MTHFR 677C>T and 1298A>C Variants in Mothers of Infants with Down Syndrome from Western Mexico.

Background: Several studies in mothers of infants with Down syndrome (DS) (MoIDS) have suggested that the 677C>T and 1298A>C variants of the 5,10-methylentetrahydrofolate reductase (MTHFR) gene can increase the risk of having a child with DS. Aim: This study aimed to evaluate the MTHFR 677C>T and 1298A>C variants as potential maternal risk factors for DS. Materials and Methods: Using TaqMan allelic discrimination assay, we genotyped 95 MoIDS and 164 control mothers from western Mexico. Data were analyzed using logistic regression analysis. Results: We found that MoIDS had a significantly higher risk for the MTHFR 677TT genotype (adjusted odds ratio [aOR] = 3.4, 95% confidence interval [95% CI]: 1.1-10.6), and the MTHFR 677T allele (aOR = 1.5, 95% CI: 1.0-2.3), particularly in MoIDS <35 years of age. Conclusions: Our findings indicate that the presence of the 677TT genotype and 677T allele of the MTHFR 677C>T variant are maternal risk factors for DS in Mexican MoIDS.

Venous Thromboembolism in Children and Teenagers Admitted for Trauma: A 5-Year Nationwide Perspective.

Venous thromboembolism (VTE) in pediatric trauma patients is under-investigated. The purpose of this study was to perform an evaluation of the risk factors for VTE after pediatric trauma, including readmissions across the United States. The Nationwide Readmissions Database for 2016-2020 was queried for all patients under the age of 18 years admitted for trauma. 276 670 patients were identified; 2063 (.8%) were diagnosed with VTE. Among those with VTE, 300 (15%) were identified during a readmission. Higher rates of VTE were seen in ages 15-17 years (n = 1,294, 1.3%, P < .001), penetrating injuries (n = 478, .9%, P < .001), and assault (n = 271, 2.7%, P < .001). The strongest risk factor for VTE was prolonged mechanical ventilation (OR 5.5 [4.9-6.3] P < .001). Our study found that a significant portion of post-traumatic VTE in children and teenagers occur during readmissions. A deeper understanding of the risk factors outlined here can guide enhanced clinical protocols, ensuring early detection and prevention of this complication.

The Role of Pharmaceutical Innovation in Clinical Practice Guidelines for Chronic Diseases.

Background: Over the last 25 years, clinical practice guidelines have emerged as a means to standardize and improve care. As pharmaceutical innovations develop, guidelines are updated to incorporate new interventions. However, the extent to which pharmacotherapies are represented as treatment options in guideline recommendations has not been well elucidated. This study aimed to quantify the role pharmacotherapy has played in clinical practice guidelines across a range of chronic diseases over the past 20 years. Methods: Clinical practice guidelines published from 2000 to 2021 were identified for five chronic diseases: ischemic heart disease (IHD), non-small cell lung cancer (NSCLC), chronic obstructive pulmonary disease (COPD), Alzheimer's disease (AD), and type 2 diabetes (T2D). Guidelines were reviewed and data on treatment recommendations were collected, including the type of intervention, line of therapy, and, for pharmacotherapies, year of regulatory approval and year of inclusion in guidelines. Results: In total, 92 clinical practice guidelines were reviewed. Among the 184 discrete recommended interventions across the five disease areas, 146 (79.3%) were pharmacotherapies, 21 (11.4%) were behavioral modifications, 6 (3.3%) were surgical interventions, and 11 (6%) were other interventions. Across guidelines, when a line of therapy was specified, behavioral modifications and pharmacotherapies were most frequently recommended as first-line interventions, whereas surgical interventions were more often recommended for subsequent lines of treatment. The time from regulatory approval of novel pharmacotherapies to inclusion in guideline recommendations varied considerably by disease area and geography. Conclusions: Across the reviewed disease areas, behavioral interventions and pharmacotherapies are shown to be critical components of clinical practice. Over the last 20 years, novel pharmaceutical innovations have been incorporated into clinical practice guideline recommendations; however, with varying speeds of adoption. Given the increasing pace of pharmacologic innovation, timely updates of clinical practice guidelines are critical to evolving the standard of care and practicing evidence-based medicine.

