Treatment resistance to melanoma therapeutics on a single cell level.

Therapy targeting the BRAF-MEK cascade created a treatment revolution for patients with BRAF mutant advanced melanoma. Unfortunately, 80% patients treated will progress by 5 years follow-up. Thus, it is imperative we study mechanisms of melanoma progression and therapeutic resistance. We created a scRNA (single cell RNA) atlas of 128,230 cells from 18 tumors across the treatment spectrum, discovering melanoma cells clustered strongly by transcriptome profiles of patients of origins. Our cell-level investigation revealed gains of 1q and 7q as likely early clonal events in metastatic melanomas. By comparing patient tumors and their derivative cell lines, we observed that PD1 responsive tumor fraction disappears when cells are propagated in vitro. We further established three anti-BRAF-MEK treatment resistant cell lines using three BRAF mutant tumors. ALDOA and PGK1 were found to be highly expressed in treatment resistant cell populations and metformin was effective in targeting the resistant cells. Our study suggests that the investigation of patient tumors and their derivative lines is essential for understanding disease progression, treatment response and resistance.

Effect of machine learning models on clinician prediction of postoperative complications: the Perioperative ORACLE randomised clinical trial.

BACKGROUND: Anaesthesiologists might be able to mitigate risk if they know which patients are at greatest risk for postoperative complications. This trial examined the impact of machine learning models on clinician risk assessment. METHODS: This single-centre, prospective, randomised clinical trial enrolled surgical patients aged ≥18 yr. Anaesthesiologists and nurse anaesthetists providing remote telemedicine support reviewed electronic health records with (assisted group) or without (unassisted group) reviewing machine learning predictions. Clinicians predicted the likelihood of postoperative 30-day all-cause mortality and postoperative acute kidney injury (AKI) within 7 days. The primary outcome was area under the receiver operating characteristic curve (AUROC) for clinician predictions of mortality and AKI, comparing AUROCs between assisted and unassisted assessments. RESULTS: We analysed 5071 patients (mean [range] age: 58 [18-100] yr; 52% female) assessed by 89 clinicians. Of these, 98 (2.2%) patients died within 30 days of surgery and 450 (11.1%) patients sustained AKI. Clinician predictions agreed with the models more strongly in the assisted vs unassisted group (weighted kappa 0.75 vs 0.62 for death, mean difference: 0.13 [95% CI 0.10-0.17]; and 0.79 vs 0.54 for AKI, mean difference: 0.25 [95% CI 0.21-0.29]). Clinical prediction of death was similar between the assisted (AUROC 0.793) and unassisted (AUROC 0.780) groups (mean difference: 0.013 [95% CI -0.070 to 0.097]; P=0.76). Prediction of AKI had an AUROC of 0.734 in the assisted group vs 0.688 in the unassisted group (difference 0.046 [95% CI -0.003 to 0.091]; P=0.06). CONCLUSIONS: Clinician performance was not improved by machine learning assistance. Further work is needed to clarify the role of machine learning in real-time perioperative risk stratification. CLINICAL TRIAL REGISTRATION: NCT05042804.

Does Total Turbinectomy Always Lead to Empty Nose Syndrome? A Computational Virtual Surgery Study.

