Association of adjuvant radiation and survival in human papilloma virus-positive oropharynx squamous cell carcinoma with lymphovascular invasion as the sole adverse pathologic feature.

BACKGROUND: Postoperative radiotherapy radiation therapy (PORT) for early-stage human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) with positive lymphovascular invasion (LVI) has an unclear association with overall survival (OS). METHODS: This retrospective cohort study queried the National Cancer Database for surgically treated, T1-2, N0-1 HPV+ OPSCC from 2010 to 2019. Primary exposures were LVI and PORT, and the main outcome was 5-year OS. Odds ratios and hazard ratios (HR) with 95% confidence intervals (CIs) were generated using multivariable models and Cox proportional hazard models, respectively. RESULTS: Of 2768 patients, average age was 59.3 years, 2207 (79.7%) were male, and 386 (13.9%) had LVI. Of patients with LVI as their sole adverse pathologic feature, 220 (57.0%) received PORT, which was not associated with 5-year OS (HR, 1.13; CI, 0.65-1.19). CONCLUSIONS: Patients with surgically treated, early-stage HPV+ OPSCC and positive LVI as their only pathologic adverse feature may not require PORT.

What Can You Learn About Psychiatry Programs from Their Website? A Content Evaluation for Potential Applicants.

OBJECTIVE: This project aimed to assess the information contained on general psychiatry program websites and identify common themes that may be useful and informative for residency applicants. METHODS: A survey study design was used to evaluate all US general psychiatry program websites as listed in the FREIDA database. The evaluation form included 44 binary (yes or no) items. Two reviewers rated each item on all program websites between September 2021 and January 2022. Item discrepancies were settled by a third reviewer. Fisher's exact tests evaluated differences between geographic regions and program types. Multidimensional scaling and Rasch modeling were conducted to examine clustering and the probability of items reported on program websites. RESULTS: A total of 285 websites were identified; 13 were excluded. Internal consistency was high among reviewers, Cronbach's Alpha = 0.927; κ = 0.863. Websites varied considerably in quality. Significant inconsistent reporting was observed by region for current residents' photos and alumni careers (fellowship/jobs); p<0.001. Program types varied regarding information about program faculty, which included significant differences for faculty photo, faculty research interest, and faculty research publications; p<0.001. CONCLUSIONS: While inter-rater reliability was high, considerable variation among websites was observed. Residency programs could be improved by consistently reporting resident and faculty information. Results show that applicants may encounter issues finding pertinent information, as programs' FREIDA link did not direct the user to the residency program website two-thirds of the time.

Association Between Antibiotic Prescribing and Time to Diagnosis of Head and Neck Cancer.

Importance: Diagnostic delay can negatively affect patient outcomes in head and neck cancer (HNC). Neck mass and other symptoms of undiagnosed HNC may be treated with antibiotics, delaying diagnosis and treatment, despite current clinical practice guidelines. Objective: To investigate temporal trends, associated factors, and time from symptom onset to antibiotic prescribing before an HNC diagnosis. Design, Setting, and Participants: A retrospective cohort study was conducted using data obtained from a deidentified electronic health records data set from January 1, 2011, to December 31, 2018. Patients with HNC enrolled in the data set for at least 1 year before diagnosis date determined by either 1 inpatient encounter or first of 2 outpatient encounters within 6 months were included. Data analysis was conducted from May 1 to November 9, 2022. Exposure: Antibiotic prescription within 3 months before HNC diagnosis date. Main Outcomes and Measures: The primary outcome was days from the first documented symptom to HNC diagnosis. Results: The cohort included 7811 patients with HNC (4151 [53.1%] men, mean [SD] age, 60.2 [15.8] years). At least 1 antibiotic was prescribed for 1219 patients (15.6%) within 3 months before HNC diagnosis. This represented an increase over the 8.9% prescribing rate during the baseline period 12 to 9 months before diagnosis. The rate of antibiotic prescribing within 3 months before diagnosis did not change significantly over time (quarterly percent change, 0.49%; 95% CI, -3.06% to 4.16%). Patients receiving an antibiotic prescription within 3 months of an HNC diagnosis had a 21.1% longer time between symptom onset and HNC diagnoses (adjusted rate ratio [ARR], 1.21; 95% CI, 1.14-1.29). Compared with diagnosis by otolaryngologists, primary care/internal medicine physicians were most likely to prescribe antibiotics for patients who were diagnosed with a presenting symptom (adjusted prevalence ratio, 1.60; 95% CI, 1.27-2.02). In patients presenting with neck mass/swelling, those presenting with other symptoms were more likely to have longer intervals from symptom onset to diagnosis (ARR, 1.31; 95% CI, 1.08-1.59). Conclusions and Relevance: The findings of this cohort study suggest there is an increased rate of antibiotic prescription in the 3 months before HNC diagnosis, which is associated with an increased time to diagnosis. These findings identify an area for improvement in HNC care and guidelines.

