Impaired unsaturated fatty acid elongation alters mitochondrial function and accelerates metabolic dysfunction-associated steatohepatitis progression.

BACKGROUND AND AIMS: Although qualitative and quantitative alterations in liver Polyunsaturated Fatty Acids (PUFAs) are observed in MASH in humans, a causal relationship of PUFAs biosynthetic pathways is yet to be clarified. ELOVL5, an essential enzyme in PUFA elongation regulates hepatic triglyceride metabolism. Nonetheless, the long-term consequences of elongase disruption, particularly in murine models of MASH, have not been evaluated. APPROACH & RESULTS: In humans, transcriptomic data indicated that PUFAs biosynthesis enzymes and notably ELOVL5 were induced during MASH progression. Moreover, gene module association determination revealed that ELOVL5 expression was associated with mitochondrial function in both humans and mice. WT and Elovl5-deficient mice were fed a high-fat, high-sucrose (HF/HS) diet for four months. Elovl5 deficiency led to limited systemic metabolic alterations but significant hepatic phenotype was observed in Elovl5-/- mice after the HF/HS diet, including hepatomegaly, pronounced macrovesicular and microvesicular steatosis, hepatocyte ballooning, immune cell infiltration, and fibrosis. Lipid analysis confirmed hepatic triglyceride accumulation and a reshaping of FA profile. Transcriptomic analysis indicated significant upregulation of genes involved in immune cell recruitment and fibrosis, and downregulation of genes involved in oxidative phosphorylation in Elovl5-/- mice. Alterations of FA oxidation and energy metabolism were confirmed by non-targeted metabolomic approach. Analysis of mitochondrial function in Elovl5-/- mice showed morphological alterations, qualitative cardiolipin changes with an enrichment in species containing shorter unsaturated FAs, and decreased activity of I and III respiratory chain complexes. CONCLUSION: Enhanced susceptibility to diet-induced MASH and fibrosis in Elovl5-/- mice is intricately associated with disruptions in mitochondrial homeostasis, stemming from a profound reshaping of mitochondrial lipids, notably cardiolipins.

Hypothermic Oxygenated machine PErfusion for high-risk liver grafts for transplantation: A systematic review and meta-analysis.

BACKGROUND: Hypothermic Oxygenated machine PErfusion (HOPE) can reduce ischemic reperfusion injury and improve outcomes for liver transplant recipients. However, the effect of HOPE on high-risk extended criteria donor (ECD) and donation after circulatory death determination (DCDD) grafts is incomplete, despite the expectation that this cohort benefit maximally from HOPE. Accordingly, this paper aims to characterize the effect of HOPE on ECD and DCDD grafts. METHODS: This study includes all papers comparing HOPE to static cold storage for high-risk ECD and DCDD grafts. Systematic searches of Medline, Embase, and Scopus were completed using the terms "HOPE" OR "hypothermic oxygenated machine perfusion" AND "liver transplantation". Data were extracted and analyzed using IBM SPSS to perform the meta-analysis. RESULTS: A total of 2286 records were identified, with 10 meeting the inclusion criteria. Overall, the quality of evidence is heterogenous with many papers relying on retrospective controls. However, pooled analysis demonstrates HOPE to significantly reduce the rate of early allograft dysfunction, 12-month graft failure, re-transplantation, total biliary complications, and non-anastomotic strictures for high-risk grafts. CONCLUSIONS: There is good evidence that HOPE improves outcomes following liver transplantation across a number of biochemical and clinical endpoints for high-risk grafts. Of note, the reduction in biliary complications and re-transplantation is particularly significant given the morbidity associated with these endpoints. However, further, high-quality prospective trials with contemporary controls and clinically relevant primary endpoints are needed to better define the impact of HOPE for this cohort of grafts.

Off-Protocol Radiation Therapy in Phase 3 Metastatic Solid Tumor Trials.

