Accuracy of Patient-Collected Vital Signs.

Introduction: Telehealth has emerged as an important clinical setting for managing acute respiratory tract infections (ARIs), potentially reducing emergency department and urgent care overcrowding, and reducing nosocomial transmission. Many current algorithms for ARI management incorporate information on patient vital signs. However, the accuracy of vital signs collected by patients using readily available home devices and techniques has not been studied. Methods: A cross-sectional sample of patients seen for urgent conditions at a hospital emergency and urgent care center were given instructions and low-cost, readily available devices to collect their vital signs. A trained research coordinator collected a parallel set of vital signs using standard hospital equipment, serving as the gold standard. We analyzed the performance of patient-collected vital signs compared with vital signs collected by a trained research coordinator. Results: A total of 300 patients completed the study. Patient-collected vital signs were highly specific for traditional levels of abnormalities (HR >100 beats per min, RR >24 breaths per min, temperature >100.4 degrees Fahrenheit, oxygen saturation <94 percent); however, sensitivity was poor for elevated heart rate by pulse estimation (25%) and elevated respiratory rate (60%). Heart rate and oxygen saturation by pulse oximeter and oral temperature had higher sensitivity. Conclusions: Vital signs measured and provided by patients are not uniformly accurate, particularly when using manual techniques rather than automated devices. Telehealth algorithms that rely on these values could provide incorrect triage and management advice.

Efficacy of Gastric-Stimulator as an Adjunct to Pyloroplasty for Gastroparesis: Characterizing Patients Suitable for Single Procedure versus Dual Procedure Approach.

BACKGROUND: Pyloroplasty is an effective surgery for gastroparesis. However, some patients fail to improve after pyloric drainage and may require subsequent gastric electric stimulation. There is a paucity of data on the efficacy of gastric stimulator as an adjunct to failed pyloroplasty. This study aimed to describe our experience with pyloroplasty, determine the efficacy of gastric-stimulator for failed pyloroplasty, and compare the final outcomes of those who required pyloroplasty with and without gastric stimulator for gastroparesis. METHODS: Records of patients who underwent primary pyloroplasty for gastroparesis at our institution were reviewed. Patients with poor symptomatic improvement after pyloroplasty underwent subsequent gastric-stimulator. Symptoms were assessed using the gastroparesis cardinal symptom index (GCSI) preoperatively and after each surgery. Severe gastroparesis was defined as GSCI total score ≥3. Outcomes were assessed after pyloroplasty in all patients and after stimulator in patients who failed pyloroplasty. Final outcomes were then compared between those who did and did not require adjunct gastric-stimulator. RESULTS: The study population consisted of 104 patients (89.4% female) with a mean (SD) age of 42.2(11) and BMI of 26.9(7). Gastroparesis etiologies were 71.2% idiopathic, 17.3% diabetic, and 11.5% postsurgical. At 18.7(12) months after pyloroplasty there was a decrease in the GCSI total score [3.5(1) to 2.7(1.2), p=0.0012] and the rate of severe gastroparesis (71.9% to 29.3%, p<0.0001). Gastric emptying scintigraphy (GES) 4-hr retention decreased [36.5(24) to 15.3(18), p=0.0003]. Adjunct gastric-stimulator was required by 30 (28.8%) patients due to suboptimal outcomes with no improvement in GCSI (p=0.201) or GES (p=0.320). These patients were younger [40.5(10.6) vs 49.6(15.2), p=0.0016)], with higher baseline GSCI-Total scores [4.3(0.7)-vs-3.7(1.1), p<0.001] and more severe gastroparesis (100%-vs-55.6%, p<0.001). All other preoperative characteristics were similar. At 21.7(15) months after gastric-stimulator there was improvement in GCSI [4.1(0.7) to 2.6(1.1), p<0.0001], severe gastroparesis (100% to 33.3%, p<0.0001), and GES 4-hr retention [21.2(22) to 7.6(10), p=0.054]. Prior to gastric stimulator, those who failed pyloroplasty had significantly worse GCSI (p=0.0009) and GES (p=0.048). However, after gastric stimulator, GCSI and GES improved, and were comparable to those who only required pyloroplasty (p>0.05). CONCLUSION: Pyloroplasty improved gastroparesis symptoms and gastric emptying, yet 28% failed, requiring gastric stimulator. Younger patients and those with preoperative GCSI scores ≥3 were more likely to fail. Gastric stimulator improved outcomes after failed pyloroplasty, with comparable final GCSI and GES to those who did not fail.

A Randomized Controlled Comparison of Guardian-Perceived Cosmetic Outcome of Simple Lacerations Repaired With Either Dermabond, Steri-Strips, or Absorbable Sutures.