What do female medical students know about planned oocyte cryopreservation and what are their personal attitudes?

PURPOSE: This study aimed to assess medical student knowledge and attitudes regarding oocyte cryopreservation, as well as attitudes regarding future intentions of utilizing this procedure. METHODS: This cross-sectional web-based survey study was distributed to 873 medical students at the University of Kansas from July through September 2018. The survey was self-reported and female medical student responses were analyzed. Students were surveyed through a variety of multiple-choice questions on demographics, knowledge of oocyte cryopreservation, and factors and attitudes that would impact personal and professional use of oocyte cryopreservation. RESULTS: A total of 122 female responses were collected (30%). A majority of female medical students were aware of oocyte cryopreservation, less than half correctly identified a dramatic drop in female fertility as well as oocyte cryopreservation success and cost-effectiveness. Three-quarters felt pressure to delay childbearing and nearly two-thirds would consider freezing their oocytes. Several factors were found to alter their decision toward oocyte cryopreservation including personal factors, procedure complexity and availability, and outcomes. CONCLUSIONS: A majority of female medical students are amenable to the possibility of using oocyte cryopreservation to delay childbearing. Though nearly all knew of oocyte cryopreservation, knowledge regarding fertility and oocyte cryopreservation was low.

Trends and Implications of Adjuvant Systemic Therapy for Head and Neck Cancer Without High-Risk Features.

OBJECTIVE: Determine trends and survival implications of adjuvant systemic therapy use for lower risk head and neck cancer. STUDY DESIGN: Retrospective cohort study. SETTING: US National Cancer Database, 2010 to 2019. METHODS: Patients with mucosal head and neck squamous cell carcinoma treated with surgery and postoperative radiation therapy were identified. Adjuvant systemic therapy trends in those with and without extranodal extension or positive margins were assessed as annual percent change by JoinPoint analysis. Factors associated with adjuvant systemic therapy and overall survival were assessed with multivariable models and cox proportional hazard models, respectively. RESULTS: From 2010 to 2019, approximately one-third of head and neck cancer patients without extranodal extension or positive margins received adjuvant systemic therapy. This rate decreased throughout the study period, with the highest annual percent change from 2016 to 2019 (12.21%; 95% confidence interval: 3.73%-19.95%). Younger age, male sex, Hispanic ethnicity, community program setting, advanced stage, and lymphovascular invasion increased the odds a patient would receive adjuvant systemic therapy. Adjuvant systemic therapy was associated with inferior overall survival when used in those without extranodal extension or positive margins after controlling for covariates. CONCLUSION: Though decreasing, adjuvant systemic therapy use is still common in the absence of extranodal extension and positive margins, and a variety of patient, provider, and oncologic factors may influence its use. The inferior overall survival after adjuvant systemic therapy in the absence of high-risk features suggests any oncologic benefit may not outweigh the costs and morbidity of the therapy.

Can the Publication of Case Series or Case Reports Lead to a Change in Clinical Practice?

This column provides some criteria for evaluating whether a case series or case report may warrant publication. It will emphasize the value of having biomarker data in addition to clinical data to enhance the potential validation of the report and provide ways to test the findings in randomized, controlled clinical trials (RCTs). The potential validity of the case series or report is also high if the outcome is something that would not normally be expected such as, by way of example but not limited to, sudden death or malignant hypertension in someone who had always been normotensive. Examples illustrating how case series/case reports have changed the course of clinical practice or regulatory rules governing drug approval by the US Food and Drug Administration are presented, as well as examples of how those reports have been validated by more rigorous studies including RCTs. The column also includes a discussion of situations in which case series/case reports might have an endpoint (eg, sudden death) that would not be ethical to investigate in an RCT, as well as how biomarkers have been used in such instances to avoid serious untoward outcomes for a participant while still testing the hypothesis.

