Bexotegrast in Patients with Idiopathic Pulmonary Fibrosis: The INTEGRIS-IPF Clinical Trial.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare and progressive disease that causes progressive cough, exertional dyspnea, impaired quality of life, and death. Objectives: Bexotegrast (PLN-74809) is an oral, once-daily, investigational drug in development for the treatment of IPF. Methods: This Phase-2a multicenter, clinical trial randomized participants with IPF to receive, orally and once daily, bexotegrast at 40 mg, 80 mg, 160 mg, or 320 mg, or placebo, with or without background IPF therapy (pirfenidone or nintedanib), in an approximately 3:1 ratio in each bexotegrast dose cohort, for at least 12 weeks. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Exploratory efficacy endpoints included change from baseline in FVC, quantitative lung fibrosis (QLF) extent (%), and changes from baseline in fibrosis-related biomarkers. Measurements and Main Results: Bexotegrast was well tolerated, with similar rates of TEAEs in the pooled bexotegrast and placebo groups (62/89 [69.7%] and 21/31 [67.7%], respectively). Diarrhea was the most common TEAE; most participants with diarrhea also received nintedanib. Participants who were treated with bexotegrast experienced a reduction in FVC decline over 12 weeks compared with those who received placebo, with or without background therapy. A dose-dependent antifibrotic effect of bexotegrast was observed with QLF imaging, and a decrease in fibrosis-associated biomarkers was observed with bexotegrast versus placebo. Conclusions: Bexotegrast demonstrated a favorable safety and tolerability profile, up to 12 weeks for the doses studied. Exploratory analyses suggest an antifibrotic effect according to FVC, QLF imaging, and circulating levels of fibrosis biomarkers. Clinical trial registered with www.clinicaltrials.gov (NCT04396756).

Pulmonary Fibrosis Stakeholder Summit: A Joint NHLBI, Three Lakes Foundation, and Pulmonary Fibrosis Foundation Workshop Report.

Despite progress in elucidation of disease mechanisms, identification of risk factors, biomarker discovery, and the approval of two medications to slow lung function decline in idiopathic pulmonary fibrosis and one medication to slow lung function decline in progressive pulmonary fibrosis, pulmonary fibrosis remains a disease with a high morbidity and mortality. In recognition of the need to catalyze ongoing advances and collaboration in the field of pulmonary fibrosis, the NHLBI, the Three Lakes Foundation, and the Pulmonary Fibrosis Foundation hosted the Pulmonary Fibrosis Stakeholder Summit on November 8-9, 2022. This workshop was held virtually and was organized into three topic areas: 1) novel models and research tools to better study pulmonary fibrosis and uncover new therapies, 2) early disease risk factors and methods to improve diagnosis, and 3) innovative approaches toward clinical trial design for pulmonary fibrosis. In this workshop report, we summarize the content of the presentations and discussions, enumerating research opportunities for advancing our understanding of the pathogenesis, treatment, and outcomes of pulmonary fibrosis.

A Computer Vision Algorithm to Predict Superior Mesenteric Artery Margin Status for Patients with Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: To evaluate the feasibility of developing a computer vision algorithm that uses preoperative computed tomography (CT) scans to predict superior mesenteric artery (SMA) margin status in patients undergoing Whipple for pancreatic ductal adenocarcinoma (PDAC), and to compare algorithm performance to that of expert abdominal radiologists and surgical oncologists. SUMMARY BACKGROUND DATA: Complete surgical resection is the only chance to achieve a cure for PDAC; however, current modalities to predict vascular invasion have limited accuracy. METHODS: Adult patients with PDAC who underwent Whipple and had preoperative contrast-enhanced CT scans were included (2010-2022). The SMA was manually annotated on the CT scans, and we trained a U-Net algorithm for SMA segmentation and a ResNet50 algorithm for predicting SMA margin status. Radiologists and surgeons reviewed the scans in a blinded fashion. SMA margin status per pathology reports was the reference. RESULTS: Two hundred patients were included. Forty patients (20%) had a positive SMA margin. For the segmentation task, the U-Net model achieved a Dice Similarity Coefficient of 0.90. For the classification task, all readers demonstrated limited sensitivity, although the algorithm had the highest sensitivity at 0.43 (versus 0.23 and 0.36 for the radiologists and surgeons, respectively). Specificity was universally excellent, with the radiologist and algorithm demonstrating the highest specificity at 0.94. Finally, the accuracy of the algorithm was 0.85 versus 0.80 and 0.76 for the radiologists and surgeons, respectively. CONCLUSIONS: We demonstrated the feasibility of developing a computer vision algorithm to predict SMA margin status using preoperative CT scans, highlighting its potential to augment the prediction of vascular involvement.