INTRODUCTION: Computational fluid dynamic (CFD) modeling has previously indicated that distorted nasal airflow patterns may contribute to empty nose syndrome (ENS); however, no data show that aggressive turbinate surgery always leads to ENS. We aim to use virtual surgery planning (VSP) to investigate how a total inferior turbinectomy affects airflow parameters compared with ENS patients. METHODS: We retrospectively recruited six nasal obstruction patients who underwent turbinate reduction surgery. We virtually performed total inferior turbinectomy on these patients to compare CFD modeling results to patients' actual surgical outcomes and to that of a previously collected ENS patient cohort (n = 27). RESULTS: Patients' actual surgery outcomes were excellent, with Nasal-Obstruction Symptom Evaluation (NOSE) score (pre: 72.5 ± 13.2 vs post-surgery: 10.8 ± 9.8, p < 0.001) and unilateral visual analog scale (VAS) scores of nasal obstruction (pre: 6 ± 2.56 vs post-surgery: 1.2 ± 1, p < 0.001) improved and was statistically significant. The virtual turbinectomy does not create the same distorted nasal airflow patterns as seen in ENS patients, with no statistically significant difference in nasal resistance as compared with post-actual surgery (virtual turbinectomy: 0.10 ± 0.03 Pa/mL*s; actual surgery: 0.12 ± 0.04 Pa/mL*s; ENS: 0.11 ± 0.04, p > 0.05) nor in regional wall shear force distribution, an important indicator of air/mucosa stimulation (inferior turbinate WSF%: virtual 47.3% ± 11.3% vs actual 51.5% ± 15.1%, p > 0.05); however, both are statistically significant higher than that of ENS patients (WSF: 32.2% ± 12.5%, p < 0.001), despite ENS cohort having wider inferior airway cross-sectional area (CSA) than actual surgeries. CONCLUSION: Empty nose syndrome is likely a multifactorial disease process that cannot be solely attributed to aggressive turbinate reduction surgery. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Tivozanib plus nivolumab versus tivozanib monotherapy in patients with renal cell carcinoma following an immune checkpoint inhibitor: results of the phase 3 TiNivo-2 Study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors are cornerstones of first-line treatment for advanced renal cell carcinoma; however, optimal treatment sequencing after progression is unknown. This study aimed to assess clinical outcomes of tivozanib-nivolumab versus tivozanib monotherapy in patients with metastatic renal cell carcinoma who have progressed following one or two lines of therapy in the post-ICI setting. METHODS: TiNivo-2 is a multicentre, randomised, open-label, phase 3 trial at 190 sites across 16 countries, in Australia, Europe, North America, and South America. Patients with advanced renal cell carcinoma and progression during or after one to two previous lines of therapy (including one ICI) were randomised 1:1 to tivozanib (0·89 mg per day, orally) plus nivolumab (480 mg every 4 weeks, intravenously) or tivozanib (1·34 mg per day, orally). Randomisation was stratified by immediate previous therapy (ICI or non-ICI) and International Metastatic Renal Cell Carcinoma Database Consortium risk category. The primary endpoint was progression-free survival (PFS), defined as the time from randomisation to first documentation of objective progressive disease according to RECIST 1·1 or death from any cause, whichever came first, by independent radiology review. Efficacy was evaluated in the intention-to-treat population, and safety was assessed in patients who received one or more doses of the study drug. This trial was registered on ClinicalTrials.gov (NCT04987203) and is active and not recruiting. FINDINGS: From Nov 4, 2021, to June 16, 2023, 343 patients were randomly assigned to tivozanib-nivolumab (n=171) or tivozanib monotherapy (n=172). Median follow-up was 12·0 months. Median PFS was 5·7 months (95% CI 4·0-7·4) with tivozanib-nivolumab and 7·4 months (5·6-9·2) with tivozanib monotherapy (hazard ratio 1·10, 95% CI 0·84-1·43; p=0·49). Among those with an ICI as their immediate previous therapy (n=244), median PFS was 7·4 months (95% CI 5·6-9·6) with tivozanib-nivolumab and 9·2 months (7·4-10·0) with tivozanib monotherapy. With non-ICIs as the most recent therapy, lower median PFS was observed, with no difference between groups (tivozanib-nivolumab 3·7 months [95% CI 2·7-5·4] and with tivozanib monotherapy 3·7 months [1·9-7·2]). Serious adverse events occurred in 54 (32%) of 168 patients receiving tivozanib-nivolumab and 64 (37%) of 171 patients receiving tivozanib monotherapy. One (<1%) treatment-related death occurred (tivozanib group). INTERPRETATION: These data further support that ICI rechallenge should be discouraged in patients with advanced renal cell carcinoma. Furthermore, these data suggest that tivozanib monotherapy has efficacy in the post-ICI setting. FUNDING: Aveo Pharmaceuticals.

Characterization of the Posterior Femoral Cutaneous Nerve and Its Clinical Application for Autologous Breast Reconstruction.

INTRODUCTION: Autologous breast reconstruction (ABR) uses a harvested tissue flap from the abdomen, posterior thigh, or buttocks to rebuild the breast postmastectomy. Identification of nerves for use in autologous sensate breast reconstruction flaps is an important surgical consideration as loss of breast sensation is a common risk of ABR. The posterior femoral cutaneous nerve (PFCN) and its branches supply sensory innervation to skin of the posterior thigh, leg, perineum, and buttocks, creating a feasible candidate for sensate profunda artery perforator (PAP) flaps for reestablishing breast sensation through ABR. This study characterized PFCN perforating branches located within the PAP flap region as compared to an anatomical landmark intersection (ALI). Twenty-three posterior thigh regions from 15 formalin-embalmed donors were dissected to the level of deep fascia to identify PFCN branches. PFCN branch diameter (mean, 1.34 ± 0.35 mm) and length (mean, 8.82 ± 5.78 mm) piercing the deep fascia were measured; branches were retro-dissected proximally to the PFCN trunk and the distance recorded (mean, 92.55 ± 38.00 mm). The distance to branch emergence from ALI (mean, 113.55 ± 19.80 mm) and from the midline of the posterior thigh (mean, 18.90 ± 11.17 mm) were calculated. Two-Tailed T-tests comparing the left and right limb of 7 donors determined bilateral, statistically significant difference between the length of branch emergence back to the main trunk of PFCN (P = .00). These findings illustrate the presence of adequate yet variable PFCN branches within the PAP flap region in regards to diameter, length, and location for use in sensate ABR.