Improving Vaccine Equity: How Community Engagement and Informatics Facilitate Health System Outreach to Underrepresented Groups.

BACKGROUND: Given the inequities in access to health care resources like COVID-19 vaccination, health systems should carefully consider how to reach underrepresented groups. Reflecting on vaccine rollout efforts holds insight on the role of community engagement and informatics support in promoting health equity. OBJECTIVES: This study aimed to assess the effectiveness of four outreach strategies deployed by University of Washington (UW) Medicine in improving vaccine equity over traditional vaccine scheduling online or by phone, we report on appointment scheduling and completion of appointments (i.e., vaccine administration) through (1) automated outreach to individuals from underrepresented groups, (2) temporary "pop-up" clinics in neighborhoods highly impacted by COVID-19, (3) vulnerable population clinics, and (4) mobile vaccine vans. METHODS: We conducted a 6-month retrospective analysis of electronic health records (EHR) to describe the sociodemographic characteristics of individuals who scheduled appointments using the outreach strategies and characteristics associated with a greater likelihood of vaccine administration based on appointment completion. To help explain trends in the EHR data, we engaged 10 health system leaders and staff who spearheaded the outreach strategies in follow-up conversations to identify qualitative insights into what worked and why. RESULTS: Compared with traditional scheduling, all outreach strategies except vulnerable population clinics had higher vaccine appointment completion rates, including automated outreach (N = 3,734 [94.7%], p < 0.001), pop-up clinics (N = 4,391 [96.0%], p < 0.001), and mobile vans (N = 4,198 [99.1%], p < 0.001); and lower cancellation rates, including automated outreach (N = 166 [1.1%], p < 0.001), pop-up clinics (N = 155 [0.6%], p < 0.001), and mobile vans (N = 0 [0%], p < 0.001). Qualitative insights emphasized ongoing community partnerships and information resources in successful outreach. CONCLUSION: Vaccine equity outreach strategies improved the proportion of patients who scheduled and completed vaccination appointments among populations disproportionately impacted by COVID-19. Engaging community partners and equity-focused informatics tools can facilitate outreach. Lessons from these outreach strategies carry practical implications for health systems to amplify their health equity efforts.

Acute promyelocytic leukemia with PML/RARA (bcr1, bcr2 and bcr3) transcripts in a pediatric patient.

Patients with acute promyelocytic leukemia (APL) exhibit the t(15;17)(q24.1;q21.2) translocation that produces the promyelocytic leukemia (PML)/retinoic acid receptor α (RARA) fusion gene. Different PML breakpoints yield three alternative molecular transcripts, bcr1, bcr2 and bcr3. The present study reports the simultaneous presence of three PML/RARA transcripts in a pediatric female patient diagnosed with APL, according to the clinical characteristics, immunophenotype and karyotype of the patient. The simultaneous presence of the PML/RARA transcripts were detected using reverse transcription-quantitative PCR (RT-qPCR). This was confirmed with HemaVision-28N Multiplex RT-qPCR, HemaVision-28Q qualitative RT-qPCR and the AmpliSeq RNA Myeloid Panel. To the best of our knowledge, the pediatric patient described in the present study is the first case found to exhibit all three PML/RARA transcripts (bcr1, bcr2 and bcr3). Additionally, a microarray analysis was performed to determine the expression profile, potential predictive biomarkers and the implications of this uncommon finding. According to the information obtained from molecular monitoring, the results reported in the present study were associated with a good patient prognosis. In addition, upregulated genes that are rare in acute myeloid leukemia were identified, and these genes may be promising diagnostic biomarkers for further study. For example, CCL-1 is present in leukemic stem cells, causing treatment failure and relapse, and α- and ß-defensins have been reported exclusively in chronic myeloid leukemia. However, the results of the present study confirmed that they may also be present in APL. Thus, these findings suggested a possible signaling pathway that involves the PML/RARA oncoprotein in APL.