Lower systemic inflammation is associated with gut firmicutes dominance and reduced liver injury in a novel ambulatory model of parenteral nutrition.

BACKGROUND: Total Parenteral Nutrition (TPN) provides lifesaving nutritional support to patients unable to maintain regular enteral nutrition (EN). Unfortunately, cholestasis is a significant side effect affecting 20-40% of paediatric patients. While the aetiology of TPN-associated injury remains ill-defined, an altered enterohepatic circulation in the absence of gut luminal nutrient content during TPN results in major gut microbial clonal shifts, resulting in metabolic endotoxemia and systemic inflammation driving liver injury and cholestasis. HYPOTHESIS: To interrogate the role of gut microbiota, using our novel ambulatory TPN piglet model, we hypothesized that clonal reduction of bacteria in Firmicutes phylum (predominant in EN) and an increase in pathogenic Gram-negative bacteria during TPN correlates with an increase in serum lipopolysaccharide and systemic inflammatory cytokines, driving liver injury. METHODS: Upon institutional approval, 16 animals were allocated to receive either TPN (n = 7) or EN only (n = 9). The TPN group was subdivided into a low systemic inflammation (TPN-LSI) and high systemic inflammation (TPN-HSI) based on the level of serum lipopolysaccharide. Culture-independent identification of faecal bacterial populations was determined by 16S rRNA. RESULTS: Piglets on TPN, in the TPN-HSI group, noted a loss of enterocyte protective Firmicutes bacteria and clonal proliferation of potent inflammatory and lipopolysaccharide containing pathogens: Fusobacterium, Bacteroidetes and Campylobacter compared to EN animals. Within the TPN group, the proportion of Firmicutes phylum correlated with lower portal lipopolysaccharide levels (r = -0.89). The TPN-LSI had a significantly lower level of serum bile acids compared to the TPN-HSI group (7.3 vs. 60.4 mg/dL; p = .018), increased day 14 weight (5.67 vs. 5.07 kg; p = .017) as well as a 13.7-fold decrease in serum conjugated bilirubin. CONCLUSION: We demonstrate a novel relationship between the gut microbiota and systemic inflammation in a TPN animal model. Pertinently, the degree of gut dysbiosis correlated with the severity of systemic inflammation. This study underscores the role of gut microbiota in driving liver injury mechanisms during TPN and supports a paradigm change in therapeutic targeting of the gut microbiota to mitigate TPN-related injury. KEY MESSAGESThis study identified a differential link between gut microbiota and inflammation-the higher the dysbiosis, the worse the systemic inflammatory markers.Higher levels of Firmicutes species correlated with reduced inflammation.

Canonical Wnt Signaling in the Pathology of Iron Overload-Induced Oxidative Stress and Age-Related Diseases.

Iron accumulates in the vital organs with aging. This is associated with oxidative stress, inflammation, and mitochondrial dysfunction leading to age-related disorders. Abnormal iron levels are linked to neurodegenerative diseases, liver injury, cancer, and ocular diseases. Canonical Wnt signaling is an evolutionarily conserved signaling pathway that regulates many cellular functions including cell proliferation, apoptosis, cell migration, and stem cell renewal. Recent evidences indicate that iron regulates Wnt signaling, and iron chelators like deferoxamine and deferasirox can inhibit Wnt signaling and cell growth. Canonical Wnt signaling is implicated in the pathogenesis of many diseases, and there are significant efforts ongoing to develop innovative therapies targeting the aberrant Wnt signaling. This review examines how intracellular iron accumulation regulates Wnt signaling in various tissues and their potential contribution in the progression of age-related diseases.

Carbamazepine mitigates parenteral nutrition-associated liver disease in a novel ambulatory piglet model.