OBJECTIVES: The aim of this study was to compare the guardian-perceived 3-month cosmetic outcome for pediatric lacerations repaired with absorbable sutures, Dermabond, or Steri-Strips. Secondarily, pain and satisfaction with the procedure from both guardian and provider perspectives were compared. METHODS: In this randomized controlled trial, we enrolled a convenience sample of children aged 0 to <18 years who presented with simple linear lacerations (≤5 cm in length, ≤0.5 cm in width, and <12 hours old) to a pediatric emergency department. Children were randomized to receive laceration repair with absorbable sutures, Dermabond, or Steri-Strips. Topical L.E.T. solution (lidocaine, epinephrine, tetracaine) was applied to wounds which were then closed by the primary team. Guardians and providers completed questionnaires regarding perceived pain and satisfaction with the procedure. Guardians were contacted 3 months after the repair and asked to email a picture of the scar with their perception of cosmesis rated on a visual analog scale from 0 to 100. RESULTS: Fifty-five patients were enrolled, of whom 30 completed 3-month follow-up (12 suture, 7 Dermabond, 11 Steri-strips). There was no statistical evidence of an association between scar appearance and closure method based on medians and interquartile ranges for cosmetic ratings of scar: suture median 70.5 (IQR 59.8-76.8), Dermabond median 85 (IQR 73-90), Steri-strips median 67 (IQR 55-78) (P = 0.254). Guardian satisfaction with length of stay, guardian and physician satisfaction with the procedure, and guardian and physician-perceived pain also showed no differences. CONCLUSIONS: No differences were observed in guardian-perceived cosmesis of simple lacerations repaired with sutures, Dermabond, or Steri-Strips when evaluated 3 months after intervention. In addition, there were no differences in guardian or physician-perceived pain or satisfaction with the closure methods. The results of this study suggest that all 3 closure methods appear to be clinically equivalent, which is largely consistent with other evidence. Further study should be expanded to a larger demographic.

Exercise and weight loss with a left ventricular assist device: A case report and review of the literature.

With changes in the heart transplant allocation system in the United States, the use of left ventricular device therapy (LVAD) as a bridge to transplant has decreased. Currently, one of the primary reasons to implant a device is for patient support until they can lose weight to qualify for transplant. This paper reviews the outcomes of various weight loss strategies for patients with LVADs including weight reduction surgery and cardiac rehab. Additionally, results of the use of GLP1 agonists on weight loss in general and in heart failure patients is reviewed. Finally, because of the unique issues involving exercise for patients with LVADs, we review safe exercise techniques with instructions for patients.

Effects of Low-Level Light Therapy on Resting-State Connectivity Following Moderate Traumatic Brain Injury: Secondary Analyses of a Double-blinded Placebo-controlled Study.

Background Low-level light therapy (LLLT) has been shown to modulate recovery in patients with traumatic brain injury (TBI). However, the impact of LLLT on the functional connectivity of the brain when at rest has not been well studied. Purpose To use functional MRI to assess the effect of LLLT on whole-brain resting-state functional connectivity (RSFC) in patients with moderate TBI at acute (within 1 week), subacute (2-3 weeks), and late-subacute (3 months) recovery phases. Materials and Methods This is a secondary analysis of a prospective single-site double-blinded sham-controlled study conducted in patients presenting to the emergency department with moderate TBI from November 2015 to July 2019. Participants were randomized for LLLT and sham treatment. The primary outcome of the study was to assess structural connectivity, and RSFC was collected as the secondary outcome. MRI was used to measure RSFC in 82 brain regions in participants during the three recovery phases. Healthy individuals who did not receive treatment were imaged at a single time point to provide control values. The Pearson correlation coefficient was estimated to assess the connectivity strength for each brain region pair, and estimates of the differences in Fisher z-transformed correlation coefficients (hereafter, z differences) were compared between recovery phases and treatment groups using a linear mixed-effects regression model. These analyses were repeated for all brain region pairs. False discovery rate (FDR)-adjusted P values were computed to account for multiple comparisons. Quantile mixed-effects models were constructed to quantify the association between the Rivermead Postconcussion Symptoms Questionnaire (RPQ) score, recovery phase, and treatment group. Results RSFC was evaluated in 17 LLLT-treated participants (median age, 50 years [IQR, 25-67 years]; nine female), 21 sham-treated participants (median age, 50 years [IQR, 43-59 years]; 11 female), and 23 healthy control participants (median age, 42 years [IQR, 32-54 years]; 13 male). Seven brain region pairs exhibited a greater change in connectivity in LLLT-treated participants than in sham-treated participants between the acute and subacute phases (range of z differences, 0.37 [95% CI: 0.20, 0.53] to 0.45 [95% CI: 0.24, 0.67]; FDR-adjusted P value range, .010-.047). Thirteen different brain region pairs showed an increase in connectivity in sham-treated participants between the subacute and late-subacute phases (range of z differences, 0.17 [95% CI: 0.09, 0.25] to 0.26 [95% CI: 0.14, 0.39]; FDR-adjusted P value range, .020-.047). There was no evidence of a difference in clinical outcomes between LLLT-treated and sham-treated participants (range of differences in medians, -3.54 [95% CI: -12.65, 5.57] to -0.59 [95% CI: -7.31, 8.49]; P value range, .44-.99), as measured according to RPQ scores. Conclusion Despite the small sample size, the change in RSFC from the acute to subacute phases of recovery was greater in LLLT-treated than sham-treated participants, suggesting that acute-phase LLLT may have an impact on resting-state neuronal circuits in the early recovery phase of moderate TBI. ClinicalTrials.gov Identifier: NCT02233413 © RSNA, 2024 Supplemental material is available for this article.