PURPOSE: Increasing data suggest that radiation therapy, particularly ablative radiation therapy, alters the natural history of metastatic disease. For patients with metastatic disease enrolled in prospective trials testing systemic therapy, the use of off-protocol radiation therapy to improve clinical symptoms or extend the duration of study systemic therapy may influence study endpoints. We sought to evaluate how often off-protocol radiation therapy was permitted among systemic therapy phase 3 trials, how often off-protocol radiation therapy is used, and whether off-protocol radiation therapy correlated with study outcomes. METHODS AND MATERIALS: Two-arm, superiority-design, phase 3 randomized trials testing systemic therapy were screened from ClinicalTrials.gov. Protocol availability was required to assess the trial approach to off-protocol radiation therapy if not described in the manuscript. Adjusted odds ratios with 95% CI were calculated by logistic regression. RESULTS: A total of 112 trials enrolling 80,134 patients were included, with publication dates between 2010 and 2019. Of these, off-protocol radiation therapy was allowed, not discussed, or prohibited during study systemic therapy in 52% (N =58), 25% (N = 28), and 23% (N = 26) of trials, respectively. However, only 2% (2 of 112) of trials reported off-protocol radiation therapy utilization rates, although no data were reported on the use of ablative off-protocol radiation therapy. No trials evaluated or adjusted for the potential influence of off-protocol radiation therapy on study endpoints. Among the subset of open-label studies, trials permissive toward off-protocol radiation therapy were more likely to meet their primary endpoint (adjusted odds ratio, 4.50; 95% CI, 1.23-20.23; P = .04). CONCLUSIONS: Although most trials allowed off-protocol radiation therapy during the receipt of the study systemic therapy, the influence of off-protocol radiation therapy, especially ablative radiation therapy, on study outcomes is underevaluated among phase 3 systemic therapy trials.

Improving the clinical meaning of surrogate endpoints: An empirical assessment of clinical progression in phase III oncology trials.

Disease progression in clinical trials is commonly defined by radiologic measures. However, clinical progression may be more meaningful to patients, may occur even when radiologic criteria for progression are not met, and often requires a change in therapy in clinical practice. The objective of this study was to determine the utilization of clinical progression criteria within progression-based trial endpoints among phase III trials testing systemic therapies for metastatic solid tumors. The primary manuscripts and protocols of phase III trials were reviewed for whether clinical events, such as refractory pain, tumor bleeding, or neurologic compromise, could constitute a progression event. Univariable logistic regression computed odds ratios (OR) and 95% CI for associations between trial-level covariates and clinical progression. A total of 216 trials enrolling 148,190 patients were included, with publication dates from 2006 through 2020. A major change in clinical status was included in the progression criteria of 13% of trials (n = 27), most commonly as a secondary endpoint (n = 22). Only 59% of trials (n = 16) reported distinct clinical progression outcomes that constituted the composite surrogate endpoint. Compared with other disease sites, genitourinary trials were more likely to include clinical progression definitions (16/33 [48%] vs. 11/183 [6%]; OR, 14.72; 95% CI, 5.99 to 37.84; p < .0001). While major tumor-related clinical events were seldom considered as disease progression events, increased attention to clinical progression may improve the meaningfulness and clinical applicability of surrogate endpoints for patients with metastatic solid tumors.

Proportional Hazards Violations in Phase III Cancer Clinical Trials: A Potential Source of Trial Misinterpretation.

