cancer were enrolled between March 2002 and August 2008, of whom 1499 were eligible and included in data analysis with a median follow-up of 8.4 years (range, 0.02-13 years). Patients were treated with either 3-dimensional conformal radiation therapy or intensity-modulated radiation therapy according to institutional practice without the addition of androgen deprivation and randomized to receive either standard-dose radiation therapy of 70.2 Gy or dose-escalated radiation therapy of 79.2 Gy of radiation therapy to the prostate only with standard fractionation. Univariate and multivariate analyses were performed to determine whether initial factors were predictive of late toxicity at the time of treatment and at later time points. RESULTS: As patients proceed further from completion of radiation therapy without the development of toxicity, the subsequent risk of both grade 2+ genitourinary (GU) and GI toxicity decreases with time. At the time of enrollment, the risk of developing grade 2+ toxicity over the next 5 years was 9.57% and 17.89%, respectively. After 5 years of toxicity-free survival, the risk of developing grade 2+ GU or GI toxicity in the subsequent 5 years was 3.02% and 1.54%, respectively. Baseline treatment and patient-related factors predicted late toxicity both at trial enrollment and after 2 years of toxicity-free survivorship. Baseline urinary dysfunction and dose-escalated radiation therapy were associated with increased late GU toxicity. Acute GI toxicity and dose-escalated radiation therapy were associated with increased risk of late GI toxicity. Treatment with intensity-modulated radiation therapy was associated with reduced risk of either toxicity. CONCLUSIONS: The conditional risk of grade 2+ toxicities decreases as patients proceed further from treatment, with most toxicities occurring in the first few years after treatment completion. Baseline patient and treatment characteristics remain relevant at both enrollment and later time points.

Simultaneous Protonation and Metalation of a Porphyrin Covalent Organic Framework Enhance Photodynamic Therapy.

Covalent organic frameworks (COFs) have been explored for photodynamic therapy (PDT) of cancer, but their antitumor efficacy is limited by excited state quenching and low reactive oxygen species generation efficiency. Herein, we report a simultaneous protonation and metalation strategy to significantly enhance the PDT efficacy of a nanoscale two-dimensional imine-linked porphyrin-COF. The neutral and unmetalated porphyrin-COF (Ptp) and the protonated and metalated porphyrin-COF (Ptp-Fe) were synthesized via imine condensation between 5,10,15,20-tetrakis(4-aminophenyl)porphyrin and terephthalaldehyde in the absence and presence of ferric chloride, respectively. The presence of ferric chloride generated both doubly protonated and Fe3+-coordinated porphyrin units, which red-shifted and increased the Q-band absorption and disrupted exciton migration to prevent excited state quenching, respectively. Under light irradiation, rapid energy transfer from protonated porphyrins to Fe3+-coordinated porphyrins in Ptp-Fe enabled 1O2 and hydroxyl radical generation via type II and type I PDT processes. Ptp-Fe also catalyzed the conversion of hydrogen peroxide to hydroxy radical through a photoenhanced Fenton-like reaction under slightly acidic conditions and light illumination. As a result, Ptp-Fe-mediated PDT exhibited much higher cytotoxicity than Ptp-mediated PDT on CT26 and 4T1 cancer cells. Ptp-Fe-mediated PDT afforded potent antitumor efficacy in subcutaneous CT26 murine colon cancer and orthotopic 4T1 murine triple-negative breast tumors and prevented metastasis of 4T1 breast cancer to the lungs. This work underscores the role of fine-tuning the molecular structures of COFs in significantly enhancing their PDT efficacy.

Development and preliminary validation of the personalized cystic fibrosis medication questionnaire (PCF-MQ).