Intranasal administration of unadjuvanted SARS-CoV-2 spike antigen boosts antigen-specific immune responses induced by parenteral protein subunit vaccine prime in mice and hamsters.

With the continued transmission of SARS-CoV-2 across widely vaccinated populations, it remains important to develop new vaccines and vaccination strategies capable of providing protective immunity and limiting the spread of disease. Heterologous prime-boost vaccination based on the selection of different vaccine formulations and administration routes for priming and booster doses presents a promising strategy for inducing broader immune responses in key systemic and respiratory mucosal compartments. Intranasal vaccination can induce mucosal immune responses at the site of SARS-CoV-2 infection; however, the lack of clinically approved mucosal adjuvants makes it difficult to induce robust immune responses with protein subunit vaccines. Herein, we evaluated the immunogenicity of heterologous prime-boost regimens in mice and hamsters based on a parenteral vaccination of the antigen in combination with sulfated lactosylarchaeol (SLA) archaeosomes, a liposome adjuvant comprised of a single semisynthetic archaeal lipid, followed by an intranasally administered unadjuvanted SARS-CoV-2 spike antigen. Intranasal administration of unadjuvanted spike to mice and hamsters increased serum spike-specific IgG titers and spike-neutralizing activity compared with nonboosted animals. Spike-specific IgA responses were also detected in the bronchoalveolar lavage fluid in the lungs of mice that received an intranasal boost. In hamsters, the intranasal boost showed high efficacy against SARS-CoV-2 infection by protecting from body weight loss and reducing viral titers in the lungs and nasal turbinate. Overall, our heterologous intramuscular prime-intranasal boost with SLA-adjuvanted and unadjuvanted spike, respectively, demonstrated the potential of protein subunit formulations to promote antigen-specific systemic and mucosal immune responses.

Magnetic Sphincter Augmentation for Laryngopharyngeal Reflux: An Assessment of Efficacy and Predictors of Outcome.

INTRODUCTION: Magnetic sphincter augmentation (MSA) is an effective treatment for typical reflux symptoms, but data on its impact on laryngopharyngeal reflux (LPR) is limited. This study aimed to determine the efficacy of MSA for LPR and to identify predictors of outcome. METHODS: This was a retrospective review of 775 patients who underwent MSA between 2013 and 2021. LPR was defined as presence of atypical reflux symptoms and a reflux symptom index (RSI) score >13. Favorable outcome was defined as primary symptom resolution, freedom from proton pump inhibitors, and five-point improvement or RSI score normalization. Preoperative clinical, high-resolution manometry, and impedance-pH data were analyzed for impact on favorable outcome using univariate followed by multivariable analysis. RESULTS: There were 128 patients who underwent MSA for LPR. At a mean (SD) follow-up of 13 (5.4) months, favorable outcome was achieved by 80.4% of patients, with median (IQR) RSI score improving from 29 (22-35) to 9 (4-17), (P < 0.001). Independent predictors of favorable outcome on multivariable analysis included LPR with typical reflux symptoms [OR (95% CI): 8.9 (2.3-31.1), P = 0.001], >80% intact swallow on high-resolution manometry [OR (95% CI): 3.8 (1.0-13.3), P = 0.035], upper esophageal sphincter (UES) resting pressure >34 mmHg [OR (95% CI): 4.1 (1.1-14.1), P = 0.027] and short total proximal acid clearance time [OR (95% CI): 1.1 (1.0-1.1), P = 0.031]. Impedance parameters including number of LPR events, full column reflux and proximal acid exposure events were similar between outcome groups (P > 0.05). CONCLUSION: MSA is an effective surgery for patients with LPR. Patients with concomitant typical reflux symptoms, normal esophageal body motility, and competent UES benefit the most from surgery. Individual impedance-pH parameters were not associated with outcome.

Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses.

Gastroesophageal cancer dynamics and drivers of clinical responses with immune checkpoint inhibitors (ICI) remain poorly understood. Potential synergistic activity of dual programmed cell death protein 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) inhibition may help improve immunotherapy responses for these tumors. We report a phase Ib trial that evaluated neoadjuvant nivolumab (Arm A, n = 16) or nivolumab-relatlimab (Arm B, n = 16) in combination with chemoradiotherapy in 32 patients with resectable stage II/stage III gastroesophageal cancer together with an in-depth evaluation of pathological, molecular and functional immune responses. Primary endpoint was safety; the secondary endpoint was feasibility; exploratory endpoints included pathological complete (pCR) and major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS). The study met its primary safety endpoint in Arm A, although Arm B required modification to mitigate toxicity. pCR and MPR rates were 40% and 53.5% for Arm A and 21.4% and 57.1% for Arm B. Most common adverse events were fatigue, nausea, thrombocytopenia and dermatitis. Overall, 2-year RFS and OS rates were 72.5% and 82.6%, respectively. Higher baseline programmed cell death ligand 1 (PD-L1) and LAG-3 expression were associated with deeper pathological responses. Exploratory analyses of circulating tumor DNA (ctDNA) showed that patients with undetectable ctDNA post-ICI induction, preoperatively and postoperatively had a significantly longer RFS and OS; ctDNA clearance was reflective of neoantigen-specific T cell responses. Our findings provide insights into the safety profile of combined PD-1 and LAG-3 blockade in gastroesophageal cancer and highlight the potential of ctDNA analysis to dynamically assess systemic tumor burden during neoadjuvant ICI that may open a therapeutic window for future intervention. ClinicalTrials.gov registration: NCT03044613 .

Capturing CO2 in Quadrupolar Binding Pockets: Broadband Microwave Spectroscopy of Pyrimidine-(CO2)n, n = 1,2.

Pyrimidine has two in-plane CH(δ+)/N̈(δ-)/CH(δ+) binding sites that are complementary to the (δ-/2δ+/δ-) quadrupole moment of CO2. We recorded broadband microwave spectra over the 7.5-17.5 GHz range for pyrimidine-(CO2)n with n = 1 and 2 formed in a supersonic expansion. Based on fits of the rotational transitions, including nuclear hyperfine splitting due to the two 14N nuclei, we have assigned 313 hyperfine components across 105 rotational transitions for the n = 1 complex and 208 hyperfine components across 105 rotational transitions for the n = 2 complex. The pyrimidine-CO2 complex is planar, with CO2 occupying one of the quadrupolar binding sites, forming a structure in which the CO2 is stabilized in the plane by interactions with the C-H hydrogens adjacent to the nitrogen atom. This structure is closely analogous to that of the pyridine-CO2 complex studied previously by (Doran, J. L. J. Mol. Struct. 2012, 1019, 191-195). The fit to the n = 2 cluster gives rotational constants consistent with a planar cluster of C2v symmetry in which the second CO2 molecule binds in the second quadrupolar binding pocket on the opposite side of the ring. The calculated total binding energy in pyrimidine-CO2 is -13.7 kJ mol-1, including corrections for basis set superposition error and zero-point energy, at the CCSD(T)/ 6-311++G(3df,2p) level, while that in pyrimidine-(CO2)2 is almost exactly double that size, indicating little interaction between the two CO2 molecules in the two binding sites. The enthalpy, entropy, and free energy of binding are also calculated at 300 K within the harmonic oscillator/rigid-rotor model. This model is shown to lack quantitative accuracy when it is applied to the formation of weakly bound complexes.

Impact of Change in Sizing Protocol on Outcome of Magnetic Sphincter Augmentation.