Oxymetazoline as a predictor of turbinate reduction surgery outcomes: Objective support from a prospective, single-blinded, computational fluid dynamics study.

BACKGROUND: A patient's subjective response to topical nasal decongestant is often used to screen for turbinate reduction surgery suitability. However, this anecdotal strategy has not been objectively and quantitatively evaluated. METHODS: Prospective, longitudinal, and single-blinded cohort study employing computational fluid dynamic modeling based on computed tomography scans at baseline, 30 min postoxymetazoline, and 2 months postsurgery on 11 patients with chronic turbinate hypertrophy. RESULTS: Nasal obstruction symptom evaluation (NOSE) and visual analogue scale (VAS) obstruction scores significantly improved from baseline to postoxymetazoline and again to postsurgery (NOSE: 71.82 ± 14.19 to 42.27 ± 25.26 to 22.27 ± 21.04; VAS: 6.09 ± 2.41 to 4.14 ± 2.20 to 2.08 ± 1.56; each interaction p < 0.05), with significant correlation between the latter two states (r∼0.37-0.69, p < 0.05). Oxymetazoline had a broader anatomical impact throughout inferior and middle turbinates than surgery (many p < 0.05); however, the improvement in regional airflow is similar (most p > 0.05) and predominantly surrounding the inferior turbinate. Strong postoxymetazoline to postsurgery correlations were observed in decreased nasal resistance (r = 0.79, p < 0.05), increased regional airflow rates (r = -0.47 to -0.55, p < 0.05) and regional air/mucosa shear force and heat flux (r = 0.43 to 0.58, p < 0.05); however, only increasing peak heat flux significantly correlated to symptom score improvement (NOSE: r = 0.48, p < 0.05). CONCLUSION: We present the first objective evidence that the "topical decongestant test" can help predict turbinate reduction surgery outcomes. The predictive effect is driven by similar improvementin regional airflow that leading to improved air/mucosa stimulations (peak heat flux) rather than through reduced nasal resistance.

Structural basis for allosteric regulation of human phosphofructokinase-1.

Phosphofructokinase-1 (PFK1) catalyzes the rate-limiting step of glycolysis, committing glucose to conversion into cellular energy. PFK1 is highly regulated to respond to the changing energy needs of the cell. In bacteria, the structural basis of PFK1 regulation is a textbook example of allostery; molecular signals of low and high cellular energy promote transition between an active R-state and inactive T-state conformation, respectively. Little is known, however, about the structural basis for regulation of eukaryotic PFK1. Here, we determine structures of the human liver isoform of PFK1 (PFKL) in the R- and T-state by cryoEM, providing insight into eukaryotic PFK1 allosteric regulatory mechanisms. The T-state structure reveals conformational differences between the bacterial and eukaryotic enzyme, the mechanisms of allosteric inhibition by ATP binding at multiple sites, and an autoinhibitory role of the C-terminus in stabilizing the T-state. We also determine structures of PFKL filaments that define the mechanism of higher-order assembly and demonstrate that these structures are necessary for higher-order assembly of PFKL in cells.

Next-generation sequencing has diagnostic utility in challenging small/flat urothelial lesions.

