Intravenous versus oral acetaminophen for pain and quality of recovery after ambulatory spine surgery: a randomized controlled trial.

INTRODUCTION: As ambulatory spine surgery increases, efficient recovery and discharge become essential. Multimodal analgesia is superior to opioids alone. Acetaminophen is a central component of multimodal protocols and both intravenous and oral forms are used. While some advantages for intravenous acetaminophen have been touted, prospective studies with patient-centered outcomes are lacking in ambulatory spine surgery. A substantial cost difference exists. We hypothesized that intravenous acetaminophen would be associated with fewer opioids and better recovery. METHODS: Patients undergoing ambulatory spine surgery were randomized to preoperative oral placebo and intraoperative intravenous acetaminophen or preoperative oral acetaminophen. All patients received general anesthesia and multimodal analgesia. The primary outcome was 24-hour opioid use in intravenous morphine milligram equivalents (MMEs), beginning with arrival to the postanesthesia care unit (PACU). Secondary outcomes included pain, Quality of Recovery (QoR)-15 scores, postoperative nausea and vomiting, recovery time, and correlations between pain catastrophizing, QoR-15, and pain. RESULTS: A total of 82 patients were included in final analyses. Demographics were similar between groups. For the primary outcome, the median 24-hour MMEs did not differ between groups (12.6 (4.0, 27.1) vs 12.0 (4.0, 29.5) mg, p=0.893). Postoperative pain ratings, PACU MMEs, QoR-15 scores, and recovery time showed no differences. Spearman's correlation showed a moderate negative correlation between postoperative opioid use and QoR-15. CONCLUSION: Intravenous acetaminophen was not superior to the oral form in ambulatory spine surgery patients. This does not support routine use of the more expensive intravenous form to improve recovery and accelerate discharge. TRIAL REGISTRATION NUMBER: NCT04574778.

Class A capsid assembly modulator apoptotic elimination of hepatocytes with high HBV core antigen level in vivo is dependent on de novo core protein translation.

Capsid assembly is critical in the hepatitis B virus (HBV) life cycle, mediated by the viral core protein. Capsid assembly is the target for new anti-viral therapeutics known as capsid assembly modulators (CAMs) of which the CAM-aberrant (CAM-A) class induces aberrant shaped core protein structures and leads to hepatocyte cell death. This study aimed to identify the mechanism of action of CAM-A modulators leading to HBV-infected hepatocyte elimination where CAM-A-mediated hepatitis B surface antigen (HBsAg) reduction was evaluated in a stable HBV replicating cell line and in AAV-HBV-transduced C57BL/6, C57BL/6 SCID, and HBV-infected chimeric mice with humanized livers. Results showed that in vivo treatment with CAM-A modulators induced pronounced reductions in hepatitis B e antigen (HBeAg) and HBsAg, associated with a transient alanine amino transferase (ALT) increase. Both HBsAg and HBeAg reductions and ALT increase were delayed in C57BL/6 SCID and chimeric mice, suggesting that adaptive immune responses may indirectly contribute. However, CD8+ T cell depletion in transduced wild-type mice did not impact antigen reduction, indicating that CD8+ T cell responses are not essential. Transient ALT elevation in AAV-HBV-transduced mice coincided with a transient increase in endoplasmic reticulum stress and apoptosis markers, followed by detection of a proliferation marker. Microarray data revealed antigen presentation pathway (major histocompatibility complex class I molecules) upregulation, overlapping with the apoptosis. Combination treatment with HBV-specific siRNA demonstrated that CAM-A-mediated HBsAg reduction is dependent on de novo core protein translation. To conclude, CAM-A treatment eradicates HBV-infected hepatocytes with high core protein levels through the induction of apoptosis, which can be a promising approach as part of a regimen to achieve functional cure. IMPORTANCE: Treatment with hepatitis B virus (HBV) capsid assembly modulators that induce the formation of aberrant HBV core protein structures (CAM-A) leads to programmed cell death, apoptosis, of HBV-infected hepatocytes and subsequent reduction of HBV antigens, which differentiates CAM-A from other CAMs. The effect is dependent on the de novo synthesis and high levels of core protein.