PURPOSE: Survival analyses of novel agents with long-term responders often exhibit differential hazard rates over time. Such proportional hazards violations (PHV) may reduce the power of the log-rank test and lead to misinterpretation of trial results. We aimed to characterize the incidence and study attributes associated with PHVs in phase III oncology trials and assess the utility of restricted mean survival time and maximum combination test as additional analyses. EXPERIMENTAL DESIGN: Clinicaltrials.gov and PubMed were searched to identify two-arm, randomized, phase III superiority-design cancer trials with time-to-event primary endpoints and published results through 2020. Patient-level data were reconstructed from published Kaplan-Meier curves. PHVs were assessed using Schoenfeld residuals. RESULTS: Three hundred fifty-seven Kaplan-Meier comparisons across 341 trials were analyzed, encompassing 292,831 enrolled patients. PHVs were identified in 85/357 [23.8%; 95% confidence interval (CI), 19.7%, 28.5%] comparisons. In multivariable analysis, non-overall survival endpoints [OR, 2.16 (95% CI, 1.21, 3.87); P = 0.009] were associated with higher odds of PHVs, and immunotherapy comparisons [OR 1.94 (95% CI, 0.98, 3.86); P = 0.058] were weakly suggestive of higher odds of PHVs. Few trials with PHVs (25/85, 29.4%) prespecified a statistical plan to account for PHVs. Fourteen trials with PHVs exhibited discordant statistical signals with restricted mean survival time or maximum combination test, of which 10 (71%) reported negative results. CONCLUSIONS: PHVs are common across therapy types, and attempts to account for PHVs in statistical design are lacking despite the potential for results exhibiting nonproportional hazards to be misinterpreted.

Fallacy of attributing the U.S. firearm mortality epidemic to mental health.

BACKGROUND: Annual global data on mental disorders prevalence and firearm death rates for 2000-2019, enables the U.S. to be compared with comparable counties for these metrics. METHODS: The Institute for Health Metrics and Evaluation (IHME) Global Health Burden data were used to compare the prevalence of mental disorders with overall, homicide and suicide firearm death rates including homicides and suicides, in high sociodemographic (SDI) countries. RESULTS: Overall and in none of the nine major categories of mental disorders did the U.S. have a statistically-significant higher rate than any of 40 other high SDI countries during 2019, the last year of available data. During the same year, the U.S. had a statistically-significant higher rate of all deaths, homicides, and suicides by firearm (all p<<0.001) than all other 40 high SDI countries. Suicides accounted for most of the firearm death rate differences between the U.S. and other high SDI countries, and yet the prevalence of mental health disorders associated with suicide were not significantly difference between the U.S. and other high SDI countries. CONCLUSION: Mental disorder prevalence in the U.S. is similar in all major categories to its 40 comparable sociodemographic countries, including mental health disorders primarily associated with suicide. It cannot therefore explain the country's strikingly higher firearm death rate, including suicide. Reducing firearm prevalence, which is correlated with the country's firearm death rate, is a logical solution that has been applied by other countries.

A Comprehensive Survey of 2024 Funding for Radiation Oncology Visiting Medical Student Electives.

Visiting electives provide an opportunity for medical students to engage with radiation oncology (RO) programs, likely influencing residency match outcomes. However, some student's out-of-pocket costs may be prohibitive, and in attempts to offset the financial burden of visiting electives, particularly for students underrepresented in medicine (URiM), some institutions offer scholarships. Here, we characterized the current domestic landscape of funded RO electives. Visiting electives were identified through the FREIDA and VSLO databases in April 2024. Funded elective availability and departmental characteristics were identified via internet search by two independent reviewers. Fisher's exact test was used to determine whether there was a difference in the distribution of scholarships across the US due to the small sample size. Ninety-two visiting electives were identified, with 40 programs offering URiM elective scholarships (43.5%). Twelve (30%) were funded specifically by RO departments, and 28 (70%) were part of broader institutional URiM scholarship initiatives. The median stipend provided was $2000 (IQR $500), range $1000-$5000. Analysis of scholarships by US census division and metro area revealed unequal distribution. Electives in New England, Mountain, and East North Central divisions had higher funding proportion compared to electives in the East South Central, West South Central, and Middle Atlantic divisions. Only 1/9 electives in New York City were funded compared with 4/6 in Los Angeles. Departments with funded electives had more faculty physicians and medical residents. In our review of the 2024 landscape, over 40% of RO electives offer financial support. However, we identified geographical disparities in the distribution of scholarships, highlighting the need for interventions to address unequal access to a wide array of training programs. Our study represents a valuable resource for students interested in RO and highlights the continued need to positively contribute to increasing diversity in the field. Future work exploring the impact of funded electives is needed.