Small/flat urothelial lesions are challenging and currently available ancillary immunohistochemistry testing often cannot reliably distinguish between reactive lesions and urothelial carcinoma (UCa). UCa has a characteristic molecular profile, but small/flat urothelial lesions are typically considered too small to perform next generation sequencing (NGS). Herein, we present our institution's experience with utilizing comprehensive DNA-based NGS to evaluate small/flat urothelial lesions (n = 13 cases). NGS was ordered on 7/13 small/flat urothelial lesions initially diagnosed as urothelial atypia, ordered by the pathologist to aid in further diagnosis; the remaining 6/13 cases were diagnosed as urothelial carcinoma in situ (uCIS), ordered by a treating oncologist. The test was considered as adding value if it yielded pathogenic or likely pathogenic alterations previously associated with urothelial carcinoma in the literature. Macroscopic dissection was determined necessary in all cases and obtained either by scraping (7), punch biopsy (5) or scooping (1) of paraffin tissue blocks. In 4/13 cases, tumor content was considered low (<25%); in 2/13 cases, DNA quantity yield was considered below optimal (<250 ng); all cases met required DNA quantity for testing (>50 ng). Mean target coverage ranged: 498 to 985 (optimal >500 reads). NGS testing identified mutations compatible with urothelial carcinoma in all 7 cases initially diagnosed as atypical; and in one case, the tumor recurred as a lung metastasis. All 6 uCIS had NGS testing results concordant with UCa. In conclusion, despite small sample quantity with low tumor content and DNA concentration yield, NGS testing with appropriate methodology can be considered in the setting of small/flat urothelial lesions to aid in diagnosis or per oncologist request and yield interpretable results.

Re-Envisioning Electronic Health Records to Optimize Patient-Centered Cancer Care, Quality, Surveillance, and Research.

Electronic health records (EHRs) are a significant advancement over paper records. However, the full potential of EHRs for improving care quality, patient outcomes, surveillance, and research in cancer care is yet to be realized. The organic evolution of EHRs has resulted in a number of unanticipated consequences including increased time spent by clinicians interfacing with the EHR for daily workflows. Patient access to clinicians and their records has been an important advancement in patient-centered care; however, this has brought to light additional gaps and challenges in EHRs meeting these needs. A significant challenge for EHR design and physician workflows is how best to meet the complex goals and priorities of various stakeholders including providers, researchers, patients, health systems, payors, and regulatory agencies. The National Cancer Policy Forum convened a 2022 workshop, "Innovations in Electronic Health Records for Oncology Care, Research and Surveillance," to address these challenges and to facilitate collaboration across all user groups with the goal of re-envisioning EHRs that will better support shared goals of improving patient outcomes and advancing cancer care and research without overburdening clinicians with administrative tasks. Here, we summarize the current EHR ecosystem as discussed at the workshop and highlight opportunities to improve EHR contributions to oncology evidence and care.

The Impact of Social Deprivation on Anterior Urethral Stricture Recurrence After Urethroplasty - A Trauma and Urologic Reconstructive Network of Surgeons (TURNS) Analysis.

INTRODUCTION AND OBJECTIVES: Several factors influence recurrence after urethral stricture repair. The impact of socioeconomic factors on stricture recurrence after urethroplasty is poorly understood. This study aims to assess the impact that social deprivation, an area-level measure of disadvantage, has on urethral stricture recurrence after urethroplasty. METHODS: We performed a retrospective review of patients undergoing urethral reconstruction by surgeons participating in a collaborative research group. Home zip code was used to calculate Social Deprivation Indices (SDI; 0-100), which quantifies the level of disadvantage across several sociodemographic domains collected in the American Community Survey. Patients without zip code data were excluded from the analysis. The Cox Proportional Hazards model was used to study the association between SDI and the hazard of functional recurrence, adjusting for stricture characteristics as well as age and body mass index. RESULTS: Median age was 46.0 years with a median follow up of 367 days for the 1452 men included in the study. Patients in the fourth SDI quartile (worst social deprivation) were more likely to be active smokers with traumatic and infectious strictures compared to the first SDI quartile. Patients in the fourth SDI quartile had 1.64 times the unadjusted hazard of functional stricture recurrence vs patients in the first SDI quartile (95% CI 1.04-2.59). Compared to anastomotic ± excision, substitution only repair had 1.90 times the unadjusted hazard of recurrence. The adjusted hazard of recurrence was 1.08 per 10-point increase in SDI (95% CI 1.01-1.15, P = .027). CONCLUSIONS: Patient social deprivation identifies those at higher risk for functional recurrence after anterior urethral stricture repair, offering an opportunity for preoperative counseling and postoperative surveillance. Addressing these social determinants of health can potentially improve outcomes in reconstructive surgery.

Clinical Utility of Plasma Microbial Cell-Free DNA Sequencing Among Immunocompromised Patients With Pneumonia.