Identification of a potent and specific retinoic acid-inducible gene 1 pathway activator as a Hepatitis B Virus antiviral through a novel cell-based reporter assay.

Chronic Hepatitis B Virus (HBV) infection remains a global burden. To identify small molecule RIG-I agonists as antivirals against HBV, we developed an HBV-pgRNA-based interferon-ß (IFN-ß) luciferase reporter assay with high level of assay sensitivity, specificity and robustness. Through HTS screening, lead compound (JJ#1) was identified to activate RIG-I signaling pathway by inducing TBK1 phosphorylation. Knockdown experiments demonstrated that JJ#1-induced retinoic acid-inducible gene 1 (RIG-I) signaling pathway activation was MAVS-dependent. Furthermore, JJ#1 exhibited HBV antiviral potency in HBV-infected cell models by reducing HBV DNA and antigens (HBsAg and HBeAg).

The effects of a multidisciplinary pathway for perioperative management of patients with hip fracture.

OBJECTIVES: To determine if a multidisciplinary pathway focused on non-opioid pain management, delirium assessment, and resource utilization improved outcomes in geriatric hip fracture patients. The goal was to reduce opioid usage, consultation not congruent with guidelines, and increase use of regional anesthesia to reduce delirium and improve outcomes. METHODS: An observational study was performed on hip fracture patients before and after the intervention. Hospitalists were educated on indications for preoperative cardiac consultation and specialized preoperative cardiac testing according to evidence-based guidelines with the inpatient cardiology service. Additional education on multimodal analgesia, limiting opioids, and peripheral nerve blocks was provided by the acute pain service. Pre-intervention outcomes from 1 July 20171 July 2017 to 31 May 201831 May 2018 (N = 92) were compared to post-intervention outcomes from 1 July 20181 July 2018 to 31 May 201931 May 2019 (N = 98) and included delirium, length of stay, 30-day readmission rate, time from arrival to procedure start time, time to first physical therapy session, and completion of cardiology consult time. We examined adherence, use of nerve blocks, and pre- and post-operative pain scores and opioid use. RESULTS: Delirium was reduced from 50.0% (N = 46/92) to 28.6% (N = 28/98); p = 0.002. Postoperative opioid use (IV morphine milligram equivalents) decreased from an average of 57.2 mg (±67.7) to 42.6 mg (±58.2),P < .0001. There was a significant decrease in mean pre-operative (5.4 ± 4.14 to 5.05 ± 2.8, P < .0001) and post-operative pain scores (4.3 ± 5.2 to 3.2 ± 2.2, P < .0001). There was a significant reduction in time to cardiology consultation from 18 h] to 12 h ; p < .001). CONCLUSIONS: A multidisciplinary collaboration between hospitalists, anesthesiologists, and cardiologists for hip fracture patients was associated with a reduction in pain and delirium and time to cardiologist evaluation. Prospective studies focusing on additional patient-centered outcomes are warranted.

Indirect Modulation by FLP-1 Peptides on Chemotaxis and Dispersal Behavior in C. elegans.

Parasitic nematodes infect and cause morbidity in over one billion people worldwide, with current anthelmintic drugs decreasing in efficacy. To date, nematodes produce more types of neuropeptides than any other animal. We are interested in the role of neuropeptide signaling systems as a possible target for new anthelmintic drugs. Although FMRFamide-related peptides are found throughout the animal kingdom, the number of these peptides in nematodes greatly exceeds that of any other phylum. We are using Caenorhabditis elegans as a model for examining FMRFamide-like peptides, all of which share a C-terminal Arg-Phe-amide and which are known as FLPs in nematodes. Our previous work indicated interactions between the daf-10 , tax-4 , and flp-1 signaling pathways. In this paper, we further explore these interactions with chemotaxis and dispersal assays.

Physician Burnout and Medical Errors: Exploring the Relationship, Cost, and Solutions.