Long-Duration Neoadjuvant Therapy with FOLFIRINOX Yields Favorable Outcomes for Patients Who Undergo Surgery for Pancreatic Cancer.

BACKGROUND: In 2023 alone, it's estimated that over 64,000 patients will be diagnosed with PDAC and more than 50,000 patients will die of the disease. Current guidelines recommend neoadjuvant therapy for patients with borderline resectable and locally advanced PDAC, and data is emerging on its role in resectable disease. Neoadjuvant chemotherapy may increase the number of patients able to receive complete chemotherapy regimens, increase the rate of microscopically tumor-free resection (R0) margin, and aide in identifying unfavorable tumor biology. To date, this is the largest study to examine surgical outcomes after long-duration neoadjuvant chemotherapy for PDAC. METHODS: Retrospective analysis of single-institution data. RESULTS: The routine use of long-duration therapy in our study (median cycles: FOLFIRINOX = 10; gemcitabine-based = 7) is unique. The majority (85%) of patients received FOLFIRINOX without radiation therapy; the R0 resection rate was 76%. Median OS was 41 months and did not differ significantly among patients with resectable, borderline-resectable, or locally advanced disease. CONCLUSIONS: This study demonstrates that in patients who undergo surgical resection after receipt of long-duration neoadjuvant FOLFIRINOX therapy alone, survival outcomes are similar regardless of pretreatment resectability status and that favorable surgical outcomes can be attained.

Diagnostic approach to hepatic vascular lesions: a paediatric perspective.

The pathological evaluation of hepatic vascular lesions in children requires special consideration. Inconsistent terminology, rarity of pathology specimens and overlapping pathological features between various lesions may pose a serious diagnostic challenge. In this review, we highlight the importance of using the International Society for the Study of Vascular Anomalies (ISSVA) classification scheme to characterise these lesions. Selected entities are discussed, including hepatic vascular tumours exclusively seen in the paediatric age group, hepatic infantile haemangioma and hepatic congenital haemangioma. Vascular malformations, with emphasis on their syndromic associations (venous malformation in blue rubber bleb naevus syndrome) and complications (hepatocellular nodules in Abernethy malformation) are also covered.

Interstitial lung abnormality evaluated by an automated quantification system: prevalence and progression rate.

BACKGROUND: Despite the importance of recognizing interstitial lung abnormalities, screening methods using computer-based quantitative analysis are not well developed, and studies on the subject with an Asian population are rare. We aimed to identify the prevalence and progression rate of interstitial lung abnormality evaluated by an automated quantification system in the Korean population. METHODS: A total of 2,890 healthy participants in a health screening program (mean age: 49 years, men: 79.5%) with serial chest computed tomography images obtained at least 5 years apart were included. Quantitative lung fibrosis scores were measured on the chest images by an automated quantification system. Interstitial lung abnormalities were defined as a score ≥ 3, and progression as any score increased above baseline. RESULTS: Interstitial lung abnormalities were identified in 251 participants (8.6%), who were older and had a higher body mass index. The prevalence increased with age. Quantification of the follow-up images (median interval: 6.5 years) showed that 23.5% (59/251) of participants initially diagnosed with interstitial lung abnormality exhibited progression, and 11% had developed abnormalities (290/2639). Older age, higher body mass index, and higher erythrocyte sedimentation rate were independent risk factors for progression or development. The interstitial lung abnormality group had worse survival on follow-up (5-year mortality: 3.4% vs. 1.5%; P = 0.010). CONCLUSIONS: Interstitial lung abnormality could be identified in one-tenth of the participants, and a quarter of them showed progression. Older age, higher body mass index and higher erythrocyte sedimentation rate increased the risk of development or progression of interstitial lung abnormality.