Hospitalizations and Mortality From Myasthenia Gravis: Trends From 2 US National Datasets

BACKGROUND AND OBJECTIVES: Myasthenia gravis (MG) is a rare neuromuscular disorder where IgG antibodies damage the communication between nerves and muscles, leading to muscle weakness that can be severe and have a significant impact on patients' lives. MG exacerbations include myasthenic crisis with respiratory failure, the most serious manifestation of MG. Recent studies have found MG prevalence increasing, especially in older patients. This study examined trends in hospital admissions and in-hospital mortality for adult patients with MG and readmissions and postdischarge mortality in older (65 years or older) adults with MG. METHODS: Data from the Nationwide Inpatient Sample (NIS), an all-payer national database of hospital discharges, were used to characterize trends in hospitalizations and in-hospital mortality related to MG exacerbations and MG crisis among adult patients aged 18 years or older. The Medicare Limited Data Set, a deidentified, longitudinal research database with demographic, enrollment, and claims data was used to assess hospitalizations, length of stay (LOS), readmissions, and 30-day postdischarge mortality among fee-for-service Medicare beneficiaries aged 65 years or older. The study period was 2010-2019. Multinomial logit models and Poisson regression were used to test for significance of trends. RESULTS: Hospitalization rates for 19,715 unique adult patients and 56,822 admissions increased from 2010 to 2019 at an average annualized rate of 4.9% (MG noncrisis: 4.4%; MG crisis: 6.8%; all p < 0.001). Readmission rates were approximately 20% in each study year for both crisis and noncrisis hospitalizations; the in-hospital mortality rate averaged 1.8%. Among patients aged 65 years or older, annualized increases in hospitalizations were estimated at 5.2%, 4.2%, and 7.7% for all, noncrisis, and crisis hospitalizations, respectively (all p < 0.001). The average LOS was stable over the study period, ranging from 11.3 to 13.1 days, but was consistently longer for MG crisis admissions. Mortality among patients aged 65 years or older was higher compared with that in all patients, averaging 5.0% across each of the study years. DISCUSSION: Increasing hospitalization rates suggest a growing burden associated with MG, especially among older adults. While readmission and mortality rates have remained stable, the increasing hospitalization rates indicate that the raw numbers of readmissions-and deaths-are also increasing. Mortality rates are considerably higher in older patients hospitalized with MG.

Dynamic, sex- and diet-specific pleiotropism in the PAC1 receptor-mediated regulation of arcuate proopiomelanocortin and Neuropeptide Y/Agouti related peptide neuronal excitability by anorexigenic ventromedial nucleus PACAP neurons.

This study furthers the investigation of how pituitary adenylate cyclase activating polypeptide (PACAP) and the PAC1 receptor (PAC1R) regulate the homeostatic energy balance circuitry. We hypothesized that apoptotic ablation of PACAP neurones in the hypothalamic ventromedial nucleus (VMN) would affect both energy intake and energy expenditure. We also hypothesized that selective PAC1R knockdown would impair the PACAP-induced excitation in anorexigenic proopiomelanocortin (POMC) neurones and inhibition of orexigenic neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurones in the hypothalamic arcuate nucleus (ARC). The results show CASPASE-3-induced ablation of VMN PACAP neurones leads to increased energy intake and meal frequency as well as decreased energy expenditure in lean animals. The effects were more robust in obese males, whereas we saw the opposite effects in obese females. We then utilized visualized whole-cell patch clamp recordings in hypothalamic slices. PAC1R knockdown in POMC neurones diminishes the PACAP-induced depolarization, increase in firing, decreases in energy intake and meal size, as well as increases in CO2 production and O2 consumption. Similarly, the lack of expression of the PAC1R in NPY/AgRP neurones greatly attenuates the PACAP-induced hyperpolarization, suppression of firing, decreases in energy intake and meal frequency, as well as increases in energy expenditure. The PACAP response in NPY/AgRP neurones switched from predominantly inhibitory to excitatory in fasted animals. Finally, the anorexigenic effect of PACAP was potentiated when oestradiol was injected into the ARC in ovariectomized females. This study demonstrates the critical role of anorexigenic VMN PACAP neurones and the PAC1R in exciting POMC and inhibiting NPY/AgRP neurons to control homeostatic feeding.