OBJECTIVE: To evaluate and compare magnetic sphincter augmentation (MSA) device sizing protocols on postoperative outcomes and dysphagia. SUMMARY BACKGROUND DATA: Among predictors of dysphagia after MSA, device size is the only factor that may be modified. Many centers have adopted protocols to increase device size. However, there is limited data on the impact of MSA device upsizing protocols on the surgical outcomes. METHODS: Patients who underwent MSA were implanted with 2 or 3-beads above the sizing device's pop-off point (POP). Clinical and objective outcomes >1-year after surgery were compared between patients implanted with POP+2-vs-POP+3 sizing protocols. Multiple subgroups were analyzed for benefit from upsizing. Pre- and postoperative characteristics were compared between size patients received, regardless of protocol. RESULTS: A total of 388 patients were implanted under POP+2 and 216 under POP+3. At a mean of 14.2(7.9) months pH normalization was 73.6% and 34.1% required dilation, 15.9% developed persistent dysphagia, and 4.0% required removal. Sizing protocol had no impact on persistent dysphagia ( P =0.908), pH normalization ( P =0.822), or need for dilation ( P =0.210) or removal ( P =0.191). Subgroup analysis found that upsizing reduced dysphagia in patients with <80 percent peristalsis (10.3-vs-31%, P =0.048) or DCI >5000 (0-vs-30.4%, P =0.034). Regardless of sizing protocol, as device size increased there was a stepwise increase in percent male sex ( P <0.0001), BMI>30 ( P <0.0001), and preoperative hiatal hernia>3 cm ( P <0.0001), LA grade C/D esophagitis ( P <0.0001), and DeMeester score ( P <0.0001). Increased size was associated with decreased pH-normalization ( P <0.0001) and need for dilation ( P =0.043) or removal ( P =0.014). CONCLUSIONS: Upsizing from POP+2 to POP+3 does not reduce dysphagia or affect other MSA outcomes; however, patients with poor peristalsis or hypercontractile esophagus do benefit. Regardless of sizing protocol, preoperative clinical characteristics varied among device sizes, suggesting size is not a modifiable factor, but a surrogate for esophageal circumference.

Esophageal body adaptation to Nissen fundoplication: Increased esophagogastric outflow resistance yields delayed and sustained peristaltic contractions without increased amplitude.

BACKGROUND: Improvement in lower esophageal sphincter (LES) competency after laparoscopic Nissen fundoplication (LNF) is well established, yet esophageal body physiology data are limited. We aimed to describe the impact of LNF on whole esophagus physiology using standard and novel manometric characteristics. METHODS: A cohort of patients with an intact fundoplication without herniation and no postoperative dysphagia were selected and underwent esophageal manometry at one-year after surgery. Pre- and post-operative manometry files were reanalyzed using standard and novel manometric characteristics and compared. KEY RESULTS: A total of 95 patients were included in this study. At 16.1 (8.7) months LNF increased LES overall and abdominal length and resting pressure (p < 0.0001). Outflow resistance (IRP) increased [5.8 (3-11) to 11.1 (9-15), p < 0.0001] with a 95th percentile of 20 mmHg in this cohort of dysphagia-free patients. Distal contractile integral (DCI) also increased [1177.0 (667-2139) to 1321.1 (783-2895), p = 0.002], yet contractile amplitude was unchanged (p = 0.158). There were direct correlations between pre- and post-operative DCI [R: 0.727 (0.62-0.81), p < 0.0001] and postoperative DCI and postoperative IRP [R: 0.347 (0.16-0.51), p = 0.0006]. Contractile front velocity [3.5 (3-4) to 3.2 (3-4), p = 0.0013] was slower, while distal latency [6.7 (6-8) to 7.4 (7-9), p < 0.0001], the interval from swallow onset to proximal smooth muscle initiation [4.0 (4-5) to 4.4 (4-5), p = 0.0002], and the interval from swallow onset to point when the peristaltic wave meets the LES [9.4 (8-10) to 10.3 (9-12), p < 0.0001] were longer. Esophageal length [21.9 (19-24) to 23.2 (21-25), p < 0.0001] and transition zone (TZ) length [2.2 (1-3) to 2.5 (1-4), p = 0.004] were longer. Bolus clearance was inversely correlated with TZ length (p = 0.0002) and time from swallow onset to proximal smooth muscle initiation (p < 0.0001). Bolus clearance and UES characteristics were unchanged (p > 0.05). CONCLUSIONS & INFERENCES: Increased outflow resistance after LNF required an increased DCI. However, this increased contractile vigor was achieved through sustained, not stronger, peristaltic contractions. Increased esophageal length was associated with increased TZ and delayed initiation of smooth muscle contractions.

The Dubai Definition and Diagnostic Criteria of Laryngopharyngeal Reflux: The IFOS Consensus.

OBJECTIVE: The objective of this work was to gather an international consensus group to propose a global definition and diagnostic approach of laryngopharyngeal reflux (LPR) to guide primary care and specialist physicians in the management of LPR. METHODS: Forty-eight international experts (otolaryngologists, gastroenterologists, surgeons, and physiologists) were included in a modified Delphi process to revise 48 statements about definition, clinical presentation, and diagnostic approaches to LPR. Three voting rounds determined a consensus statement to be acceptable when 80% of experts agreed with a rating of at least 8/10. Votes were anonymous and the analyses of voting rounds were performed by an independent statistician. RESULTS: After the third round, 79.2% of statements (N = 38/48) were approved. LPR was defined as a disease of the upper aerodigestive tract resulting from the direct and/or indirect effects of gastroduodenal content reflux, inducing morphological and/or neurological changes in the upper aerodigestive tract. LPR is associated with recognized non-specific laryngeal and extra-laryngeal symptoms and signs that can be evaluated with validated patient-reported outcome questionnaires and clinical instruments. The hypopharyngeal-esophageal multichannel intraluminal impedance-pH testing can suggest the diagnosis of LPR when there is >1 acid, weakly acid or nonacid hypopharyngeal reflux event in 24 h. CONCLUSION: A global consensus definition for LPR is presented to improve detection and diagnosis of the disease for otolaryngologists, pulmonologists, gastroenterologists, surgeons, and primary care practitioners. The approved statements are offered to improve collaborative research by adopting common and validated diagnostic approaches to LPR. LEVEL OF EVIDENCE: 5 Laryngoscope, 134:1614-1624, 2024.