Delays in definitive endoscopic resection of previously manipulated colorectal polyps as a risk factor for inferior resection outcomes.

BACKGROUND AND AIMS: Manipulation of colorectal polyps by biopsy, incomplete resection, or tattoo placement under the lesion has been shown to cause submucosal fibrosis and associated inferior outcomes. The effect of delays between index manipulation and definitive resection on the incidence of fibrosis is unknown. METHODS: Patients undergoing EMR of previously manipulated colorectal polyps ≥10 mm from 2016 to 2021 at a tertiary referral center were included. Time from index manipulation to definitive resection and the presence of fibrosis were noted. The effects of fibrosis on EMR outcomes were assessed. RESULTS: Among 221 previously manipulated lesions (180 biopsy, 23 incomplete/failed resection, 1 tattoo under lesion, 17 multiple types of manipulation), 51 (23%) demonstrated fibrosis. Fibrotic lesions were found to have been resected significantly later than nonfibrotic lesions (76 vs 61 days; P = .014). In a multivariate analysis controlling for other predictors of fibrosis, each 2-week delay was associated with a 14% increase in the odds of fibrosis. Fibrotic lesions had inferior outcomes with a lower en-bloc resection rate (8% vs 24%; P = .014) and longer procedure time (71 vs 52 minutes; P < .001). Adverse event and recurrence rates were similar between groups. CONCLUSIONS: Delays in definitive resection of previously manipulated polyps are associated with an increased incidence of fibrosis with time and associated inferior outcomes. Manipulation should be discouraged, and if it occurs, prompt referral and scheduling for definitive resection should be prioritized.

Impact of Biologics and Small-Molecule Agents on Postoperative Complications in IBD: A Systematic Review.

BACKGROUND: Patients with IBD may require colectomy for severe disease unresponsive or refractory to pharmacological therapy. The question of the impact of biologic use on postoperative complications is a topic of active investigation. OBJECTIVE: A systematic literature review was performed to describe the current state of knowledge of the impact of perioperative biologic and tofacitinib use on postoperative complications in patients with IBD. DATA SOURCES: PubMed and Cochrane databases were searched. STUDY SELECTION: Studies between January 2000 and January 2023, in any language, were searched, followed by a snowball search identifying further studies in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Articles regarding pediatric or endoscopic management were excluded. INTERVENTIONS: Preoperative or perioperative exposure to biologics in IBD was included. MAIN OUTCOME MEASURES: Infectious and noninfectious complications, including anastomotic leaks, surgical site infections, urinary tract infections, pneumonia, sepsis, septic shock, postoperative length of stay, readmission, and reoperation, were the main outcomes measured. RESULTS: A total of 28 studies were included for analysis in this review, including 7 meta-analyses or systematic reviews and 5 randomized studies. Snowball search identified 11 additional studies providing topical information. Overall, tumor necrosis factor inhibitors likely do not increase the risk of postoperative adverse outcomes, while data on other biologics and small-molecule agents are emerging. LIMITATIONS: This is a qualitative review including all study types. The varied nature of study types precludes quantitative comparison. CONCLUSIONS: Although steroids increase postoperative infectious and noninfectious complications, tumor necrosis factor inhibitors do not appear to increase postoperative infectious and noninfectious complications. There is a need for further perioperative data for other agents. See video from symposium .

Construction and validation of a brain magnetic resonance imaging template for normal older Koreans.