Physician burnout has demonstrated risks to providers and patients through medical errors. This review aims to synthesize current data surrounding burnout and its impacts on quality to inform targeted interventions that benefit providers and patients. Preferred Reporting Items for Systematic Reviews and Meta-Analyses scoping review methodology was utilized to identify studies of quantitative metrics for burnout and medical errors. Three independent reviewers conducted screening, study selection, and data extraction. Of 1096 identified articles, 21 were analyzed. Overall, 80.9% used the Maslach Burnout Inventory to evaluate for burnout. Moreover, 71.4% used self-reported medical errors as their primary outcome measure. Other outcome measures included observed/identified clinical practice errors and medication errors. Ultimately, 14 of 21 studies found links between burnout and clinically significant errors. Significant associations exist between burnout and medical errors. Physician demographics, including psychological factors, well-being, and training level, modulate this relationship. Better metrics are necessary to quantify errors and their impacts on outcomes. These findings may inform novel interventions that target burnout and improve experiences.

Analgesic options for anterior approach to scoliosis repair: a scoping review.

PURPOSE: The ideal analgesic regimen for the anterior approach to scoliosis repair is not clearly defined. The purpose of the study was to summarize and identify gaps in the current literature specific to the anterior approach to scoliosis repair. METHODS: A scoping review was conducted in July 2022 utilizing PubMed, Cochrane, and Scopus databases guided by the PRISMA-ScR framework. RESULTS: The database search generated 641 possible articles, 13 of which met all inclusion criteria. All articles focused on the effectiveness and safety of regional anesthetic techniques, while a minority also provided both opioid and non-opioid medication frameworks. CONCLUSION: Continuous Epidural Analgesia (CEA) is the most well-studied intervention for pain control in anterior scoliosis repair, but other, more novel regional anesthetic techniques offer safe and effective potential alternatives. More research is indicated to compare the effectiveness of different regional techniques and perioperative medication regimens specific to anterior scoliosis repair.

Differential response of HBV envelope-specific CD4 + T cells is related to HBsAg loss after stopping nucleos(t)ide analogue therapy.

BACKGROUND AND AIM: Long-term maintenance of viral control, even HBsAg loss, remains a challenge for chronic hepatitis B (CHB) patients undergoing nucleos(t)ide analogue (NA) discontinuation. This study aimed to investigate the relationship between HBV-specific T-cell responses targeting peptides spanning the whole proteome and clinical outcomes in CHB patients after NA discontinuation. APPROACH AND RESULTS: Eighty-eight CHB patients undergoing NA discontinuation were classified as responders (remained relapse-free up to 96 weeks) or relapsers (relapsed patients who underwent NA retreatment for up to 48 weeks and reachieved stable viral control). HBV-specific T-cell responses were detected at baseline and longitudinally throughout the follow-up. We found responders had a greater magnitude of HBV polymerase (Pol)-specific T-cell responses than relapsers at baseline. After long-term NA discontinuation, simultaneously enhanced HBV Core-induced and Pol-induced responses were observed in responders. Particularly, responders with HBsAg loss possessed enhanced HBV Envelope (Env)-induced responses after short-term and long-term follow-up. Notably, CD4 + T cells accounted for the predominance of HBV-specific T-cell responses. Correspondingly, CD4-deficient mice showed attenuated HBV-specific CD8 + T-cell responses, reduced HBsAb-producing B cells, and delayed HBsAg loss; in contrast, in vitro addition of CD4 + T cells promoted HBsAb production by B cells. Besides, IL-9, rather than PD-1 blockade, enhanced HBV Pol-specific CD4 + T-cell responses. CONCLUSION: HBV-specific CD4 + T-cell responses induced by the targeted peptide possess specificities for long-term viral control and HBsAg loss in CHB patients undergoing NA discontinuation, indicating that CD4 + T cells specific to distinct HBV antigens may endow with divergent antiviral potential.

Coupled thermal-hemodynamics computational modeling of cryoballoon ablation for pulmonary vein isolation.