Background: Plasma microbial cell-free DNA (mcfDNA) sequencing can establish the etiology of multiple infectious syndromes by identifying microbial DNA in plasma. However, data are needed to define the clinical scenarios where this tool offers the highest clinical benefit. Methods: We conducted a prospective multicenter observational study that evaluated the impact of plasma mcfDNA sequencing compared with usual care testing among adults with hematologic malignancies. This is a secondary analysis of an expanded cohort that evaluated the clinical utility of plasma mcfDNA sequencing across prespecified and adjudicated outcomes. We examined the percentage of participants for whom plasma mcfDNA sequencing identified a probable cause of pneumonia or clinically relevant nonpneumonia infection. We then assessed potential changes in antimicrobial therapy based on plasma mcfDNA sequencing results and the potential for early mcfDNA testing to avoid bronchoscopy and its associated adverse events. Results: Of 223 participants, at least 1 microbial detection by plasma mcfDNA sequencing was adjudicated as a probable cause of pneumonia in 57 (25.6%) and a clinically relevant nonpneumonia infection in 88 (39.5%). A probable cause of pneumonia was exclusively identified by plasma mcfDNA sequencing in 23 (10.3%) participants. Antimicrobial therapy would have changed for 41 (18.4%) participants had plasma mcfDNA results been available in real time. Among the 57 participants with a probable cause of pneumonia identified by plasma mcfDNA sequencing, bronchoscopy identified no additional probable cause of pneumonia in 52 (91.2%). Conclusions: Plasma mcfDNA sequencing could improve management of both pneumonia and other concurrent infections in immunocompromised patients with suspected pneumonia.

Ventilator strategies in congenital diaphragmatic hernia.

This review focuses on contemporary mechanical ventilator practices used in the initial management of neonates born with congenital diaphragmatic hernia (CDH). Both conventional and non-conventional ventilation modes in CDH are reviewed. Special emphasis is placed on the rationale for gentle ventilation and the current evidence-based clinical practice guidelines that are recommended for supporting these fragile infants. The interplay between CDH lung hypoplasia and other key cardiopulmonary elements of the disease, namely a reduced pulmonary vascular bed, abnormal pulmonary vascular remodeling, and left ventricular hypoplasia, are discussed. Finally, we provide insights into future avenues for mechanical ventilator research in CDH.

Femoral versus radial access for middle meningeal artery embolization for chronic subdural hematomas: multicenter propensity score matched study.

BACKGROUND: With transradial access (TRA) being more progressively used in neuroendovascular procedures, we compared TRA with transfemoral access (TFA) in middle meningeal artery embolization (MMAE) for chronic subdural hematoma (cSDH). METHODS: Consecutive patients undergoing MMAE for cSDH at 14 North American centers (2018-23) were included. TRA and TFA groups were compared using propensity score matching (PSM) controlling for: age, sex, concurrent surgery, previous surgery, hematoma thickness and side, midline shift, and pretreatment antithrombotics. The primary outcome was access site and overall complications, and procedure duration; secondary endpoints were surgical rescue, radiographic improvement, and technical success and length of stay. RESULTS: 872 patients (median age 73 years, 72.9% men) underwent 1070 MMAE procedures (54% TFA vs 46% TRA). Access site hematoma occurred in three TFA cases (0.5%; none required operative intervention) versus 0% in TRA (P=0.23), and radial-to-femoral conversion occurred in 1% of TRA cases. TRA was more used in right sided cSDH (58.4% vs 44.8%; P<0.001). Particle embolics were significantly higher in TFA while Onyx was higher in TRA (P<0.001). Following PSM, 150 matched pairs were generated. Particles were more utilized in the TFA group (53% vs 29.7%) and Onyx was more utilized in the TRA group (56.1% vs 31.5%) (P=0.001). Procedural duration was longer in the TRA group (median 68.5 min (IQR 43.1-95) vs 59 (42-84); P=0.038), and radiographic success was higher in the TFA group (87.3% vs 77.4%; P=0.036). No differences were noted in surgical rescue (8.4% vs 10.1%, P=0.35) or technical failures (2.4% vs 2%; P=0.67) between TFA and TRA. Sensitivity analysis in the standalone MMAE retained all associations but differences in procedural duration. CONCLUSIONS: In this study, TRA offered comparable outcomes to TFA in MMAE for cSDH in terms of access related and overall complications, technical feasibility, and functional outcomes. Procedural duration was slightly longer in the TRA group, and radiographic success was higher in the TFA group, with no differences in surgical rescue rates.

Association of tumor growth rate with overall survival and recurrence among patients with laryngeal squamous cell carcinoma.