Sitravatinib combined with PD-1 blockade enhances cytotoxic T-cell infiltration by M2 to M1 tumor macrophage repolarization in esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a leading cause of cancer-related mortality. Sitravatinib is a novel multi-gene tyrosine kinase inhibitor (TKI) that targets tumor-associated macrophage (TAM) receptors, VEGF, PDGF and c-Kit. Currently, sitravatinib is actively being studied in clinical trials across solid tumors and other TKIs have shown efficacy in combination with immune checkpoint inhibitors (ICI) in cancer models. In this study, we investigated the anti-tumor activity of sitravatinib alone and in combination with PD-1 blockade in an EAC rat model. Treatment response was evaluated by mortality, pre- and post-treatment MRI, gene expression, immunofluorescence and immunohistochemistry. Our results demonstrated adequate safety and significant tumor shrinkage in animals treated with sitravatinib, and more profoundly, sitravatinib and PD-1 inhibitor, AUNP-12 (P < 0.01). Suppression of TAM receptors resulted in increased gene expression of pro-inflammatory cytokines and decreased expression of anti-inflammatory cytokines, enhanced infiltration of CD8+ T cells, and M2 to M1 macrophage phenotype repolarization in the tumor microenvironment of treated animals (P < 0.01). Moreover, endpoint immunohistochemistry staining corroborated the anti-tumor activity by downregulation of Ki67 and upregulation of Caspase-3 in the treated animals. Additionally, pretreatment gene expression of TAM receptors and PD-L1 were significantly higher in major responders compared with the non-responders, in animals that received sitravatinib and AUNP-12 (P < 0.02), confirming that TAM suppression enhances the efficacy of PD-1 blockade. In conclusion, this study proposes a promising immunomodulatory strategy using a multi-gene TKI to overcome developed resistance to an ICI in EAC, establishing rationale for future clinical development.

Production, purification and immunogenicity of Gag virus-like particles carrying SARS-CoV-2 components.

The virus-like particle (VLP) platform is a robust inducer of humoral and cellular immune responses; hence, it has been used in vaccine development for several infectious diseases. In the current work, VLPs carrying SARS-CoV-2 Spike (S) protein (Wuhan strain) with an HIV-1 Gag core were produced using suspension HEK 293SF-3F6 cells by transient transfection. The Gag was fused with green fluorescent protein (GFP) for rapid quantification of the VLPs. Five different versions of Gag-Spike VLPs (Gag-S-VLPs) consisting of Gag-S alone or combined with other SARS-CoV-2 components, namely Gag-S-Nucleocapsid (N), Gag-S-Matrix (M), Gag-S-Envelope (E), Gag-S-MEN, along with Gag alone were produced and processed by clarification, nuclease treatment, concentration by tangential flow filtration (TFF) and diafiltration. A pilot mouse study was performed to evaluate the immunogenicity of the Gag-S-VLPs through the measurement of the humoral and/or cellular responses against all the mentioned SARS-CoV-2 components. Antibody response to Spike was observed in all variants. The highest number of Spike-specific IFN-γ + T cells was detected with Gag-S-VLPs. No induction of antigen-specific cellular responses to M, N or E proteins were detected with any of the Gag-S, M, E/or N VLPs tested. Therefore, the Gag-S-VLP, by reason of consistently eliciting strong antigen-specific cellular and antibody responses, was selected for further evaluation. The purification process was improved by replacing the conventional centrifugation by serial microfiltration in the clarification step, followed by Spike-affinity chromatography to get concentrated VLPs with higher purity. Three different doses of Gag-S-VLP in conjunction with two adjuvants (Quil-A or AddaVax) were used to assess the dose-dependent antigen-specific cellular and antibody responses in mice. The Gag-S-VLP adjuvanted with Quil-A resulted in a stronger Spike-specific cellular response compared to that adjuvanted with AddaVax. A strong spike neutralisation activity was observed for all doses, independent of the adjuvant combination.