Dyslipidemia Update.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. The development and progression of atherosclerotic CVD are largely dependent on a multitude of modifiable and nonmodifiable risk factors. Current therapeutic strategies involve risk factor modification, especially dyslipidemia. The treatment of dyslipidemia continues to be dynamic, and in this paper, we review the current strategies for risk assessment, diagnosis, and treatment. As treatments for the management of dyslipidemia continue to evolve with ever-increasing options for therapeutic targets, an understanding of lipid-lowering therapies remains an essential topic of understanding for all health care providers.

Fulminant Overwhelming Necrotizing Vibrio vulnificus Sepsis Secondary to Oyster Consumption.

Vibrio vulnificus is an opportunistic gram-negative rod-shaped bacteria found in warm, low salinity waters. Transmission through open wounds or consumption of contaminated seafood can lead to wound infections, sepsis, and potentially death. A 44-year-old man with a history of poly-substance abuse, cirrhosis, and recent oyster consumption presented to the emergency department in June with acute onset bilateral leg pain associated with rash and fever. Within 6 hours of his arrival, the rash rapidly progressed to large bullae with extensive necrosis ascending to the level of the abdomen, and he developed septic shock. Despite prompt surgical intervention and appropriate antibiotic and resuscitative therapies, the patient had progressive multi-system organ failure and died 7 days after admission. Concurrent necrotizing fasciitis with sepsis secondary to V. vulnificus infection is rare and potentially fatal, as demonstrated in this case.

Impostor phenomenon in registered dietitians: an exploratory survey.

BACKGROUND: Impostor phenomenon, also referred to as imposter syndrome or impostorism, was initially identified among high achieving women who felt undeserving of their successes because they felt they were earned through luck or chance, rather than skill or experience. It's prevalence has been identified in many health professions; however, there are no known studies of Registered Dietitians' (RDs) perceptions of impostor phenomenon. This study assesses the following among RDs: [1] prevalence of impostor phenomenon and differences in impostor phenomenon levels, if any, based on [2] highest educational level achieved and [3] years of experience as an RD. METHODS: A cross-sectional survey was sent electronically to 5,000 RDs credentialed by the Commission on Dietetic Registration in the United States. Respondents' agreement with 20 impostor phenomenon statements from the Clance Impostor Phenomenon Scale were measured. The sum score from the scale was used to classify levels of impostor phenomenon. Descriptive statistics and chi square analyses for comparison were evaluated. RESULTS: Of the 445 (9%) who began the survey, 266 (5%) completed it and were included in analyses. Over 76% of 266 individuals reported at least moderate impostorism (score of 40 or fewer points out of 100). No difference was seen based on educational level (p = .898); however, those with less than five years' experience reported higher impostor phenomenon (p < .05). Among those with five to 39 years' experience, over 40% reported moderate impostorism. CONCLUSION: Impostor phenomenon is prevalent among RDs. Moderate impostorism was pervasive among all those with less than 40 years' experience and could potentially negatively impact these respondents. Future research could explore ways to reduce impostor phenomenon in RDs.

Peripheral T-cell receptor repertoire dynamics in small cell lung cancer.