BACKGROUND: Delay in time to treatment initiation (TTI) is associated with worsened survival outcomes in laryngeal squamous cell carcinoma (LSCC). It is unclear whether this is due to tumor growth or an increased risk of metastatic disease. METHODS: This retrospective cohort study at one academic center included patients with LSCC who underwent radiotherapy/chemoradiotherapy between 2005 and 2017. We examined the association between tumor growth rate (TGR) and survival outcomes. RESULTS: Among 105 patients (mean age, 63.8 ± 11.1 years; 72% male), the threshold between "slow-growing" and "fast-growing" tumors was >0.036 mL/day (survival) and >0.082 mL/day (recurrence). Faster growth was associated with worse overall survival (OS) (hazard ratio, 1.97; 95% confidence interval [CI], 0.94-4.13) and increased recurrence (odds ratio, 9.10; 95% CI, 2.40-34.4). CONCLUSIONS: TGR >0.036 mL/day during TTI was associated with decreased OS, and >0.082 mL/day was associated with increased recurrence. Tumor measurement in patients experiencing delay may identify those who could benefit from escalated therapy.

Decompressive craniectomy in symptomatic intracerebral hemorrhage after ischemic stroke: a multicenter retrospective cohort study.

OBJECTIVE: Symptomatic intracerebral hemorrhage (sICH) after stroke is a devastating neurological complication. Current guidelines support a "possible benefit" of decompressive craniectomy (DC) for large supratentorial sICH with significant mass effect. METHODS: The authors conducted a retrospective study of 8 comprehensive stroke centers. They included all patients who sustained an sICH after acute ischemic stroke (AIS), as defined by the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST), from January 2016 to December 2020. They compared patients who underwent DC to those who were treated with standard medical treatment to measure functional outcome at 90 days, primarily as defined by the modified Rankin Scale (mRS) and secondarily by the Glasgow Outcome Scale-Extended (GOS-E). RESULTS: Eighty-five patients were identified, 26 of whom (30.5%) underwent DC. Patients who underwent DC were younger (58 years [DC] vs 76 years [no DC], p < 0.001). No patient with a previous history of cancer underwent DC (n = 14, p = 0.004). Twenty-five patients (96.2%) in the DC group underwent thrombectomy versus 54 (91.5%) in the non-DC group (p = 0.443). Patients who underwent DC had a longer ICU stay (median [IQR] 240 [38-408] hours vs 24 [5-96] hours in non-DC patients, p = 0.002). At 90 days, 3 patients (4.1%) had obtained an mRS score of 0-2 and 10 patients (11.7%) an mRS score of 0-3. Patients who had improved functional outcome were younger (mRS score, OR 1.06, 95% CI 1.01-1.10, p = 0.012). Patients with a history of cancer had worse 90-day mRS scores (OR 8.49, 95% CI 1.54-159, p = 0.046). The rate of in-hospital mortality or discharge to hospice was significantly higher in the non-DC cohort (10 [38.5%] patients in the DC cohort vs 38 [64.4%] in the non-DC cohort, p = 0.026). Ninety days later, patients who underwent DC were more likely to have improved outcome (mRS mean rank 30.0 vs 40.0, p = 0.027). In multivariable analysis, history of cancer (OR 12.2, 95% CI 1.26-118, p = 0.031) and older age (OR 1.07, 95% CI 1.02-1.13, p = 0.011) increased the odds of worse mRS outcomes while DC did not (OR 1.34, 95% CI 0.357-5.03, p = 0.665). CONCLUSIONS: DC after sICH did not improve functional outcome at 90 days according to multivariable analysis, although younger age and absence of previous cancer history were associated with improved outcomes.

Optimizing word embeddings for small dataset: a case study on patient portal messages from breast cancer patients.