Gas-Bloat Syndrome after Magnetic Sphincter Augmentation: Incidence, Natural History, Risk Factors, and Impact on Surgical Outcomes Over Time.

BACKGROUND: The notion that gas-bloat syndrome (GBS) after magnetic sphincter augmentation (MSA) is less detrimental has not been substantiated by data. This study aimed to identify the incidence, natural history, risk factors, and impact on outcomes of GBS after MSA. STUDY DESIGN: Records of patients who underwent MSA at our institution were reviewed. GBS was defined as a score of 4 or more on the gas bloat-specific item within the GERD health-related quality-of-life (GERD-HRQL) questionnaire. Preoperative clinical and objective testing data were compared between those with and without GBS at 1 year using univariate followed by multivariable analysis. GBS evolution over time and its impact on outcomes were assessed in those with 1- and 2-year follow-up. RESULTS: A total of 489 patients underwent MSA. At a mean (SD) follow-up of 12.8 (2.1) months, patient satisfaction was 88.8%, 91.2% discontinued antisecretory medications, and 74.2% achieved DeMeester score normalization.At 1 year, 13.3% of patients developed GBS, and had worse GERD-HRQL scores and antisecretory medication use and satisfaction (p < 0.0001). DeMeester score normalization was comparable (p = 0.856). Independent predictors of GBS were bloating (odds ratio [OR] 1.8, p = 0.043), GERD-HRQL score greater than 30 (OR 3, p = 0.0010), and MSA size 14 or less beads (OR 2.5, p = 0.004). In a subgroup of 239 patients with 2-year follow-up, 70.4% of patients with GBS at 1 year had resolution by 2 years. The GERD-HRQL total score improved when GBS resolved from 11 (7 to 19) to 7 (4 to 10), p = 0.016. Patients with persistent GBS at 2 years had worse 2-year GERD-HRQL total scores (20 [5 to 31] vs 5 [3 to 12], p = 0.019). CONCLUSIONS: GBS affects 13.3% of patients at 1 year after MSA and substantially diminishes outcomes. However, GBS resolves spontaneously with quality-of-life improvement. Patients with preoperative bloating, high GERD-HRQL scores, or small MSA devices are at greatest risk of this complication.

Clinical Management of Neuropathic Itch.

This JAMA Network Insight reviews the underlying mechanisms and management of peripheral sensory itch conditions.

Photophysical oxidation of HCHO produces HO2 radicals.

Formaldehyde, HCHO, is the highest-volume carbonyl in the atmosphere. It absorbs sunlight at wavelengths shorter than 330 nm and photolyses to form H and HCO radicals, which then react with O2 to form HO2. Here we show HCHO has an additional HO2 formation pathway. At photolysis energies below the energetic threshold for radical formation we directly detect HO2 at low pressures by cavity ring-down spectroscopy and indirectly detect HO2 at 1 bar by Fourier-transform infrared spectroscopy end-product analysis. Supported by electronic structure theory and master equation simulations, we attribute this HO2 to photophysical oxidation (PPO): photoexcited HCHO relaxes non-radiatively to the ground electronic state where the far-from-equilibrium, vibrationally activated HCHO molecules react with thermal O2. PPO is likely to be a general mechanism in tropospheric chemistry and, unlike photolysis, PPO will increase with increasing O2 pressure.

Chevalier Jackson: father of endoscopic surgery, and champion of women in medicine, social justice, and public health.

BACKGROUNDS: Chevalier Jackson (1865-1958) was a pioneering force in the medical world, whose extraordinary contributions to surgery and public health have left an indelible impact. He developed the endoscope and perfected the bronchoscope, and his mastery of these tools enabled him to transform the prognosis of foreign body aspiration from 98% mortality to 98% survival. He was also a passionate advocate of public health chairing the national committee on lye legislation, which culminated in the Caustic Poison Act, responsible for poison and antidote labels. Yet Jackson's accomplishments were not limited to these. The aim of this manuscript was to shed light on Chevalier Jackson's lesser-known contributions to surgical science and culture, and to celebrate and honor the life of this remarkable surgeon. METHODS: Digital and physical historical records from the National Library of Medicine, Smithsonian Institution, Heinz History Center in Pittsburgh PA, and Sunrise Mill Museum, Montgomery County PA were reviewed for Chevalier Jackson's scientific, cultural, and social contributions to the field of surgery. RESULTS: Among his lesser-known contributions, Chevalier Jackson was the first to describe erosive esophagitis. He developed the first standardized tracheotomy procedure, still in use today. He was ahead of his time in many ways, pioneering a multidisciplinary approach to medicine, advocating for patient-centered care, and advancing the inclusion of women in the medical profession. CONCLUSION: Chevalier Jackson's legacy extends far beyond the tools and techniques he invented. He was a champion of social justice, a protector of patients, and an inspiration to medical professionals across the globe.