Background: Identifying a circulating biomarker predictive of immune checkpoint inhibitor (ICI) benefit in patients with small cell lung cancer (SCLC) remains an unmet need. Characteristics of peripheral and intratumoral T-cell receptor (TCR) repertoires have been shown to predict clinical outcomes in non-small cell lung cancer (NSCLC). Recognizing a knowledge gap, we sought to characterize circulating TCR repertoires and their relationship with clinical outcomes in SCLC. Methods: SCLC patients with limited (n=4) and extensive (n=10) stage disease were prospectively enrolled for blood collection and chart review. Targeted next-generation sequencing of TCR beta and alpha chains of peripheral blood samples was performed. Unique TCR clonotypes were defined by identical CDR3, V gene, and J gene nucleotide sequences of the beta chain and subsequently used to calculate TCR diversity indices. Results: Patients with stable versus progressive and limited versus extensive stage disease did not demonstrate significant differences in V gene usage. Kaplan-Meier curve and log-rank analysis did not identify a statistical difference in progression-free survival (PFS) (P=0.900) or overall survival (OS) (P=0.200) between high and low on-treatment TCR diversity groups, although the high diversity group exhibited a trend toward increased OS. Conclusions: We report the second study investigating peripheral TCR repertoire diversity in SCLC. With a limited sample size, no statistically significant associations between peripheral TCR diversity and clinical outcomes were observed, though further study is warranted.

Comparing Severely Injured Trauma Patients Admitted to Investor-Owned versus Public and Not-For-Profit Hospitals Reveals Opportunities for Improvement in the US.

BACKGROUND: Non-elderly trauma patients represent the largest portion of preventable years of life loss in the US. The purpose of this study was to compare outcomes in patients admitted to investor-owned vs public and not-for-profit hospitals across the US. MATERIAL AND METHODS: The Nationwide Readmissions Database 2018 was queried for trauma patients with an Injury Severity Score greater than 15 and age 18-65 years. The primary outcome was mortality; secondary outcomes were prolonged length of stay (LOS) greater than 30 days, readmission within 30 days, and readmission to a different hospital. Patients admitted to investor-owned hospitals were compared to public and not-for-profit hospitals. Univariable analysis was performed using chi-squared tests. Multivariable logistic regression was performed for each outcome. RESULTS: 157 945 patients were included with 11.0% (n = 17 346) admitted to investor-owned hospitals. The overall mortality rate and prolonged LOS were similar for both groups. The overall readmission rate was 9.2% (n = 13 895), with the rate in investor-owned hospitals at 10.5% (n = 1,739, P < .001). Multivariable logistic regression revealed investor-owned hospitals had an increased risk of readmission (OR 1.2 [1.1-1.3] P < .001) and readmission to a different hospital (OR 1.3 [1.2-1.5] P < .001). DISCUSSION: Severely injured trauma patients have similar rates of mortality and prolonged length of stay in investor-owned vs public and not-for-profit hospitals. However, patients admitted to investor-owned hospitals have an increased risk of readmission and readmission to different hospitals. Efforts to improve outcomes after trauma must consider hospital ownership and readmission to different hospitals.

Expert consensus established around flexible, individualized migraine treatment utilizing a modified Delphi panel.

OBJECTIVE: To characterize treatment decision-making processes and formalize consensus regarding key factors headache specialists consider in treatment decisions for patients with migraine, considering novel therapies. BACKGROUND: Migraine therapies have long been subject to binary classification, acute versus preventive, due to limitations of available drugs. The emergence of novel therapies that can be used more flexibly creates an opportunity to rethink this binary classification. To determine the role of these novel therapies in treatment, it is critical to understand whether existing guidelines reflect clinical practice and to establish consensus around factors driving management. METHODS: A three-round modified Delphi process was conducted with migraine clinical experts. Round 1 consisted of an online questionnaire; Round 2 involved an online discussion of aggregated Round 1 results; and Round 3 allowed participants to revise Round 1 responses, incorporating Round 2 insights. Questions elicited likelihood ratings (0 = highly unlikely to 100 = highly likely), rankings, and estimates on treatment decision-making. RESULTS: Nineteen experts completed three Delphi rounds. Experts strongly agreed on definitions for "acute" (median = 100, inter-quartile range [IQR] = 5) and "preventive" treatment (median = 90, IQR = 15), but noted a need for treatment customization for patients (median = 100, IQR = 6). Experts noted certain aspects of guidelines may no longer apply based on established tolerability and efficacy of newer acute and preventive agents (median = 91, IQR = 17). Further, experts agreed on a treatment category referred to as "situational prevention" (or "short-term prevention") for patients with reliable and predictable migraine triggers (median = 100, IQR = 10) or time-limited periods when headache avoidance is important (median = 100, IQR = 12). CONCLUSIONS: Using the modified Delphi method, a panel of migraine experts identified the importance of customizing treatment for people with migraine and the utility of "situational prevention," given the ability of new treatment options to meet this need and the potential to clinically identify patients and time periods when this approach would add value.