BACKGROUND: A personalized approach to assessing medication knowledge may identify opportunities for education to support self-management of cystic fibrosis (CF). This project describes the development, scoring, and preliminary validity of the Personalized CF Medication Questionnaire (PCF-MQ), designed to assess knowledge of prescribed CF medication purpose, administration, and dose and frequency. METHODS: Participants completed the PCF-MQ, the Knowledge of Disease Management (KDM-CF), and the Cystic Fibrosis-Medication Beliefs Questionnaire (CF-MBQ). Prescribed regimens were abstracted from medical records. Eligibility criteria were age 12 years and older, diagnosed with CF, and prescribed a CF medication. Statistical analyses were conducted using R software. Spearman rho was used to test correlations between measures. RESULTS: Sixty people with CF (pwCF) were enrolled; three people reported a regimen that substantially deviated from the medical record and were excluded from the analyses. The mean (SD) age was 20.2 (7.3) years, 54 % were female, and 74 % had a FEV1pp ≥70 %. The mean (SD) PCF-MQ total score was 77.8 (12.3) and knowledge scores ranged from a low of 58.3 for levalbuterol to 100 for ivacaftor. The PCF-MQ total score correlated with the KDM total score and subscales (Spearman Rho= 0.32-0.59, p < 0.05) and was not correlated with the CF-MBQ subscales (p > 0.05)). CONCLUSIONS: The PCF-MQ was correlated with another measure of general CF knowledge, but not health beliefs; because of the small sample size, this should be considered preliminary evidence of its validity. Advantages over existing CF knowledge measures include its practicality for use to help assess pwCF's knowledge about their prescribed regimen.

Return to sporting activities following long fusions to the pelvis in adult spinal deformity.

BACKGROUND CONTEXT: Returning to recreational sporting activities after adult spinal deformity (ASD) correction may significantly impact the patient's perceived quality of life. PURPOSE: This study sought to characterize participation in sporting activities before and after ASD surgery, and to identify factors associated with impaired return to sports. STUDY DESIGN: Cross-sectional survey and retrospective review of prospectively collected data. PATIENT SAMPLE: Patients who underwent posterior-only thoracolumbar ASD surgery between 2016 and 2021 with ≥1 year follow-up and ≥3 levels of fusion to the pelvis were included. OUTCOME MEASURES: Preoperative and postoperative participation in sports, timing of return to these activities, and reasons for limited sports participation postoperatively were assessed. METHODS: A survey was used to evaluate outcome measures. Differences in demographic, surgical, and perioperative variables between patients who reported improved, unchanged, or worsened activity tolerance were evaluated. RESULTS: Ninety-five patients were included (mean age: 64.3±10.1 years; BMI: 27.3±6.1 kg/m2; median levels fused: 7). The survey was completed at an average of 43.5±15.9 months after surgery. Sixty-eight (72%) patients participated in sports preoperatively. The most common sports were swimming (n=33, 34.7%), yoga (n=23, 24.2%), weightlifting (n=20, 21.1%), elliptical (n=19, 20.0%), and golf (n=11, 11.6%). Fifty-seven (83.8%) returned to at least one sport postoperatively, most commonly 6-12 months after surgery (45%). Elliptical had the highest rate of equal or improved participation (53%). Patients generally returned below their preoperative level to all other sports. Reasons for reduced sporting activities included physical limitation (51.4%), fear (20.0%), pain (17.1%), and surgeon advice (8.6%). There were no differences in the demographic, surgical, or perioperative characteristics between those who returned to sports at the same or better level compared with those who returned at a lower level. CONCLUSIONS: About 84% of patients successfully resumed sporting activities after undergoing fusion to the sacrum/pelvis for ASD. However, this return is typically at a lower level of participation than their preoperative participation, particularly in higher demand sports. Understanding trends in sporting activity may be valuable for counseling patients and setting expectations.

Replenishing IRAK-M expression in retinal pigment epithelium attenuates outer retinal degeneration.

Chronic inflammation is a constitutive component of many age-related diseases, including age-related macular degeneration (AMD). Here, we identified interleukin-1 receptor-associated kinase M (IRAK-M) as a key immunoregulator in retinal pigment epithelium (RPE) that declines during the aging process. Rare genetic variants of IRAK3, which encodes IRAK-M, were associated with an increased likelihood of developing AMD. In human samples and mouse models, IRAK-M abundance in the RPE declined with advancing age or exposure to oxidative stress and was further reduced in AMD. Irak3-knockout mice exhibited an increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors. The absence of IRAK-M led to a disruption in RPE cell homeostasis, characterized by compromised mitochondrial function, cellular senescence, and aberrant cytokine production. IRAK-M overexpression protected RPE cells against oxidative or immune stressors. Subretinal delivery of adeno-associated virus (AAV)-expressing human IRAK3 rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration in Irak3-knockout mice. Our data show that replenishment of IRAK-M in the RPE may redress dysregulated pro-inflammatory processes in AMD, suggesting a potential treatment for retinal degeneration.