Cryoballoon ablation (CBA) is a cryo-energy based minimally invasive treatment procedure for patients suffering from left atrial (LA) fibrillation. Although this technique has proved to be effective, it is prone to reoccurrences and some serious thermal complications. Also, the factors affecting thermal distribution at the pulmonary vein-antrum junction that are critical to the treatment success is poorly understood. Computer modeling of CBA can resolve this issue and help understand the factors affecting this treatment. To do so, however, numerical challenges associated with the simulation of advection-dominant transport process must be resolved. Here, we describe the development of a thermal-hemodynamics computational framework to simulate incomplete occlusion in a patient-specific LA geometry during CBA. The modeling framework uses the finite element method to predict hemodynamics, thermal distribution, and lesion formation during CBA. An incremental pressure correction scheme is used to decouple velocity and pressure in the Navier-Stokes equation, whereas several stabilization techniques are also applied to overcome numerical instabilities. The framework was implemented using an open-source FE library (FEniCS). We show that model predictions of the hemodynamics in a realistic human LA geometry match well with measurements. The effects of cryoballoon position, pulmonary vein blood velocity and mitral regurgitation on lesion formation during CBA was investigated. For a -700C cryoballoon temperature, the model predicts lesion formation for gaps less than 2.5 mm and increasing efficiency of CBA for higher balloon tissue contact areas. The simulations also predict that lesion formation is not sensitive to variation in pulmonary vein blood velocity and mitral regurgitation. The framework can be applied to optimize CBA in patients for future clinical studies.

Commercial Gene Panels for Congenital Anterior Segment Anomalies: Are They All the Same?

PURPOSE: We compared next generation sequencing multigene panels (NGS-MGP) from 5 commercial laboratories to inform ophthalmologists' decision making in diagnostic genetic testing for congenital anterior segment anomalies (CASAs). DESIGN: Comparison of commercial genetic testing panels. METHODS: This observational study gathered publicly available information on NGS-MGP from 5 commercial laboratories for the following: cataracts, glaucoma, anterior segment dysgenesis (ASD), microphthalmia-anophthalmia-coloboma (MAC), corneal dystrophies, and Axenfeld-Rieger syndrome (ARS). We compared gene panel composition, consensus rate (genes covered by all the panels per condition, "concurrent"), dissensus rate (genes covered by only 1 panel per condition, "standalone"), and intronic variant coverage. For individual genes, we compared publication history and association with systemic conditions. RESULTS: Altogether, cataract, glaucoma, corneal dystrophies, MAC, ASD, and ARS panels tested 239, 60, 36, 292, and 10 discrete genes, respectively. The consensus rate varied between 16% and 50%, and the dissensus rate varied between 14% and 74%. After pooling concurrent genes from all conditions, 20% of these genes were concurrent in 2 or more conditions. For both cataract and glaucoma, concurrent genes had significantly stronger correlation with the condition than standalone genes. CONCLUSIONS: The genetic testing of CASAs using NGS-MGPs is complicated, owing to their number, variety, and phenotypic and genetic overlap. Although the inclusion of additional genes, such as the standalone ones, might increase diagnostic yield, these genes are also less well studied, indicating uncertainty over their role in CASA pathogenesis. Rigorous prospective diagnostic yield studies of NGS-MGPs will aid in making decisions of panel selection for the diagnosis of CASAs.

The Evolving Curriculum in Quality Improvement and Patient Safety in Undergraduate and Graduate Medical Education: A Scoping Review.

Quality Improvement and Patient Safety (QIPS) has become an increasingly important area of focus within undergraduate and graduate medical education. A variety of different QIPS curriculums have been developed, but standardization and effectiveness of these curriculums is largely unknown. The authors conducted a scoping review to explore the status of undergraduate and graduate nondegree QIPS curriculum in the United States. A scoping review was performed using The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) model as a guide. Two databases were screened from January 2019 to March 2022 to identify relevant articles. Forty-seven articles met eligibility criteria, with most articles (n = 38) focused on graduate medical education. Of those 38, 86.8% (33/38) were developed as curriculum specific to a particular specialty. The article highlights similarities and differences in structure, evaluation metrics, and outcomes, and subsequently offers insight into curriculum components that should help guide standardization of successful curriculum development moving forward.