BACKGROUND: Parenteral nutrition (PN) remains a critical therapeutic option in patients who cannot tolerate enteral feeding. However, although lifesaving, PN is associated with significant side effects, including liver injury, the etiology of which is multifactorial. Carbamazepine (CBZ), an antiepileptic medication, is known to modulate hepatic fibrosis and hepatocellular injury in a variety of liver diseases. We hypothesized that CBZ could prevent PN-associated liver disease (PNALD), which we tested by using our novel ambulatory PN piglet model. METHODS: Piglets were fitted with jugular catheters and infusion pumps for PN and randomized to enteral nutrition (n = 7), PN (n = 6), or PN with parenteral CBZ (n = 6) for 2 weeks. Serum and liver tissue were analyzed via light microscopy, quantification of serum liver injury markers, Ki67 and cytokeratin-7 indexing, and real-time quantitative polymerase chain reaction. RESULTS: PN-fed piglets in our model developed manifestations of PNALD-particularly, increased serum bilirubin, gamma-glutamyltransferase, liver cholestasis, and Ki67 expression compared with that of EN-fed animals (P < 0.03). CBZ therapy in PN-fed animals led to a significant reduction in these markers of injury (P < 0.05). Investigation into the mechanism of these therapeutic effects revealed increased expression of sterol regulatory element-binding protein 1 (SREBP-1), peroxisome proliferator-activated receptor alpha (PPAR-α), and fatty acid binding protein (FABP) in PN-fed animals receiving CBZ (P < 0.03). Further investigation revealed increased LC3 expression and decreased lysosomal-associated membrane protein (LAMP1) expression with CBZ (P < 0.03). CONCLUSION: CBZ administration mitigates PNALD severity, suggesting a novel therapeutic strategy targeting PN-associated side effects, and may present a paradigm change to current treatment options.

Novel NMP split liver model recapitulates human IRI and demonstrates ferroptosis modulators as a new therapeutic strategy.

BACKGROUND: Almost 9%of deceased donor livers are discarded as marginal donor livers (MDL) due to concern of severe ischemia reperfusion injury (IRI). Emerging data supports ferroptosis (iron regulated hepatocellular death) as an IRI driver, however lack of robust preclinical model limits therapeutic testing. In this manuscript we describe the development of a novel rigorous internal control system utilizing normothermic perfusion of split livers to test ferroptosis regulators modulating IRI. METHODS: Upon institutional approval, split human MDLs were placed on our normothermic perfusion machine, Perfusion Regulated Organ Therapeutics with Enhanced Controlled Testing (PROTECT), pumping arterial and portal blood. Experiment 1 compared right (UR) and left (UL) lobes to validate PROTECT. Experiment 2 assessed ferroptosis regulator Deferoxamine in Deferoxamine Agent Treated (DMAT) vs. No Agent Internal Control (NAIC) lobes. Liver serology, histology, and ferroptosis genes were assessed. RESULTS: Successful MDL perfusion validated PROTECT with no ALT or AST difference between UR and UL (∆ALT UR: 235, ∆ALT UL: 212; ∆AST UR: 576, ∆AST UL: 389). Liver injury markers increased in NAIC vs. DMAT (∆ALT NAIC: 586, ∆ALT DMAT: -405; ∆AST NAIC: 617, ∆AST DMAT: -380). UR and UL had similar expression of ferroptosis regulators RPL8,HO-1 and HIFα. Significantly decreased intrahepatic iron (p = .038), HO-1 and HIFα in DMAT (HO-1 NAIC: 6.93, HO-1 DMAT: 2.74; HIFαNAIC: 8.67, HIFαDMAT: 2.60)and no hepatocellular necrosis or immunohistochemical staining (Ki67/Cytokeratin-7) differences were noted. CONCLUSION: PROTECT demonstrates the therapeutic utility of a novel normothermic perfusion split liver system for drug discovery and rapid translatability of therapeutics, driving a paradigm change in organ recovery and transplant medicine. Our study using human livers, provides preliminary proof of concept for the novel role of ferroptosis regulators in driving IRI.

PPARα agonist fenofibrate attenuates iron-induced liver injury in mice by modulating the Sirt3 and ß-catenin signaling.