Comparing Payments to Surgeons From Drug and Medical Device Corporations Reveals Inequalities Between Genders and Specialties.

INTRODUCTION: Maintaining trust in the patient-doctor relationship requires transparency in the details of the financial relationships between physicians and drug and medical device corporations. These details are publicly available through the Open Payments database, and patients are encouraged to ask surgeons to interpret their implications. The purpose of this study was to better equip surgeons in responding to these inquiries and to compare the distribution of these payments by gender and specialty. METHODS: The 2021 Open Payments dataset was searched for all payments to surgeons from the 14 different specialties recognized by the American College of Surgeons. The total payments per surgeon were compared by calculating the mean and median payments. The Gini index, a measure of income inequality, was also calculated for each specialty. RESULTS: There were 96 724 surgeons who received over $755 million in payments from drug and medical device companies. There were 72 245 (74.7%) men and 24 479 (25.3%) women. The total amount of payments to men was $712 million (94.2%) and for women it was $44 million (5.8%). The overall Gini index was .9508. The specialty with the highest Gini index was pediatric surgery (.9844) and the lowest was cardiothoracic surgery (.8656). DISCUSSION: Male surgeons received disproportionately higher payments from drug and device corporations than female surgeons. Surgeons should be aware of their own standing within the Open Payments database in order to respond appropriately to patient inquiries.

An Unusual Combination of Arthrogryposis, Gastroschisis, Cecal Volvulus, and Malignant Hyperthermia in a Young Woman: A Case Report.

BACKGROUND The purpose of this study is to discuss a patient with a history of conditions, including arthrogryposis, gastroschisis, and malignant hyperthermia, who presented with cecal volvulus requiring urgent surgical intervention. CASE REPORT A 29-year-old woman with a history of arthrogryposis, gastroschisis, malignant hyperthermia, and multiple childhood abdominal surgeries presents to the Emergency Department (ED) with 2 days of abdominal pain and bloody diarrhea. A CT abdomen/pelvis revealed findings concerning for a cecal volvulus. The patient was premedicated and monitored closely by the anesthesia team due to her history of malignant hyperthermia. She underwent an exploratory laparotomy, where a dilated cecum and proximal ascending colon were found to be completely volvulized around the mesentery. Manual bowel detorsion was performed, which resulted in reperfusion of the ischemic-appearing bowel, which then appeared viable. She recovered well after the procedure and was discharged on postoperative day 5. CONCLUSIONS This case highlights a patient who presented with a combination of 4 findings: arthrogryposis, gastroschisis, malignant hyperthermia, and cecal volvulus. With arthrogryposis reported to be associated with gastroschisis and malignant hyperthermia, this report not only corroborates this association, but also aims to draw attention to the fact that these conditions have potential to occur jointly with cecal volvulus. Given the patient's history of gastroschisis requiring extensive abdominal surgeries that contribute as risk factors for cecal volvulus, it is possible there may be other arthrogryposis patients who present with cecal volvulus similar to that seen in this patient.

A Real World Perspective of PARP Inhibitor Use in Gynecological Cancer Patients.