External validation of the COVID-19 4C mortality score in an urban United States cohort.

BACKGROUND: Identifying patients at risk for mortality from COVID-19 is crucial to triage, clinical decision-making, and the allocation of scarce hospital resources. The 4C Mortality Score effectively predicts COVID-19 mortality, but it has not been validated in a United States (U.S.) population. The purpose of this study is to determine whether the 4C Mortality Score accurately predicts COVID-19 mortality in an urban U.S. adult inpatient population. METHODS: This retrospective cohort study included adult patients admitted to a single-center, tertiary care hospital (Philadelphia, PA) with a positive SARS-CoV-2 PCR from 3/01/2020 to 6/06/2020. Variables were extracted through a combination of automated export and manual chart review. The outcome of interest was mortality during hospital admission or within 30 days of discharge. RESULTS: This study included 426 patients; mean age was 64.4 years, 43.4% were female, and 54.5% self-identified as Black or African American. All-cause mortality was observed in 71 patients (16.7%). The area under the receiver operator characteristic curve of the 4C Mortality Score was 0.85 (95% confidence interval, 0.79-0.89). CONCLUSIONS: Clinicians may use the 4C Mortality Score in an urban, majority Black, U.S. inpatient population. The derivation and validation cohorts were treated in the pre-vaccine era so the 4C Score may over-predict mortality in current patient populations. With stubbornly high inpatient mortality rates, however, the 4C Score remains one of the best tools available to date to inform thoughtful triage and treatment allocation.

Targeting TLR9 agonists to secondary lymphoid organs induces potent immune responses against HBV infection.

Despite the existence of a prophylactic vaccine against hepatitis B virus (HBV), chronic hepatitis B virus (CHB) infection remains the leading cause of cirrhosis and liver cancer in developing countries. Because HBV persistence is associated with insufficient host immune responses to the infection, development of an immunomodulator as a component of therapeutic vaccination may become an important strategy for treatment CHB. In the present study, we aimed to design a novel immunomodulator with the capacity to subvert immune tolerance to HBV. We developed a lymphoid organ-targeting immunomodulator by conjugating a naturally occurring, lipophilic molecule, α-tocopherol, to a potent CpG oligonucleotide adjuvant pharmacophore. This approach resulted in preferential trafficking of the α-tocopherol-conjugated oligonucleotide to lymphoid organs where it was internalized by antigen-presenting cells (APCs). Moreover, we show that conjugation of the oligonucleotides to α-tocopherol results in micelle-like structure formation, which improved cellular internalization and enhanced immunomodulatory properties of the conjugates. In a mouse model of chronic HBV infection, targeting CpG oligonucleotide to lymphoid organs induced strong cellular and humoral immune responses that resulted in sustained control of the virus. Given the potency and tolerability of an α-tocopherol-conjugated CpG oligonucleotide, this modality could potentially be broadly applied for therapeutic vaccine development.

Pinch Anatomy of Forehead: An Injection Guide for Forehead Filler Treatment.

Filler injections have become very popular in recent years, and injectors globally use them for facial shaping and reversing age-related changes. Detailed knowledge about important vessels' and tissue planes' anatomy is essential for injectors. While giving the filler injections, injectors tend to gently pinch or pull the tissue fold with the nondominant hand during the procedure. The deformational forces cause some changes in the anatomy of tissue layers held in a pinch. During the pinch and "pinch and pull" maneuver, the crucial vessels in the area can get pulled up in the tissue layers in a pinch or stay in their position unaffected depending on the force applied. The "pinch and pull" maneuver also increases the tissue space for injections by moving the mobile tissue layers away from the fixed ones. The injector can use knowledge of the "'pinch anatomy" in the forehead to avoid important arteries and place filler in the correct plane. With the understanding of the anatomical changes occurring during the pinched state of tissue layers, filler injection can be performed in the right and safer tissue plane in the forehead. This study reflects level of evidence V.