Secondary Endpoint Utilization and Publication Rate among Phase III Oncology Trials.

Secondary endpoints (SEP) provide crucial information in the interpretation of clinical trials, but their features are not yet well understood. Thus, we sought to empirically characterize the scope and publication rate of SEPs among late-phase oncology trials. We assessed SEPs for each randomized, published phase III oncology trial across all publications and ClinicalTrials.gov, performing logistic regressions to evaluate associations between trial characteristics and SEP publication rates. After screening, a total of 280 trials enrolling 244,576 patients and containing 2,562 SEPs met the inclusion criteria. Only 22% of trials (62/280) listed all SEPs consistently between ClinicalTrials.gov and the trial protocol. The absolute number of SEPs per trial increased over time, and trials sponsored by industry had a greater number of SEPs (median 9 vs. 5 SEPs per trial; P < 0.0001). In total, 69% of SEPs (1,770/2,562) were published. The publication rate significantly varied by SEP category [X2 (5, N = 2,562) = 245.86; P < 0.001]. SEPs that place the most burden on patients, such as patient-reported outcomes and translational correlatives, were published at 63% (246/393) and 44% (39/88), respectively. Trials with more SEPs were associated with lower overall SEP publication rates. Overall, our findings are that SEP publication rates in late-phase oncology trials are highly variable based on the type of SEP. To avoid undue burden on patients and promote transparency of findings, trialists should weigh the biological and clinical relevance of each SEP together with its feasibility at the time of trial design. SIGNIFICANCE: In this investigation, we characterized the utilization and publication rates of SEPs among late-phase oncology trials. Our results draw attention to the proliferation of SEPs in recent years. Although overall publication rates were high, underpublication was detected among endpoints that may increase patient burden (such as translational correlatives and patient-reported outcomes).

Social determinants and pre-arrest care patterns associated with cardiac arrest and mortality.

BACKGROUND: Understanding the impact of social determinants of health (SDOH) on CA, including access to care pre-cardiac arrest (CA) can improve outcomes. Large databases, such as Epic Cosmos, can help identify trends in patient demographics and SDOH that identify gaps in care. The purpose of this study was to determine the incidence of CA and subsequent mortality in a large national database across patient demographics and social determinants and characterize pre-arrest care patterns. METHODS: This was a retrospective cohort study using a large national deidentified electronic health database (Epic Cosmos) with 227 million patients. Inclusion criteria was ED encounter for CA (ICD-10-CM: I46). Patient demographics and social determinants included age, sex, race, ethnicity, social vulnerability index (SVI, a composite measure with greater SVI representing more vulnerability). The primary outcome was difference in CA incidence between groups, reported as odds ratios (ORs). The secondary outcomes were 1) incidence of pre-arrest care within 30 days and 2) post-arrest mortality at 7,30, and 180 days. Statistical analysis was performed using Chi-squared analysis (unadjusted OR) and aggregated logistic procedure (adjusted OR). RESULTS: There were 201,846 ED visits for CA between April 20, 2020, and April 19, 2023 (0.11% incidence). For all ages, males had a higher incidence of CA (OR 1.76, p < 0.0001). Black, Native Hawaiian or Pacific Islander, and American Indian or Alaska Native had a higher OR of CA while Asian patients were less likely than White patients (adjusted OR 1.85, 1.44,1.51, and 0.81 respectively, all p < 0.0001). Hispanic/Latino patients had a lower OR of CA (adjusted OR 0.72, p < 0.0001). CA was more common in the highest SVI quartile compared to the lowest (adjusted OR 1.71, p < 0.0001). Significant heterogeneities were identified in pre-arrest care across patient demographics and social determinants, where ED visits were more common than office visits among male patients, patients in the highest SVI, Hispanic/Latino, and minority patients, except for Asian patients. Post-arrest mortality after 30 days was highest in females, Black patients, and patients in the highest SVI. CONCLUSIONS: SDOH have a significant impact on the risk of CA, pre-arrest care patterns, and post-arrest mortality. Determining the impact that SDOH have on the CA care continuum provides can provide actionable targets to prevent CA and subsequent mortality.