Introduction: Over the last few years, targeted therapy has become the mainstay maintenance treatment of patients with ovarian cancer including patients with BRCA1/BRCA2 mutations. Poly ADP ribose polymerase inhibitors (PARPi) are effective in the treatment of patients who are in complete or partial remission. PARPi are known to cause hematological adverse events (AEs), but have not been compared directly to each other. Objective: Primary objective was to compare the incidence of hematological and non-hematological AEs associated with the use of PARPi. Methods: This was a single institution, retrospective study evaluating patients who were treated with PARPi for ovarian cancer from January 2017 to October 2020. Patients were stratified according to which PARP inhibitor they received. Results: Ninety-two patients were included in final analysis. Thirty-one (33.7%) patients received niraparib and 61 (66.3%) patients received olaparib. Median age of patients were 64.3 (range, 33.8 to 92.3) years, 66 (71.7%) were white, and 84 (91.3%) had an ECOG PS of 0/1. Patients in the niraparib group experienced a higher rate of hematologic AEs, with 11 (35.5%), 20 (64.5%), and 18 (58.1%) experiencing neutropenia, anemia, and thrombocytopenia, respectively. Eight (13.1%), 24 (39.3%), and 16 (26.2%) patients in the olaparib group experienced neutropenia, anemia, and thrombocytopenia, respectively. Conclusion: This single institution retrospective study outlines the hematological toxicities observed between two PARPi. Our results suggested that niraparib tended to be associated with a higher risk for hematologic toxicities than olaparib. Anemia was the most common hematologic toxicity which was consistent with what has been widely documented in the literature.

The vital role of arcuate nociceptin/orphanin FQ neurones in mounting an oestradiol-dependent adaptive response to negative energy balance via inhibition of nearby proopiomelanocortin neurones.

We tested the hypothesis that N/OFQ neurones in the arcuate nucleus (N/OFQARC ) inhibit proopiomelanocortin (POMCARC ) neurones in a diet- and hormone-dependent manner to promote a more extensive rebound hyperphagia upon re-feeding following an 18 h fast. We utilized intact male or ovariectomized (OVX) female mice subjected to ad libitum-feeding or fasting conditions. N/OFQARC neurones under negative energy balance conditions displayed heightened sensitivity as evidenced by a decreased rheobase threshold, increased firing frequency, and increased burst duration and frequency compared to ad libitum-feeding conditions. Stimulation of N/OFQARC neurones more robustly inhibited POMCARC neurones under fasting conditions compared to ad libitum-feeding conditions. N/OFQARC inhibition of POMCARC neurones is hormone dependent as chemostimulation of N/OFQARC neurones from fasted males and OVX females produced a sizable outward current in POMCARC neurones. Oestradiol (E2 ) markedly attenuated the N/OFQ-induced POMCARC outward current. Additionally, N/OFQ tonically inhibits POMCARC neurones to a greater degree under fasting conditions than in ad libitum-feeding conditions as evidenced by the abrogation of N/OFQ-nociceptin opioid peptide (NOP) receptor signalling and inhibition of N/OFQ release via chemoinhibition of N/OFQARC neurones. Intra-arcuate nucleus application of N/OFQ further elevated the hyperphagic response and increased meal size during the 6 h re-feed period, and these effects were mimicked by chemostimulation of N/OFQARC neurones in vivo. E2 attenuated the robust N/OFQ-induced rebound hyperphagia seen in vehicle-treated OVX females. These data demonstrate that N/OFQARC neurones play a vital role in mitigating the impact of negative energy balance by inhibiting the excitability of anorexigenic neural substrates, an effect that is diminished by E2 in females. KEY POINTS: Nociceptin/orphanin FQ (N/OFQ) promotes increased energy intake and decreased energy expenditure under conditions of positive energy balance in a sex- and hormone-dependent manner. Here it is shown that under conditions of negative energy balance, i.e. fasting, N/OFQ inhibits anorexigenic proopiomelanocortin (POMC) neurones to a greater degree compared to homeostatic conditions due to fasting-induced hyperexcitability of N/OFQ neurones. Additionally, N/OFQ promotes a sustained increase in rebound hyperphagia and increase in meal size during the re-feed period following a fast. These results promote greater understanding of how energy balance influences the anorexigenic circuitry of the hypothalamus, and aid in understanding the neurophysiological pathways implicated in eating disorders promoting cachexia.