BACKGROUND: Spatial normalization to a standardized brain template is a crucial step in magnetic resonance imaging (MRI) studies. Brain templates made from sufficient sample size have low brain variability, improving the accuracy of spatial normalization. Using population-specific template improves accuracy of spatial normalization because brain morphology varies according to ethnicity and age. METHODS: We constructed a brain template of normal Korean elderly (KNE200) using MRI scans 100 male and 100 female aged over 60 years old with normal cognition. We compared the deformation after spatial normalization of the KNE200 template to that of the KNE96, constructed from 96 cognitively normal elderly Koreans and to that of the brain template (OCF), constructed from 434 non-demented older Caucasians to examine the effect of sample size and ethnicity on the accuracy of brain template, respectively. We spatially normalized the MRI scans of elderly Koreans and quantified the amount of deformations associated with spatial normalization using the magnitude of displacement and volumetric changes of voxels. RESULTS: The KNE200 yielded significantly less displacement and volumetric change in the parahippocampal gyrus, medial and posterior orbital gyrus, fusiform gyrus, gyrus rectus, cerebellum and vermis than the KNE96. The KNE200 also yielded much less displacement in the cerebellum, vermis, hippocampus, parahippocampal gyrus and thalamus and much less volumetric change in the cerebellum, vermis, hippocampus and parahippocampal gyrus than the OCF. CONCLUSION: KNE200 had the better accuracy than the KNE96 due to the larger sample size and was far accurate than the template constructed from elderly Caucasians in elderly Koreans.

A needs assessment for simulation in African surgical education.

INTRODUCTION: There is a critical need for comprehensive surgical training in African countries given the unmet surgical burden of disease in this region. Collaborative and progressive initiatives in global surgical education will have the greatest impact on trainees. Little is known about surgical education needs from the perspective of practicing surgeons and trainees in low-middle-income countries (LMICs). Even less is known about the potential role for simulation to augment training. METHODS: A modified Delphi methodology with 2 rounds of responses was employed to survey program directors (PD) and associate program directors (APD) of Pan-African Association of Christian Surgeons (PAACS) general surgery residency programs across eight low-middle-income countries in Africa. 3 PD/APDs and 2 surgical residents participated in semi-structured interviews centered around the role of simulation in training. Descriptive analysis was performed to elicit key themes and illustrative examples. RESULTS: The survey of program directors revealed that teaching residents the psychomotor skills need to perform intracorporeal suturing was both high priority and desired in multiple training sites. Other high priority skills were laparoscopic camera driving and medial visceral rotation. The interviews revealed a specific desire to perform laparoscopic surgery and a need for a simulation curriculum to familiarize staff and trainees with laparoscopic techniques. Several barriers to laparoscopic surgery exist, such as lack of staff familiarity with the equipment, lack of public buy in, and lack of generalizable and adaptable educational modules. Trainees saw utility in the use of simulation to optimize time in the operating room and sought opportunities to improve their laparoscopic skills. CONCLUSION: Faculty and surgical trainees in LMICs have interest in learning advanced surgical techniques, such as laparoscopy. Developing a simulation curriculum tailored to the trainees' local context has the potential to fill this need.

Automated abdominal adipose tissue segmentation and volume quantification on longitudinal MRI using 3D convolutional neural networks with multi-contrast inputs.

OBJECTIVE: Increased subcutaneous and visceral adipose tissue (SAT/VAT) volume is associated with risk for cardiometabolic diseases. This work aimed to develop and evaluate automated abdominal SAT/VAT segmentation on longitudinal MRI in adults with overweight/obesity using attention-based competitive dense (ACD) 3D U-Net and 3D nnU-Net with full field-of-view volumetric multi-contrast inputs. MATERIALS AND METHODS: 920 adults with overweight/obesity were scanned twice at multiple 3 T MRI scanners and institutions. The first scan was divided into training/validation/testing sets (n = 646/92/182). The second scan from the subjects in the testing set was used to evaluate the generalizability for longitudinal analysis. Segmentation performance was assessed by measuring Dice scores (DICE-SAT, DICE-VAT), false negatives (FN), and false positives (FP). Volume agreement was assessed using the intraclass correlation coefficient (ICC). RESULTS: ACD 3D U-Net achieved rapid (< 4.8 s/subject) segmentation with high DICE-SAT (median ≥ 0.994) and DICE-VAT (median ≥ 0.976), small FN (median ≤ 0.7%), and FP (median ≤ 1.1%). 3D nnU-Net yielded rapid (< 2.5 s/subject) segmentation with similar DICE-SAT (median ≥ 0.992), DICE-VAT (median ≥ 0.979), FN (median ≤ 1.1%) and FP (median ≤ 1.2%). Both models yielded excellent agreement in SAT/VAT volume versus reference measurements (ICC > 0.997) in longitudinal analysis. DISCUSSION: ACD 3D U-Net and 3D nnU-Net can be automated tools to quantify abdominal SAT/VAT volume rapidly, accurately, and longitudinally in adults with overweight/obesity.