Time-Resolved Ion Mobility Spectrometry with a Stop Flow Confined Volume Reaction Region.

An ion source concept is described where the sample flow is stopped in a confined volume of an ion mobility spectrometer creating time-dependent patterns of ion patterns of signal intensities for ions from mixtures of volatile organic compounds and improved signal-to-noise rate compared to conventional unidirectional drift gas flow. Hydrated protons from a corona discharge were introduced continuously into the confined volume with the sample in air at ambient pressure, and product ions were extracted continuously using an electric field for subsequent mobility analysis. Ion signal intensities for protonated monomers and proton bound dimers were measured and computationally extracted using mobilities from mobility spectra and exhibited distinct times of appearance over 30 s or more after sample injection. Models, and experimental findings with a ternary mixture, suggest that the separation of vapors as ions over time was consistent with differences in the reaction rate for reactions between primary ions from hydrated protons and constituents and from cross-reactions that follow the initial step of ionization. The findings suggest that the concept of stopped flow, introduced here for the first time, may provide a method for the temporal separation of atmospheric pressure ions. This separation relies on ion kinetics and does not require chromatographic technology.

Disease Site Specialization in the Academic Radiation Oncology Workforce: Evidence of Gender Differences.

PURPOSE: Because some stakeholders within medicine seek to diversify and attain greater workforce equity, it is critical to understand gender-based divisions within specialization. Radiation oncology (RO) has one of the smallest proportions of women representation of all specialties, and to our knowledge, no prior studies have investigated gender differences in all the disease site specializations within RO. Thus, we analyzed the relationship between gender and disease site(s) treated in academic RO (ARO). METHODS AND MATERIALS: Faculty gender and disease site(s) treated by faculty from ARO departments were collected via publicly available department websites in January 2020. X2 analyses were conducted to assess differences between the proportions of women faculty treating each disease site. RESULTS: Of 1337 ARO faculty, 408 (30.5%) were identified as women. Breast, gynecology, and pediatrics had the largest proportions of women faculty (all >40%; P < .001). A majority (53%; P < .001) of women ARO faculty treated breast. Genitourinary, thoracic, and head and neck had the smallest proportions of women faculty (all <25%; P < .001). Women ARO faculty were twice as likely to treat breast and gynecologic malignancies compared with men faculty (risk ratio [RR] with 95% CI, 2.01 [1.75-2.50]; P < .001 and RR [95% CI], 2.06 [1.72-2.79]; P <.001, respectively). Men ARO faculty were 3 times more likely to treat genitourinary cancer compared with women faculty (RR [95% CI], 0.40 [0.34-0.48]; P < .001). There was no difference in the mean number of disease sites treated between women and men ARO faculty (2.63 vs 2.53; P = .29). CONCLUSIONS: Gender differences in disease site specialization were observed in ARO. Future research into the drivers of disease site selection should be explored.

The importance of non-technical skills in robot-assisted surgery in gynaecology.