Perioperative Outcomes in Patients With Failing Single-Ventricle Physiology Undergoing Ventricular Assist Device Placement: A Single Institutional Experience.

OBJECTIVE: To address the current lack of specified data existing regarding the perioperative characteristics and outcomes in a novel patient population, which may bridge the current understanding of how patient characteristics and perioperative management may influence the postoperative hospital course before cardiac transplantation. DESIGN: A retrospective electronic chart review included all patients with failing single- ventricle (SV) physiology receiving ventricular assist device (VAD) support at a high-volume pediatric VAD center between April 5, 2010, and December 1, 2020, using institution-based electronic medical records for retrospective analysis. SETTING: At a single pediatric hospital. PARTICIPANTS: Fourteen pediatric patients with failing SV physiology receiving ventricular assist device therapy (SVAD). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Preoperative, intraoperative, and postoperative patient demographic and medical data were obtained from prior inpatient progress notes, laboratory values, anesthetic records, cardiac catheterization reports, echocardiography reports, and postoperative surgical notes entered during inpatient encounters at the time of SVAD placement. Between April 5, 2010, and December 1, 2020, 16 VAD device implants supported 14 pediatric patients with failing SV physiology. Most patients presented with a preoperative diagnosis of hypoplastic left heart syndrome (N = 9, 64.3%). A total of 6 patients expired on VAD therapy (43%), 7 (50%) survived to receive a cardiac transplant, and 1 patient currently remains on device therapy. CONCLUSION: Although our institutional approach represents a single perspective, we anticipate that our experience institutional experience may prove helpful to others caring for peditric patients with single ventricle physiology undergoing ventricular assist device placement and promote collaborative efforts to improve their care.

Real-world outcomes in patients with first-line and second-line therapy for advanced esophageal squamous cell carcinoma.

Background: Little is known about real-world outcomes for first-line and anti-PD-1 second-line treatment for advanced/metastatic esophageal squamous cell carcinoma (ESCC). Patients & methods: Retrospective data of advanced/metastatic ESCC patients treated between 2011 and 2021 were collected from Flatiron Health. Median duration of therapy (mDoT) and median overall survival (mOS) were evaluated for patients initiating first-line and anti-PD-1 second-line therapy. Results: Among patients receiving first-line therapy (n = 948), mDoT was 1.4 months and mOS was 16.0 months, with mOS of 16.0 and 18.0 months for the non-immunotherapy and immunotherapy cohorts, respectively. Among patients receiving anti-PD-1 second-line therapy (n = 60), mDoT was 5.7 months and mOS was 10.1 months. Conclusion: Patients with advanced/metastatic ESCC have short duration of therapy, and overall survival remains limited. This real-world study underscores the need for efficacious treatments for advanced/metastatic ESCC in the first- and second-line setting. Direct comparisons of emerging therapies in the real world are urgently needed.

Hemipelvectomy as a Salvage Procedure in Massive Pelvic Trauma.

"Pedestrian struck by train" represents one of the highest magnitude blunt force traumas. Despite the severity of injuries, these patients can have good outcomes. A 25-year-old male presented after being struck by a train. He had several injuries, including extensive complex pelvic fractures, right external iliac artery and vein laceration, and right femur and tibia fracture. He was taken to the operating room for damage control surgery and attempted revascularization of the right lower extremity. The extremity became ischemic and required above knee amputation followed by hip disarticulation and hemipelvectomy. His pelvic wounds were treated with negative pressure wound therapy and gradually closed. He was eventually discharged to a rehab facility for continued recovery. This case highlights the interventions that allowed a young man who was struck by a train to survive. He improved significantly since undergoing hemipelvectomy, indicating that severe pelvic injuries from high energy trauma may necessitate hemipelvectomy.