The impact of delayed gastric emptying as measured by gastric emptying scintigraphy on the outcome of magnetic sphincter augmentation.

INTRODUCTION: The impact of delayed gastric emptying (DGE) on the outcome of anti-reflux surgery (ARS) is controversial. There is concern that poor gastric emptying diminishes outcomes. Magnetic sphincter augmentation (MSA) may have a comparatively mild impact on gastric physiology, but the relationship between DGE and MSA outcomes is unknown. This study aims to evaluate the relationship between objective DGE and MSA outcomes over time. METHODS: Patients who completed gastric emptying scintigraphy (GES) prior to MSA between 2013 and 2021 were included. DGE was defined as a 4 h retention > 10% or half emptying time > 90 min on GES. Outcomes were compared between DGE and normal gastric emptying (NGE) groups at 6 months, 1 and 2 years. Sub-analysis of patients with severe (> 35%) DGE and correlation analysis between 4-h retention and symptom and acid-normalization were performed. RESULTS: The study population consisted of 26 (19.8%) patients with DGE and 105 with NGE. DGE was associated with more 90-days readmissions (18.5 vs 2.9%, p = 0.009). At 6 months patients with DGE had higher median (IQR) GERD-HRQL total [17.0(10-29) vs 5.5(3-16), p = 0.0013], heartburn [1(1-3) vs 0(0-1), p = 0.0010) and gas-bloat [4(2-5) vs 2(1-3), p = 0.033] scores. Outcomes at 1 and 2 years follow-up were comparable (p > 0.05). From 6 months to 1-year the gas-bloat score decreased from 4(2-5) to 3(1-3), p = 0.041. Total and heartburn scores decreased, but not significantly. Severe DGE (n = 4) patients had lower antiacid medication freedom at 6 months (75 vs 87%, p = 0.014) and 1-year (50 vs 92%, p = 0.046). There were non-significant trends for higher GERD-HRQL scores, dissatisfaction, and removal rates in severe DGE at 6 months and 1-year. There was a weak correlation between 4-h retention and 6-month GERD-HRQL total score [R = 0.253, 95%CI (0.09-0.41), p = 0.039], but not acid-normalization (p > 0.05). CONCLUSION: Outcomes after MSA are diminished early on in patients with mild-to-moderate DGE, but comparable by 1 year and durable at 2 years. Severe DGE outcomes may be suboptimal.

Need for frequent dilations after magnetic sphincter augmentation: an assessment of associated factors and outcomes.

BACKGROUND: Dysphagia is the most common complaint after magnetic sphincter augmentation (MSA), with nearly one-third of patients requiring at least one dilation following MSA. A subset of patients require frequent dilations, but there is a paucity of data on the characteristics of this population. This study aimed to identify predictors of the need for frequent dilations within the first year after implant and to assess these patients' outcomes. METHODS: This is a retrospective review of prospectively collected data of patients who underwent MSA over an 8-year period. Frequent dilations were defined as 2 or more dilations within 1 year of surgery. Patients completed baseline and 1-year postoperative GERD-HRQL questionnaires and objective physiology testing. Baseline demographic, clinical characteristics, and objective testing data were compared between patients who did and did not require frequent dilations. RESULTS: A total of 697 (62.7% female) patients underwent MSA, with 62 (8.9%) patients requiring frequent dilation. At a mean (SD) of 12.3 (3.4) months follow-up, the frequent dilation group had higher median GERD-HRQL total scores (21.0 vs. 5.0, p < 0.001), PPI use (20.8% vs.10.1%, p = 0.023), dissatisfaction (46.7% vs. 11.6%, p < 0.001), and device removal (25.8% vs. 2.2%, p < 0.001) rates. Acid normalization was comparable (p = 0.997). Independent predictors of frequent dilation included preoperative odynophagia (OR 2.85; p = 0.001), IRP > 15 mmHg (OR 2.88; p = 0.006), and > 30% incomplete bolus clearance (OR 1.94; p = 0.004). At a mean (SD) of 15.7 (10.7) months, 28 (45.1%) patients underwent device removal after frequent dilation. Independent predictors of device removal after frequent dilation within 5 years of surgery were preoperative odynophagia (OR 7.18; p = 0.042), LES resting pressure > 45 mmHg (OR 28.5; p = 0.005), and ≥ 10% failed swallows (OR 23.5; p < 0.001). CONCLUSIONS: The need for frequent dilations after MSA is a marker for poor symptom control, dissatisfaction, and device removal. Patients with preoperative odynophagia, high LES pressures, and poor esophageal motility should be counseled of their risk for these poor outcomes.