Robot-assisted surgery (RAS) in gynaecology has undergone exponential growth in recent decades, with utility in treating both benign and malignant gynaecological conditions. The technological complexities and amended theatre dynamics that RAS demands mean that effective non-technical skills (NTS) are vitally important to overcome these unique challenges. However, NTS have been neglected in RAS-training programmes with focus placed instead on the exclusive acquisition of technical skills (TS). NTS include teamwork, communication, leadership, situational awareness, decision-making and stress management. Communication is the most frequently cited NTS impacted during RAS, as the physical limitations imposed by the robotic hardware make communication exchange difficult. The full immersion that RAS enables can contribute to situational awareness deficits. However, RAS can complement communication and teamwork when multidisciplinary (MDT) surgeries (such as complex endometriosis excisions) are undertaken; dual-console capabilities facilitate the involvement of specialties such as general surgery and urology. The development of NTS in RAS cannot be achieved with in-situ experience alone, and current training is poorly standardised. RAS-training programmes and curricula for gynaecology do exist, however the integration of NTS remain limited. Simulation is a viable tool to facilitate enhanced-NTS integration, yet cost implications form a barrier to its wider implementation. However, given that RAS will continue to occupy a greater proportion of the gynaecological caseload, integration of NTS within gynaecological RAS training curricula is necessary. Patients undergoing gynaecological RAS would benefit from the improved safety standards and enhanced surgical outcomes that would result.

Anesthetic Oxygen Use and Sex Are Critical Factors in the FLASH Sparing Effect.

Purpose: Ultra High Dose-Rate (UHDR) radiation has been reported to spare normal tissue, compared with Conventional Dose-Rate (CDR) radiation. However, important work remains to be done to improve the reproducibility of the FLASH effect. A better understanding of the biologic factors that modulate the FLASH effect may shed light on the mechanism of FLASH sparing. Here, we evaluated whether sex and/or the use of 100% oxygen as a carrier gas during irradiation contribute to the variability of the FLASH effect. Methods and Materials: C57BL/6 mice (24 male, 24 female) were anesthetized using isoflurane mixed with either room air or 100% oxygen. Subsequently, the mice received 27 Gy of either 9 MeV electron UHDR or CDR to a 1.6 cm2 diameter area of the right leg skin using the Mobetron linear accelerator. The primary postradiation endpoint was time to full thickness skin ulceration. In a separate cohort of mice (4 male, 4 female), skin oxygenation was measured using PdG4 Oxyphor under identical anesthesia conditions. Results: Neither supplemental oxygen nor sex affected time to ulceration in CDR irradiated mice. In the UHDR group, skin damage occured earlier in male and female mice that received 100% oxygen compared room air and female mice ulcerated sooner than male mice. However, there was no significant difference in time to ulceration between male and female UHDR mice that received room air. Oxygen measurements showed that tissue oxygenation was significantly higher when using 100% oxygen as the anesthesia carrier gas than when using room air, and female mice showed higher levels of tissue oxygenation than male mice under 100% oxygen. Conclusions: The skin FLASH sparing effect is significantly reduced when using oxygen during anesthesia rather than room air. FLASH sparing was also reduced in female mice compared to male mice. Both tissue oxygenation and sex are likely sources of variability in UHDR studies. These results suggest an oxygen-based mechanism for FLASH, as well as a key role for sex in the FLASH skin sparing effect.

Simulation-based training for intraoperative posterior capsule rupture management: an analysis of nontechnical skills development and the relationship between technical and nontechnical skills.