Iron accumulation is frequently associated with chronic liver diseases. However, our knowledge on how iron contributes to the liver injury is limited. Aberrant Wnt/ß-catenin signaling is a hallmark of several hepatic pathologies. We recently reported that peroxisome proliferator-activated receptor α (PPARα) agonist, fenofibrate, prevents iron-induced oxidative stress and ß-catenin signaling by chelating the iron. Sirtuin3 (Sirt3), a type of NAD+-dependent deacetylase, that plays a critical role in metabolic regulation was found to prevent ischemia reperfusion injury (IRI) by normalizing the Wnt/ß-catenin pathway. In the present study, we explored if fenofibrate prevents iron-induced liver injury by regulating the Sirt3 and ß-catenin signaling. In vitro and in vivo iron treatment resulted in the downregulation of PPARα, Sirt3, active ß-catenin, and its downstream target gene c-Myc in the mouse liver. Pharmacological activation of Sirt3, both in vitro and in vivo, by Honokiol (HK), a known activator of Sirt3, abrogated the inhibitory effect of iron overload on active ß-catenin expression and prevented the iron-induced upregulation of α smooth muscle actin (αSMA) and TGFß expression. Intrinsically, PPARα knockout mice showed significant downregulation of hepatic Sirt3 levels. In addition, treatment of iron overload mice with PPARα agonist fenofibrate reduced hepatic iron accumulation and prevented iron-induced downregulation of liver Sirt3 and active ß-catenin, mitigating the progression of fibrosis. Thus, our results establish a novel link between hepatic iron and PPARα, Sirt3, and ß-catenin signaling. Further exploration on the mechanisms by which fenofibrate ameliorates iron-induced liver injury likely has significant therapeutic impact on iron-associated chronic liver diseases.NEW & NOTEWORTHY Hepatic intracellular iron accumulation has been implicated in the pathophysiology of chronic liver diseases. In this study, we identified a novel mechanism involved in the progression of fibrosis. Excess iron accumulation in liver caused downregulation of PPARα-Sirt3-Wnt signaling leading to fibrosis. This work has significant translational potential as PPARα agonist fenofibrate could be an attractive therapeutic drug for the treatment of liver disorders associated with iron overload.

Parenteral Nutrition and Cardiotoxicity.

Parenteral nutrition (PN) is a life-saving nutritional therapy for those situations when patients are unable to receive enteral nutrition. However, despite a multitude of benefits offered by PN, it is associated with a variety of side effects, most notably parenteral nutrition-associated liver disease (PNALD). Adverse effects of PN on other organ systems, such as brain and cardiovascular system, have been poorly studied. There have been several case reports, studies, and a recent animal study highlighting cardiotoxic effects of PN; however, much remains unclear about the underlying mechanisms causing cardiac damage. In this review, we propose a series of potential mechanisms behind PN-associated heart injury, and we provide an overview of therapeutic strategies and recent scientific advances.

Advances in the Epidemiology, Diagnosis, and Management of Pediatric Fatty Liver Disease.

PURPOSE: Nonalcoholic fatty liver (NAFL) is a major contributor to pediatric liver disease. This review evaluated the current literature on prevalence, screening, diagnosis, and management of NAFL in children and explored recent advances in the field of pediatric NAFL. METHODS: A PubMed search was performed for manuscripts describing disease burden, diagnosis, and management strategies in pediatric NAFL published within the past 15 years. Systematic reviews, clinical practice guidelines, randomized controlled trials, and cohort and case-control studies were reviewed for the purpose of this article. FINDINGS: The prevalence of NAFL in children is increasing. It is a leading cause of liver-related morbidity and mortality in children. Screening and diagnosis of NAFL in children are a challenge. Lifestyle changes and exercise are the cornerstones of the management of NAFL. IMPLICATIONS: Further research is needed to develop better screening and diagnostic tools for pediatric NAFL, including noninvasive diagnostics. NAFL therapeutics is another area of much-needed, ongoing research.

Fenofibrate prevents iron induced activation of canonical Wnt/ß-catenin and oxidative stress signaling in the retina.