Association of race/ethnicity and socioeconomic status with COVID-19 30-day mortality at a Philadelphia medical center using a retrospective cohort study.

COVID-19 has disproportionately affected low-income communities and people of color. Previous studies demonstrated that race/ethnicity and socioeconomic status (SES) are not independently correlated with COVID-19 mortality. The purpose of our study is to determine the effect of race/ethnicity and SES on COVID-19 30-day mortality in a diverse, Philadelphian population. This is a retrospective cohort study in a single-center tertiary care hospital in Philadelphia, PA. The study includes adult patients hospitalized with polymerase-chain-reaction-confirmed COVID-19 between March 1, 2020 and June 6, 2020. The primary outcome was a composite of COVID-19 death or hospice discharge within 30 days of discharge. The secondary outcome was intensive care unit (ICU) admission. The study included 426 patients: 16.7% died, 3.3% were discharged to hospice, and 20.0% were admitted to the ICU. Using multivariable analysis, race/ethnicity was not associated with the primary nor secondary outcome. In Model 4, age greater than 75 (odds ratio [OR]: 11.01; 95% confidence interval [CI]: 1.96-61.97) and renal disease (OR: 2.78; 95% CI: 1.31-5.90) were associated with higher odds of the composite primary outcome. Living in a "very-low-income area" (OR: 0.29; 95% CI: 0.12-0.71) and body mass index (BMI) 30-35 (OR: 0.24; 95% CI: 0.08-0.69) were associated with lower odds of the primary outcome. When controlling for demographics, SES, and comorbidities, race/ethnicity was not independently associated with the composite primary outcome. Very-low SES, as extrapolated from census-tract-level income data, was associated with lower odds of the composite primary outcome.

Comparing reliability of ICD-10-based COVID-19 comorbidity data to manual chart review, a retrospective cross-sectional study.

International Statistical Classification of Disease and Related Health Problems, 10th Revision codes (ICD-10) are used to characterize cohort comorbidities. Recent literature does not demonstrate standardized extraction methods. OBJECTIVE: Compare COVID-19 cohort manual-chart-review and ICD-10-based comorbidity data; characterize the accuracy of different methods of extracting ICD-10-code-based comorbidity, including the temporal accuracy with respect to critical time points such as day of admission. DESIGN: Retrospective cross-sectional study. MEASUREMENTS: ICD-10-based-data performance characteristics relative to manual-chart-review. RESULTS: Discharge billing diagnoses had a sensitivity of 0.82 (95% confidence interval [CI]: 0.79-0.85; comorbidity range: 0.35-0.96). The past medical history table had a sensitivity of 0.72 (95% CI: 0.69-0.76; range: 0.44-0.87). The active problem list had a sensitivity of 0.67 (95% CI: 0.63-0.71; range: 0.47-0.71). On day of admission, the active problem list had a sensitivity of 0.58 (95% CI: 0.54-0.63; range: 0.30-0.68)and past medical history table had a sensitivity of 0.48 (95% CI: 0.43-0.53; range: 0.30-0.56). CONCLUSIONS AND RELEVANCE: ICD-10-based comorbidity data performance varies depending on comorbidity, data source, and time of retrieval; there are notable opportunities for improvement. Future researchers should clearly outline comorbidity data source and validate against manual-chart-review.

Physician Executive Leadership Plus: An Approach to Business and Management Education for Medical Students.