Polypharmacy and Elevated Risk of Severe Adverse Events in Older Adults Based on the Korea Institute of Drug Safety and Risk Management-Korea Adverse Event Reporting System Database.

BACKGROUND: Older adults are at a higher risk of severe adverse drug events (ADEs) because of multimorbidity, polypharmacy, and lower physiological function. This study aimed to determine whether polypharmacy, defined as the use of ≥ 5 active drug ingredients, was associated with severe ADEs in this population. METHODS: We used ADE reports from the Korea Institute of Drug Safety and Risk Management-Korea Adverse Event Reporting System Database, a national spontaneous ADE report system, from 2012 to 2021 to examine and compare the strength of association between polypharmacy and severe ADEs in older adults (≥ 65 years) and younger adults (20-64 years) using disproportionality analysis. RESULTS: We found a significant association between severe ADEs of cardiac and renal/urinary Medical Dictionary for Regulatory Activities System Organ Classes (MedDRA SOC) with polypharmacy in older adults. Regarding individual-level ADEs included in these MedDRA SOCs, acute cardiac arrest and renal failure were more significantly associated with polypharmacy in older adults compared with younger adults. CONCLUSION: The addition of new drugs to the regimens of older adults warrants close monitoring of renal and cardiac symptoms.

Lack of Association of A1C With Postoperative Complications in Children With Type 1 or Type 2 Diabetes.

Not meeting recommended A1C targets may be associated with postoperative complications in adults, but there are no studies reporting on the relationship between preoperative A1C and postoperative complications in children with type 1 or type 2 diabetes. The objective of this study was to determine whether elevated A1C levels were associated with an increased incidence of postoperative complications in children with diabetes presenting for elective noncardiac surgery or diagnostic procedures. It found no such association, suggesting no need to delay elective surgery in children with diabetes until A1C is optimized.

Transcatheter Arterial Radioembolization-Induced Gastric Ulcer in an Excluded Stomach After Roux-en-Y Gastric Bypass.

Transcatheter arterial radioembolization (TARE) is a common locoregional treatment for hepatocellular carcinoma. It is associated with peptic ulcer disease in up to 5% of patients. A 70-year-old man with Roux-en-Y gastric bypass and liver cirrhosis with hepatocellular carcinoma treated with TARE 6 months earlier was evaluated for continued melena and was found to have an ulcer in the excluded stomach. This was successfully treated with liquid proton pump inhibitor through gastrostomy tube to the excluded stomach. This represents a unique case of successful management of TARE-induced peptic ulcer disease in the excluded stomach of a Roux-en-Y gastric bypass patient.

Endovascular Inferior Vena Cava Filters Placed in Duplicated Inferior Vena Cava Syndrome.

Duplicated inferior vena cava (D-IVC) is a relatively rare anatomical anomaly. Clinically, these anomalies are incidentally found on computed tomography (CT) or magnetic resonance imaging (MRI). Lack of pre-operative identification of this congenital malformation can lead to incomplete protection against thromboembolism or hemorrhage. We present a case of a 71-year-old male with a duplicated inferior vena cava who underwent insertion of bilateral inferior vena cava filters for deep vein thrombosis (DVT) management.

Diarrhea as the Initial Presentation in a Patient With HIV Diagnosed With Hodgkin's Lymphoma.