Comparative analysis of retroviral Gag-host cell interactions: focus on the nuclear interactome.

Retroviruses exploit host proteins to assemble and release virions from infected cells. Previously, most studies focused on interacting partners of retroviral Gag proteins that localize to the cytoplasm or plasma membrane. Given that several full-length Gag proteins have been found in the nucleus, identifying the Gag-nuclear interactome has high potential for novel findings involving previously unknown host processes. Here we systematically compared nuclear factors identified in published HIV-1 proteomic studies and performed our own mass spectrometry analysis using affinity-tagged HIV-1 and RSV Gag proteins mixed with nuclear extracts. We identified 57 nuclear proteins in common between HIV-1 and RSV Gag, and a set of nuclear proteins present in our analysis and ≥ 1 of the published HIV-1 datasets. Many proteins were associated with nuclear processes which could have functional consequences for viral replication, including transcription initiation/elongation/termination, RNA processing, splicing, and chromatin remodeling. Examples include facilitating chromatin remodeling to expose the integrated provirus, promoting expression of viral genes, repressing the transcription of antagonistic cellular genes, preventing splicing of viral RNA, altering splicing of cellular RNAs, or influencing viral or host RNA folding or RNA nuclear export. Many proteins in our pulldowns common to RSV and HIV-1 Gag are critical for transcription, including PolR2B, the second largest subunit of RNA polymerase II (RNAPII), and LEO1, a PAF1C complex member that regulates transcriptional elongation, supporting the possibility that Gag influences the host transcription profile to aid the virus. Through the interaction of RSV and HIV-1 Gag with splicing-related proteins CBLL1, HNRNPH3, TRA2B, PTBP1 and U2AF1, we speculate that Gag could enhance unspliced viral RNA production for translation and packaging. To validate one putative hit, we demonstrated an interaction of RSV Gag with Mediator complex member Med26, required for RNA polymerase II-mediated transcription. Although 57 host proteins interacted with both Gag proteins, unique host proteins belonging to each interactome dataset were identified. These results provide a strong premise for future functional studies to investigate roles for these nuclear host factors that may have shared functions in the biology of both retroviruses, as well as functions specific to RSV and HIV-1, given their distinctive hosts and molecular pathology.

Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer.

Non-small-cell lung cancer (NSCLC) with concurrent mutations in KRAS and the tumour suppressor LKB1 (KL NSCLC) is refractory to most therapies and has one of the worst predicted outcomes. Here we describe a KL-induced metabolic vulnerability associated with serine-glycine-one-carbon (SGOC) metabolism. Using RNA-seq and metabolomics data from human NSCLC, we uncovered that LKB1 loss enhanced SGOC metabolism via serine hydroxymethyltransferase (SHMT). LKB1 loss, in collaboration with KEAP1 loss, activated SHMT through inactivation of the salt-induced kinase (SIK)-NRF2 axis and satisfied the increased demand for one-carbon units necessary for antioxidant defence. Chemical and genetic SHMT suppression increased cellular sensitivity to oxidative stress and cell death. Further, the SHMT inhibitor enhanced the in vivo therapeutic efficacy of paclitaxel (first-line NSCLC therapy inducing oxidative stress) in KEAP1-mutant KL tumours. The data reveal how this highly aggressive molecular subtype of NSCLC fulfills their metabolic requirements and provides insight into therapeutic strategies.

Electroconvulsive therapy in N-methyl-d-aspartate receptor encephalitis: A retrospective cohort and scoping review of literature.