OBJECTIVES: To analyse development of individual nontechnical skills (NTS) domains after undertaking a previously developed simulation-based training model and analyse the relationship between technical skills (TS) and NTS in ophthalmic surgery. METHODS: The simulation-based training model involved a cataract surgery case complicated by intraoperative posterior capsule rupture. Cataract surgeons underwent the simulation twice, separated by a training intervention. Two blinded independent experts assessed participants' NTS using HUFOES, NOn-Technical Skills for Surgeons (NOTSS), and the OSATS global rating scale for TS. Paired t-tests assessed differences in individual NTS domains, with p < 0.05 indicating significance. The Pearson Product Moment Correlation Coefficient was used to assess the correlation between scores from each scoring system. RESULTS: All NTS domains within HUFOES and NOTSS demonstrated statistically significant improvements secondary to the training intervention. Positive correlations were demonstrated between HUFOES and OSATS scores in the pre- and post-training simulations, r = 0.870 (p < 0.001) and r = 0.861 (p < 0.001), respectively. Positive correlations were also demonstrated between NOTSS and OSATS scores in pre- and post-training simulations, r = 0.849 (p < 0.001) and r = 0.757 (p = 0.001), respectively. Positive correlations were demonstrated between HUFOES and NOTSS scores; r = 0.979 (p < 0.001) (n = 17) and r = 0.959 (p < 0.001) for pre- and post-training simulations, respectively. CONCLUSION: All NTS domains contained within HUFOES and NOTSS demonstrated significant increases following the completion of the simulation-based training model. Positive correlations exist between an ophthalmic surgeon's TS and NTS. This is the first study to report these findings within ophthalmic surgery.

Robot Assisted Laparoscopic Surgery in Gynaecology: An Evolving Assistive Technology.

Laparoscopic surgery is extensively utilized to treat a range of gynaecological conditions and pathologies. The advantages of laparoscopic surgery include the minimalization of blood loss and scarring, improved recovery times, and shorter hospital admissions. However, robotic technologies have had an increasing presence within gynaecological laparoscopic surgery in recent decades. This literature review therefore aims to discuss laparoscopy from 3 perspectives. First, the evolution of laparoscopy is reviewed with a focus on its origins, its transition from a diagnostic to an operative tool, and its role in present-day gynaecology. Second, interventions for benign gynaecological conditions (including excision of benign ovarian tumours, total laparoscopic hysterectomy, and laparoscopic myomectomy) are reviewed. The laparoscopic management of malignant gynaecology (including ovarian cancer, endometrial cancer, and cervical cancer) is also discussed. Finally, whilst robot-assisted laparoscopic surgery is experiencing rapid technological advancement, it is pertinent to consider the extent of its benefits when compared to open or conventional laparoscopic approaches in gynaecological surgery.

Association of differential censoring with survival and suboptimal control arms among oncology clinical trials.

Differential censoring, which refers to censoring imbalance between treatment arms, may bias the interpretation of survival outcomes in clinical trials. In 146 phase III oncology trials with statistically significant time-to-event surrogate primary endpoints, we evaluated the association between differential censoring in the surrogate primary endpoints, control arm adequacy, and the subsequent statistical significance of overall survival results. Twenty-four (16%) trials exhibited differential censoring that favored the control arm, whereas 15 (10%) exhibited differential censoring that favored the experimental arm. Positive overall survival was more common in control arm differential censoring trials (63%) than in trials without differential censoring (37%) or with experimental arm differential censoring (47%; odds ratio = 2.64, 95% confidence interval = 1.10 to 7.20; P = .04). Control arm differential censoring trials more frequently used suboptimal control arms at 46% compared with 20% without differential censoring and 13% with experimental arm differential censoring (odds ratio = 3.60, 95% confidence interval = 1.29 to 10.0; P = .007). The presence of control arm differential censoring in trials with surrogate primary endpoints, especially in those with overall survival conversion, may indicate an inadequate control arm and should be examined and explained.

Clinical value of random esophageal biopsies in patients with dysphagia and normal endoscopy who are treated with a proton pump inhibitor.