Accumulating evidence strongly implicates iron in the pathogenesis of aging and disease. Iron levels have been found to increase with age in both the human and mouse retinas. We and others have shown that retinal diseases such as age-related macular degeneration and diabetic retinopathy are associated with disrupted iron homeostasis, resulting in retinal iron accumulation. In addition, hereditary disorders due to mutation in one of the iron regulatory genes lead to age dependent retinal iron overload and degeneration. However, our knowledge on whether iron toxicity contributes to the retinopathy is limited. Recently, we reported that iron accumulation is associated with the upregulation of retinal and renal renin-angiotensin system (RAS). Evidences indicate that multiple genes/components of the RAS are targets of Wnt/ß-catenin signaling. Interestingly, aberrant activation of Wnt/ß-catenin signaling is observed in several degenerative diseases. In the present study, we explored whether iron accumulation regulates canonical Wnt signaling in the retina. We found that in vitro and in vivo iron treatment resulted in the upregulation of Wnt/ß-catenin signaling and its downstream target genes including renin-angiotensin system in the retina. We confirmed further that iron activates canonical Wnt signaling in the retina using TOPFlash T-cell factor/lymphoid enhancer factor promoter assay and Axin2-LacZ reporter mouse. The presence of an iron chelator or an antioxidant reversed the iron-mediated upregulation of Wnt/ß-catenin signaling in retinal pigment epithelial (RPE) cells. In addition, treatment of RPE cells with peroxisome proliferator-activated receptor (PPAR) α-agonist fenofibrate prevented iron-induced activation of oxidative stress and Wnt/ß-catenin signaling by chelating the iron. The role of fenofibrate, an FDA-approved drug for hyperlipidemia, as an iron chelator has potentially significant therapeutic impact on iron associated degenerative diseases.

Role of Bile Acids and Gut Microbiota in Parenteral Nutrition Associated Injury.

Total Parenteral Nutrition (TPN) is a life-saving therapy where all nutritional requirements are provided intravenously. While this therapy is essential for individuals unable to process their nutritional needs enterically, significant complications arise such as intestinal failure associated liver injury (IFALD). IFALD includes hepatic steatosis, cholestasis, inflammation, ultimately progressing to cirrhosis and portal hypertension and some patients may need liver transplantation. The exact mechanism underlying this condition is not well understood, but studies have recently suggested that changes in gut microbiota and intraluminal bile acid signaling are known to play a role in the development of IFALD. In enterohepatic circulation with normal enteral nutrition, gut Farnesoid X Receptor (FXR) is activated by bile acids, which triggers the release of Fibroblast Growth Factor 19 (FGF19) into portal circulation. FGF19 serves to regulate intrahepatic bile acid synthesis with enteric nutrition. This signaling pathway is impaired in TPN as studies indicate decreased serum levels of FGF19 in subjects receiving TPN. Finally, gut microbiota is severely altered in TPN due to intestinal hypomobility. The shift in gut microbiota affects our immune response and promotes endotoxins that negatively affect liver function. Targeting the pathways affecting gut microbiota and bile acid signaling has promise in treating TPN associated injuries.

Radiation-induced ovarian follicle loss occurs without overt stromal changes.

Radiation damage due to total body irradiation (TBI) or targeted abdominal radiation can deplete ovarian follicles and accelerate reproductive aging. We characterized a mouse model of low-dose TBI to investigate how radiation affects the follicular and stromal compartments of the ovary. A single TBI dose of either 0.1 Gy or 1 Gy (Cesium-137 γ) was delivered to reproductively adult CD1 female mice, and sham-treated mice served as controls. Mice were euthanized either 2 weeks or 5 weeks post exposure, and ovarian tissue was harvested. To assess the ovarian reserve, we classified and counted the number of morphologically normal follicles in ovarian histologic sections for all experimental cohorts using an objective method based on immunohistochemistry for an oocyte-specific protein (MSY2). 0.1 Gy did not affect that total number of ovarian follicles, whereas 1 Gy resulted in a dramatic loss. At two weeks, there was a significant reduction in all preantral follicles, but early antral and antral follicles were still present. By five weeks, there was complete depletion of all follicle classes. We examined stromal quality using histologic stains to visualize ovarian architecture and fibrosis and by immunohistochemistry and quantitative microscopy to assess cell proliferation, cell death and vasculature. There were no differences in the ovarian stroma across cohorts with respect to these markers, indicating that this compartment is more radio-resistant relative to the germ cells. These findings have implications for reproductive health and the field of fertility preservation because the radiation doses we examined mimic scatter doses experienced in typical therapeutic regimens.