INTRODUCTION: Physicians are looked upon to lead the healthcare team, a task that has grown increasingly complex and interdisciplinary, requiring a diverse extra-clinical skillset. Physician Executive Leadership (PEL) Plus is a student-run program that uniquely utilizes both didactic and real-world project-based approaches to deliver a business and management curriculum to medical students. METHODS: We developed and implemented PEL Plus during the 2018-19 and 2019-20 academic years, geared at first- and second-year medical students. We provide an overview of this combined didactic and project-based curriculum, in addition to evaluating if the program was efficacious in teaching the desired skillset. We assessed short-term knowledge acquisition using multiple-choice questions, and investigated student perceptions of their learning and the program using Likert scales and narrative feedback. We also investigated the influence of student demographics on performance, in order to assess the appropriateness of our target audience. RESULTS: 28 students completed PEL Plus over the two years (14 students/year). Average performance on multiple-choice questions showed statistically significant improvement after the majority of sessions. There were no statistically significant effects of demographics on performance in the majority of sessions. Students self-rated stronger understandings of lecture topics after each session, and analysis of narrative feedback demonstrated thematic categories centred on teaching style, new knowledge, lecture content/material, projects, networking, program structure, and generic statements. DISCUSSION: PEL Plus is an innovative and effective approach to teaching business, leadership, and management skills in undergraduate medical education. Development of similar programs at other institutions will positively impact the broader medical student community.

Acute Esophageal Necrosis Secondary to a Paraesophageal Hernia.

Acute esophageal necrosis (AEN) or "black esophagus" is a rare clinical entity caused by necrosis of distal esophageal mucosa stemming from esophageal ischemia. Possible etiologies are broad but most commonly include possible triggers of low-flow vascular states in the esophagus, including infections, broad-spectrum antibiotic use, and gastric volvulus, among others. Patients most commonly present clinically with acute onset hematemesis and melena. Here, we describe a patient who initially presented with multiple nonspecific gastrointestinal symptoms, including abdominal pain and nausea, that progressed over a 10-day period, culminating in multiple episodes of hematemesis prior to presentation. Endoscopic evaluation confirmed the diagnosis of AEN and unveiled a possible paraesophageal hernia (PEH) as the causative factor. A subsequent videofluoroscopic barium swallow was utilized to better characterize the upper gastrointestinal anatomy and confirmed the PEH as a likely etiology. Esophagogastroduodenoscopy (EGD) can often identify PEH independently, but in patients with AEN secondary to a possible, but unclear, PEH on EGD, a videofluoroscopic barium swallow is an appropriate and useful next step in confirming the diagnosis. While treatment of AEN traditionally involves fluid resuscitation, intravenous protein pump inhibitors, and total parenteral nutrition, surgical intervention is often indicated in patients who have a contributing and symptomatic PEH.

JNJ-64794964 (AL-034/TQ-A3334), a TLR7 agonist, induces sustained anti-HBV activity in AAV/HBV mice via non-cytolytic mechanisms.

JNJ-64794964 (JNJ-4964/AL-034/TQ-A3334), an oral toll-like receptor 7 agonist, is being investigated for the treatment of chronic hepatitis B (CHB), a condition with a high unmet medical need. The anti-hepatitis B (HBV) activity of JNJ-4964 was assessed preclinically in an adeno-associated virus vector expressing HBV (AAV/HBV) mouse model. Mice were treated orally with 2, 6 or 20 mg/kg of JNJ-4964 once-per-week for 12 weeks and then followed up for 4 weeks. At 6 mg/kg, a partial decrease in plasma HBV-DNA and plasma hepatitis B surface antigen (HBsAg) was observed, and anti-HBs antibodies and HBsAg-specific T cells were observed in 1/8 animals. At 20 mg/kg, plasma HBV-DNA and HBsAg levels were undetectable for all animals 3 weeks after start of treatment, with no rebound observed 4 weeks after JNJ-4964 treatment was stopped. High anti-HBs antibody levels were observed until 4 weeks after JNJ-4964 treatment was stopped. In parallel, HBsAg-specific immunoglobulin G-producing B cells and interferon-γ-producing CD4+ T cells were detected in the spleen. In 2/4 animals, liver HBV-DNA and HBV-RNA levels and liver hepatitis B core antigen expression dropped 4 weeks after JNJ-4964 treatment-stop. In these animals, HBsAg-specific CD8+ T cells were detectable. Throughout the study, normal levels of alanine aminotransferase were observed, with no hepatocyte cell death (end of treatment and 4 weeks later) and minimal infiltrations of B and T cells into the liver, suggesting induction of cytokine-mediated, non-cytolytic mechanisms.