Rome IV recommended esophageal biopsies in patients with dysphagia and normal endoscopy to exclude mucosal disease. Thus far, studies evaluating the utility of this recommendation remain scarce. The aims of this study were to determine the value of random esophageal biopsies in heartburn patients with dysphagia and normal endoscopy and compare the yield of random esophageal biopsies between younger versus older patients. Data were collected from consecutive patients presenting with dysphagia, 18 years and older, who were on proton pump inhibitors and had normal upper endoscopy. Biopsy results of patients with and without heartburn were recorded. Logistic regression analysis was used to compare normal versus abnormal biopsy results in younger and older patients accounting for confounding variables. The number of abnormal biopsies was significantly higher than normal biopsies (68% and 32%, respectively, P = 0.0001). Among abnormal biopsy results, microscopic gastroesophageal reflux disease was significantly more common than all other findings (39%, P = 0.0495). There was no significant difference in biopsy results in patients with and without heartburn as well as younger versus older patients (P = 0.3384, P = 0.1010, and P = 0.8468, respectively). Our study demonstrated that most patients with dysphagia and normal upper endoscopy who are on proton pump inhibitor have some type of histologic mucosal abnormality, which can direct future management. Among abnormal biopsies, microscopic reflux was by far the most common finding in patients with or without a history of heartburn. While this supports the management strategy proposed by Rome IV, age did not drive esophageal biopsy results.

Disparities in outcomes and access to therapy options in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) disproportionately impacts racial and ethnic minorities and patients with lower socioeconomic status. These social determinants of health (SDH) lead to disparities in access to care and outcomes. We aim to understand the relationship between SDH and survival and locoregional treatment options in HCC. METHODS: Using the National Cancer Database, we evaluated survival and access locoregional treatments including non-transplant surgery, liver transplant (LT), and liver-directed radiation therapy (LDRT) in patients with HCC diagnosed between 2004 and 2017. Variables including clinical stage, age, sex, race, income, rurality, year of diagnosis, facility type (FT), Charlson-Deyo score (CD), and insurance were evaluated. Cox proportional hazards multivariable regression and dominance analyses were used for analyses. RESULTS: In total, 140 340 patients were included. Worse survival was seen with advanced stage, older age, Black race, rurality, public insurance, treatment at a nonacademic center, and lower income. The top predictors for survival included stage, age, and income. Completion of non-transplant surgery was best predicted by stage, FT, and insurance type, whereas LT was predicted by age, year of diagnosis, and CD score. LDRT utilization was most associated with year of diagnosis, FT, and CD score. CONCLUSION: For patients with HCC, survival was predicted primarily by stage, age, and income. The primary sociodemographic factors associated with access to surgical treatments, in addition to FT, were insurance and income, highlighting the financial burdens of health care. Work is needed to address disparities in access to care, including improved insurance access, addressing financial inequities and financial toxicities of treatments, and equalizing care opportunities in community centers.

Can I Leave? Perspectives on Parental Leave and Parenthood in Medical Training Among Program Directors and Trainees in Oncologic Specialties.

Purpose: Peak fertility commonly occurs during medical training, and delaying parenthood can complicate pregnancies. Trainee parental leave policies are varied and lack transparency. Research on the impacts of parenthood on trainee education is limited. Methods: A Qualtrics-based survey was distributed via e-mail/social media to program directors (PDs) within oncologic specialties with a request to forward a parallel survey to trainees. Questions assessed awareness of parental leave policies, supportiveness of parenthood, and impacts on trainee education. Statistical analyses included descriptive frequencies and bivariable comparisons by key groups. Results: A total of 195 PDs and 286 trainees responded. Twelve percent and 29% of PDs were unsure of maternity/paternity leave options, respectively. PDs felt they were more supportive of trainee parenthood than trainees perceived they were. Thirty-nine percent of nonparent trainees (NPTs) would have children already if not in medicine, and >80% of women trainees were concerned about declining fertility. Perceived impacts of parenthood on trainee overall education and academic productivity were more negative for women trainees when rated by PDs and NPTs; however, men/women parents self-reported equal impacts. Leave burden was perceived as higher for women trainees. Conclusions: A significant portion of PDs lack awareness of parental leave policies, highlighting needs for increased transparency. Trainees' perception of PD support for parenthood is less than PD self-reported support. Alongside significant rates of delayed parenthood and fertility concerns, this poses a problem for trainees seeking to start a family, particularly women who are perceived more negatively. Further work is needed to create a supportive culture for trainee parenthood.