Neuropsychiatric symptoms in N-methyl-d-aspartate receptor encephalitis (NMDARE) have led some to pursue empiric trials of electroconvulsive therapy (ECT). A scoping review identified 39 patients diagnosed with NMDARE undergoing ECT. Separately, a retrospective cohort was reviewed to characterize 21 patients. Clinical improvement was attributed to ECT in 49% of patients in the scoping review and 19% of patients in the retrospective cohort; timing of immunotherapies was a confounding factor. Worsening of clinical course following ECT was reported in 28% of patients in the scoping review and 38% of patient in the retrospective review. There is currently insufficient data supporting a beneficial effect of ECT in NMDARE.

Assessing the quality of artificial intelligence-generated patient counseling for rhinosinusitis.

KEY POINTS: GPT-4 generated moderate quality information in response to questions regarding sinusitis and surgery. GPT-4 generated significantly higher quality responses to questions regarding treatment of sinusitis. Future studies exploring quality of GPT responses should seek to limit bias and use validated instruments.

Discovery of Monovalent Direct Degraders of BRD4 That Act Via the Recruitment of DCAF11.

Targeted protein degradation (TPD) using the ubiquitin proteasome system (UPS) is a rapidly growing drug discovery modality to eliminate pathogenic proteins. Strategies for TPD have focused on heterobifunctional degraders that often suffer from poor drug-like properties, and molecular glues that rely on serendipitous discovery. Monovalent "direct" degraders represent an alternative approach, in which small molecules bind to a target protein and induce degradation of that protein through the recruitment of an E3 ligase complex. Using an ultra-high throughput cell-based screening platform, degraders of the bromodomain extra-terminal (BET) protein BRD4 were identified and optimized to yield a lead compound, PLX-3618. In this paper, we demonstrate that PLX-3618 elicited UPS-mediated selective degradation of BRD4, resulting in potent anti-tumor activity in vitro and in vivo. Characterization of the degradation mechanism identified DCAF11 as the E3 ligase required for PLX-3618-mediated degradation of BRD4. Protein-protein interaction studies verified a BRD4:PLX-3618:DCAF11 ternary complex, and mutational studies provided further insights into the DCAF11-mediated degradation mechanism. Collectively, these results demonstrate the discovery and characterization of a novel small molecule that selectively degrades BRD4 through the recruitment of the E3 substrate receptor, DCAF11, and promotes potent anti-tumor activity in vivo.

Sex Differences in Odds of Brain Metastasis and Outcomes by Brain Metastasis Status after Advanced Melanoma Diagnosis.

Sex differences in cancer are well-established. However, less is known about sex differences in diagnosis of brain metastasis and outcomes among patients with advanced melanoma. Using a United States nationwide electronic health record-derived de-identified database, we evaluated patients diagnosed with advanced melanoma from 1 January 2011-30 July 2022 who received an oncologist-defined rule-based first line of therapy (n = 7969, 33% female according to EHR, 35% w/documentation of brain metastases). The odds of documented brain metastasis diagnosis were calculated using multivariable logistic regression adjusted for age, practice type, diagnosis period (pre/post-2017), ECOG performance status, anatomic site of melanoma, group stage, documentation of non-brain metastases prior to first-line of treatment, and BRAF positive status. Real-world overall survival (rwOS) and progression-free survival (rwPFS) starting from first-line initiation were assessed by sex, accounting for brain metastasis diagnosis as a time-varying covariate using the Cox proportional hazards model, with the same adjustments as the logistic model, excluding group stage, while also adjusting for race, socioeconomic status, and insurance status. Adjusted analysis revealed males with advanced melanoma were 22% more likely to receive a brain metastasis diagnosis compared to females (adjusted odds ratio [aOR]: 1.22, 95% confidence interval [CI]: 1.09, 1.36). Males with brain metastases had worse rwOS (aHR: 1.15, 95% CI: 1.04, 1.28) but not worse rwPFS (adjusted hazard ratio [aHR]: 1.04, 95% CI: 0.95, 1.14) following first-line treatment initiation. Among patients with advanced melanoma who were not diagnosed with brain metastases, survival was not different by sex (rwOS aHR: 1.06 [95% CI: 0.97, 1.16], rwPFS aHR: 1.02 [95% CI: 0.94, 1.1]). This study showed that males had greater odds of brain metastasis and, among those with brain metastasis, poorer rwOS compared to females, while there were no sex differences in clinical outcomes for those with advanced melanoma without brain metastasis.