Hodgkin's lymphoma (HL) is a form of cancer that involves abnormal lymphocyte proliferation which affects the lymphatic system. Patients with HIV are at increased risk of developing HL, despite the introduction of combination antiretroviral therapy. The most common presentation of HL is painless lymphadenopathy with classic constitutional symptoms in advanced disease. Here we discuss a 39-year-old female with a history of HIV on emtricitabine/tenofovir and dolutegravir who presented with four days of worsening diarrhea along with fevers and chills. She had a similar presentation at a nearby hospital four months prior. After initial concern for gastrointestinal infection, an extensive infectious workup was conducted and was negative. After complaints of sore throat and increased confusion during the hospital stay, a CT Chest and Neck revealed diffuse lymphadenopathy. Severely elevated ferritin levels raised concern for secondary hemophagocytic lymphohistiocytosis and prompted expedited ultrasound-guided cervical lymph node (LN) core biopsy and bone marrow biopsy. Ultrasound-guided core biopsy of the LN showed classical Hodgkin's lymphoma of mixed cellularity. The patient was started on doxorubicin, vinblastine, and dacarbazine + nivolumab. This is a case of a patient with HIV who presented with chronic diarrhea of unidentifiable origin and was ultimately diagnosed with classical Hodgkin's lymphoma during her hospitalization and highlights the importance of maintaining lymphoproliferative diseases on the differential in patients with HIV and gastrointestinal symptoms.

The Sleep Health of Individuals with Visual Impairments: A Scoping Review.

PURPOSE: Amidst the global aging population and an increasing prevalence of visual impairment across all age groups, this study aims to investigate the current state of research on sleep health in visually impaired populations. METHODS: A scoping review was conducted to synthesize the existing literature on sleep health and visual impairment. We employed conceptual mapping to identify key research topics, analyzing data from four databases: PubMed (n = 290), CINAHL (n = 81), Scopus (n = 117), and PsycInfo (n = 96). A total of 83 peer-reviewed articles, published from 1977 to August 2023, were included in the review. RESULTS: Our analysis identified 11 distinct eye health conditions including blindness, glaucoma, diabetic retinopathy, low vision, cataract, retinitis pigmentosa, macular degeneration, optic neuropathy, visual field defects, ocular hypertension, and retinal vein occlusion. Additionally, 8 major sleep problems were recognized: abnormal sleep duration, daytime sleepiness, insomnia, Non-24-Hour Sleep Wake Disorder, sleep apnea, sleep disorders, sleep disturbances, and sleep disordered breathing. The dominant research themes were (1) poor sleep quality in individuals with visual impairments and ophthalmic diseases, (2) high prevalence of sleep issues in patients with ophthalmic diseases, (3) sleep apnea in patients with ophthalmic conditions, and (4) circadian rhythm disruptions in blind individuals. CONCLUSION: This review highlights research gaps that, when addressed, could greatly enhance our comprehension of the interplay between visual impairment and sleep health. Bridging these gaps promises to lead to more holistic care strategies, potentially improving vision functioning and rehabilitation outcomes for individuals with visual impairments.

The safety and efficacy of radiofrequency ablation in benign pediatric thyroid disease in the US: An initial case series.

Objective: To evaluate the efficacy and safety of radiofrequency ablation (RFA) for benign nonfunctional thyroid nodules or functional lingual thyroid gland in a pediatric population. Methods: Four pediatric patients (four female; mean age 13.50 ± 4.04, range 8-17 years) with either benign thyroid nodules or mildly obstructive lingual thyroid glands were treated with RFA from 2020 to 2021 were evaluated. The inclusion criteria for RFA therapy were (i) age < 18 years; (ii) benign cytopathological results on ultrasound guided fine needle aspiration; (iii) pressure or pain symptoms caused by the thyroid nodules; (iv) dysphagia or obstruction caused by the lingual thyroid tissue; (v) follow up for >6 months with otolaryngology or endocrinology. Results: Two patients had benign non-functioning thyroid nodules and two had mildly obstructive functioning lingual thyroid glands. Mean follow up was 10.75 ± 4.79 months. Each patient underwent one RFA session with no complications. For the patients with thyroid nodules, there was >74% reduction in nodule size at last follow up with improvement in neck swelling and pain. For the patients with lingual thyroid glands, both did not have any other functional thyroid gland identified. Both had visible decrease in size of the gland as visualized transorally with improvement in dysphagia and obstructive symptoms when lying flat. Conclusion: RFA is a safe and effective option for managing benign thyroid nodules and lingual thyroid glands in a pediatric patient population. Level of evidence: 4.