Patient portal messages often relate to specific clinical phenomena (e.g., patients undergoing treatment for breast cancer) and, as a result, have received increasing attention in biomedical research. These messages require natural language processing and, while word embedding models, such as word2vec, have the potential to extract meaningful signals from text, they are not readily applicable to patient portal messages. This is because embedding models typically require millions of training samples to sufficiently represent semantics, while the volume of patient portal messages associated with a particular clinical phenomenon is often relatively small. We introduce a novel adaptation of the word2vec model, PK-word2vec (where PK stands for prior knowledge), for small-scale messages. PK-word2vec incorporates the most similar terms for medical words (including problems, treatments, and tests) and non-medical words from two pre-trained embedding models as prior knowledge to improve the training process. We applied PK-word2vec in a case study of patient portal messages in the Vanderbilt University Medical Center electric health record system sent by patients diagnosed with breast cancer from December 2004 to November 2017. We evaluated the model through a set of 1000 tasks, each of which compared the relevance of a given word to a group of the five most similar words generated by PK-word2vec and a group of the five most similar words generated by the standard word2vec model. We recruited 200 Amazon Mechanical Turk (AMT) workers and 7 medical students to perform the tasks. The dataset was composed of 1389 patient records and included 137,554 messages with 10,683 unique words. Prior knowledge was available for 7981 non-medical and 1116 medical words. In over 90% of the tasks, both reviewers indicated PK-word2vec generated more similar words than standard word2vec (p = 0.01).The difference in the evaluation by AMT workers versus medical students was negligible for all comparisons of tasks' choices between the two groups of reviewers ( p = 0.774 under a paired t-test). PK-word2vec can effectively learn word representations from a small message corpus, marking a significant advancement in processing patient portal messages.

Lasting Effects of Surgically Used Topical Vasodilators on DIEP Artery Vascular Function.

BACKGROUND: Surgeons routinely apply papaverine, lidocaine, or verapamil to produce acute vasodilation and prevent vasospasms during microvascular surgeries. There is evidence that topical vasodilators may induce postoperative endothelial and smooth muscle dysfunction, which would present after the acute vasodilatory effects of the topical drugs wear off. Therefore, the purpose of the current study was to evaluate the lasting effects of papaverine, lidocaine, and verapamil on human deep inferior epigastric perforator artery vasodilatory function after the acute effects of the topical drugs had worn off. METHODS: Deep inferior epigastric arterial samples were obtained from 12 patients during surgery. Each artery was dissected into four rings which where incubated for 1 minute in either physiological saline solution (control), papaverine (30 mg/mL), lidocaine (20 mg/mL), or verapamil (2.5 mg/mL), followed by a 2-hour washout. Endothelial-dependent and -independent vasorelaxation were then assessed by the isometric tension responses to acetylcholine or sodium nitroprusside, respectively. RESULTS: Peak acetylcholine-evoked vasorelaxation (mean ± standard deviation) was not different between control (62 ± 23%) and lidocaine (57 ± 18%, p = 0.881), but was reduced (all p < 0.002) in papaverine (22 ± 27%) and verapamil (22 ± 20%). Peak sodium nitroprusside-evoked vasorelaxation was not different (all p > 0.692) among control (132 ± 35%), lidocaine (121 ± 22%), and verapamil (127 ± 22%), but was less in papaverine (104 ± 41%; p = 0.045) than control. CONCLUSION: Surgically used doses of papaverine and verapamil, but not lidocaine, have lasting negative effects on arterial vasodilatory function despite the acute effects of the drugs having worn off. These findings, in conjunction with the spasmolytic properties of each drug, may help guide the selection of an optimal topical vasodilator for use during microvascular surgeries.

Cost-Effectiveness of Plasma Microbial Cell-Free DNA Sequencing When Added to Usual Care Diagnostic Testing for Immunocompromised Host Pneumonia.

INTRODUCTION: Immunocompromised host pneumonia (ICHP) is an important cause of morbidity and mortality, yet usual care (UC) diagnostic tests often fail to identify an infectious etiology. A US-based, multicenter study (PICKUP) among ICHP patients with hematological malignancies, including hematological cell transplant recipients, showed that plasma microbial cell-free DNA (mcfDNA) sequencing provided significant additive diagnostic value. AIM: The objective of this study was to perform a cost-effectiveness analysis (CEA) of adding mcfDNA sequencing to UC diagnostic testing for hospitalized ICHP patients. METHODS: A semi-Markov model was utilized from the US third-party payer's perspective such that only direct costs were included, using a lifetime time horizon with discount rates of 3% for costs and benefits. Three comparators were considered: (1) All UC, which included non-invasive (NI) and invasive testing and early bronchoscopy; (2) All UC & mcfDNA; and (3) NI UC & mcfDNA & conditional UC Bronch (later bronchoscopy if the initial tests are negative). The model considered whether a probable causative infectious etiology was identified and if the patient received appropriate antimicrobial treatment through expert adjudication, and if the patient died in-hospital. The primary endpoints were total costs, life-years (LYs), equal value life-years (evLYs), quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio per QALY. Extensive scenario and probabilistic sensitivity analyses (PSA) were conducted. RESULTS: At a price of $2000 (2023 USD) for the plasma mcfDNA, All UC & mcfDNA was more costly ($165,247 vs $153,642) but more effective (13.39 vs 12.47 LYs gained; 10.20 vs 9.42 evLYs gained; 10.11 vs 9.42 QALYs gained) compared to All UC alone, giving a cost/QALY of $16,761. NI UC & mcfDNA & conditional UC Bronch was also more costly ($162,655 vs $153,642) and more effective (13.19 vs 12.47 LYs gained; 9.96 vs 9.42 evLYs gained; 9.96 vs 9.42 QALYs gained) compared to All UC alone, with a cost/QALY of $16,729. The PSA showed that above a willingness-to-pay threshold of $50,000/QALY, All UC & mcfDNA was the preferred scenario on cost-effectiveness grounds (as it provides the most QALYs gained). Further scenario analyses found that All UC & mcfDNA always improved patient outcomes but was not cost saving, even when the price of mcfDNA was set to $0. CONCLUSIONS: Based on the evidence available at the time of this analysis, this CEA suggests that mcfDNA may be cost-effective when added to All UC, as well as in a scenario using conditional bronchoscopy when NI testing fails to identify a probable infectious etiology for ICHP. Adding mcfDNA testing to UC diagnostic testing should allow more patients to receive appropriate therapy earlier and improve patient outcomes.

Induction of DEPP1 by HIF Mediates Multiple Hallmarks of Ischemic Cardiomyopathy.

BACKGROUND: HIF (hypoxia inducible factor) regulates many aspects of cardiac function. We and others previously showed that chronic HIF activation in the heart in mouse models phenocopies multiple features of ischemic cardiomyopathy in humans, including mitochondrial loss, lipid accumulation, and systolic cardiac dysfunction. In some settings, HIF also causes the loss of peroxisomes. How, mechanistically, HIF promotes cardiac dysfunction is an open question. METHODS: We used mice lacking cardiac pVHL (von Hippel-Lindau protein) to investigate how chronic HIF activation causes multiple features of ischemic cardiomyopathy, such as autophagy induction and lipid accumulation. We performed immunoblot assays, RNA sequencing, mitochondrial and peroxisomal autophagy flux measurements, and live cell imaging on isolated cardiomyocytes. We used CRISPR-Cas9 gene editing in mice to validate a novel mediator of cardiac dysfunction in the setting of chronic HIF activation. RESULTS: We identify a previously unknown pathway by which cardiac HIF activation promotes the loss of mitochondria and peroxisomes. We found that DEPP1 (decidual protein induced by progesterone 1) is induced under hypoxia in a HIF-dependent manner and localizes inside mitochondria. DEPP1 is both necessary and sufficient for hypoxia-induced autophagy and triglyceride accumulation in cardiomyocytes ex vivo. DEPP1 loss increases cardiomyocyte survival in the setting of chronic HIF activation ex vivo, and whole-body Depp1 loss decreases cardiac dysfunction in hearts with chronic HIF activation caused by VHL loss in vivo. CONCLUSIONS: Our findings identify DEPP1 as a key component in the cardiac remodeling that occurs with chronic ischemia.

HER2 overexpression in urothelial carcinoma with GATA3 and PPARG copy number gains.

HER2, encoded by the ERBB2 gene, is an important druggable driver of human cancer gaining increasing importance as a therapeutic target in urothelial carcinoma (UC). The genomic underpinnings of HER2 overexpression in ERBB2 nonamplified UC are poorly defined. To address this knowledge gap, we investigated 172 UC tumors from patients treated at the University of California San Francisco, using immunohistochemistry and next-generation sequencing. We found that GATA3 and PPARG copy number gains individually predicted HER2 protein expression independently of ERBB2 amplification. To validate these findings, we interrogated the Memorial Sloan Kettering/The Cancer Genome Atlas (MSK/TCGA) dataset and found that GATA3 and PPARG copy number gains individually predicted ERBB2 mRNA expression independently of ERBB2 amplification. Our findings reveal a potential link between the luminal marker HER2 and the key transcription factors GATA3 and PPARG in UC and highlight the utility of examining GATA3 and PPARG copy number states to identify UC tumors that overexpress HER2 in the absence of ERBB2 amplification. In summary, we found that an increase in copy number of GATA3 and PPARG was independently associated with higher ERBB2 expression in patient samples of UC. This finding provides a potential explanation for HER2 overexpression in UC tumors without ERBB2 amplification and a way to identify these tumors for HER2-targeted therapies.