Evidence Of Inflammation Research Articles

The Management of Interstitial Lung Disease in the ICU: A Comprehensive Review

Interstitial lung disease (ILD) encompasses a diverse group of parenchymal lung diseases characterized by varying degrees of inflammation and/or fibrosis. Patients with ILD frequently require hospitalization, with many needing intensive care unit (ICU) admission, most often due to respiratory failure. The diagnosis and management of ILD in the ICU present unique challenges. Diagnosis primarily relies on chest CT imaging to identify fibrosis and inflammation. Acute exacerbations, whether in idiopathic pulmonary fibrosis (IPF) or non-IPF ILD, require careful evaluation of potential triggers and differential diagnoses. Bronchoalveolar lavage may provide valuable information, such as the identification of infections, but carries risks of complications. Biopsies, whether transbronchial or surgical, can also be informative but pose significant procedural risks. Corticosteroids are the cornerstone of treatment for acute exacerbations of IPF, with higher doses potentially benefiting non-IPF ILD. Additional immunosuppressive agents may be used in cases with evidence of inflammation. Oxygen supplementation, particularly with high-flow nasal cannula, is often employed to manage severe hypoxemia, while noninvasive ventilation can be useful for worsening hypoxemia and/or hypercapnia. When mechanical ventilation is used, it is recommended to target low tidal volumes to minimize lung injury; high PEEP may be less effective and even associated with increased mortality. Prone positioning can improve oxygenation in severely hypoxemic patients. In addition to ventilatory strategies, careful fluid management and addressing concomitant pulmonary hypertension are essential components of care. Extracorporeal membrane oxygenation is a high-risk intervention reserved for the most severe cases. Lung transplantation may be considered for end-stage ILD patients in the ICU, with outcomes dependent on the urgency of transplantation and the patient’s overall condition. Managing ILD in the ICU requires a multidisciplinary approach, and despite recent advances, mortality remains high, emphasizing the need for continued research and individualized treatment strategies.

Sump syndrome: Diagnosis dilemmas and therapeutic approaches-A case series.

It is important to consider the diagnosis of Sump syndrome in patients with a history of open cholecystectomy, particularly in those who migrate from developing countries where alternative biliary interventions may be limited. The presentation may range from acute severe, mimicking acute ascending cholangitis, to chronic recurrent abdominal pain without evidence of inflammation. Management is a case-by-case decision, with principal management aims to decompress the biliary tract and address any underlying sepsis. Sump syndrome is a rare and often long-term complication of choledochoduodenostomy (CDD). The presentation and severity are variable, and management should be tailored to each patient based on several factors. Herein, we report three cases of sump syndrome, each demonstrating unique diagnostic dilemmas and therapeutic modalities. Case I describes a woman presenting with acute cholangitis, managed with percutaneous transhepatic cholangiography (PTC) and endoscopic retrograde cholangiopancreatography (ERCP). Case II illustrates a similar presentation complicated by myocardial infarction, necessitating urgent biliary decompression via PTC and subsequent unsuccessful endoscopic stenting. Case III highlights the diagnostic difficulty in a stable patient with inconclusive diagnostic imaging. This case series emphasizes the importance of considering sump syndrome diagnosis in patients with a history of CDD or open cholecystectomy, especially in elderly patients and those who come from regions where alternative biliary interventions may be limited.

Inflammation in Obesity-Related HFpEF: The STEP-HFpEF Program

BackgroundInflammation is thought to be an important mechanism for the development and progression of obesity-related heart failure with preserved ejection fraction (HFpEF). In the STEP-HFpEF Program, once-weekly 2.4 mg semaglutide improved heart failure–related symptoms, physical limitations, and exercise function, reduced the levels of C-reactive protein (CRP), a biomarker of inflammation, and reduced body weight in participants with obesity-related HFpEF. However, neither the prevalence nor the clinical characteristics of patients who have various magnitudes of inflammation in the context of obesity-related HFpEF have been well described. Furthermore, whether the beneficial effects of semaglutide on the various HF efficacy endpoints in the STEP-HFpEF Program are modified by the baseline levels of inflammation has not been fully established. Finally, the relationship between weight reduction and changes in CRP across the STEP-HFpEF Program have not been fully defined. ObjectivesThis study sought to: 1) evaluate baseline characteristics and clinical features of patients with obesity-related HFpEF that have various levels of inflammation in the STEP-HFpEF Program; 2) determine if the effects of weekly semaglutide 2.4 mg vs placebo across all key outcomes are influenced by baseline levels of inflammation assessed by CRP levels; and 3) determine the relationship between change in CRP and weight loss in the STEP-HFpEF Program. MethodsThis was a secondary analysis of pooled data from 2 international, double-blind, placebo-controlled, randomized trials (STEP-HFpEF and STEP-HFpEF DM). The outcomes were change in the dual primary endpoints (health status [measured by the Kansas City Cardiomyopathy Questionnaire—Clinical Summary Score (KCCQ-CSS)] and body weight) from baseline to 52 weeks according to baseline CRP levels. Additional efficacy endpoints included change in 6-minute walk distance (6MWD), a hierarchical composite endpoint that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6MWD, and levels of CRP in semaglutide- vs placebo-treated patients. Patients were stratified into 3 categories based on baseline CRP levels (<2, ≥2 to <10, and ≥10 mg/L). ResultsIn total, 1,145 patients were randomized, of which 71% of patients had evidence of inflammation (CRP ≥2 mg/L). At baseline, those with higher levels of inflammation were younger, were more likely to be female, and had higher body mass index, worse health status (KCCQ-CSS), and shorter 6MWD. Semaglutide vs placebo led to reductions in HF-related symptoms and physical limitations as well as body weight, and to improvements in 6MWD and the hierarchical composite endpoint that were consistent across baseline CRP categories (all P interaction nonsignificant). Semaglutide also reduced CRP to a greater extent than placebo regardless of baseline CRP levels (P interaction = 0.32). Change in CRP from baseline to 52 weeks was similar regardless of the magnitude of weight loss (P interaction = 0.91). ConclusionsInflammation is highly prevalent in obesity-related HFpEF. Semaglutide consistently improved HF-related symptoms, physical limitations, and exercise function, and reduced body weight across the categories of baseline CRP. Semaglutide also reduced inflammation, regardless of either baseline CRP or magnitude of weight loss during the trials. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF; NCT04788511]; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP HFpEF DM; NCT04916470])

Outcomes of surgical resection and vagus nerve stimulation in patients with medically refractory epilepsy and glutamic acid decarboxylase 65 antibody positivity.

Epilepsy associated with high-titer glutamic acid decarboxylase 65 (GAD65) IgG is often refractory to immunotherapies and antiseizure medication. This study sought to determine the efficacy of vagus nerve stimulation (VNS) and surgical resection in patients with drug-resistant epilepsy associated with GAD65-IgG. We retrospectively identified 15 patients with drug-resistant epilepsy and high serum GAD65 antibody titers (>20 nmol·L-1) who underwent VNS implantation (n = 6), surgical resection (n = 7), or both (n = 2). A responder to VNS was defined as someone with a ≥50% reduction in seizure frequency, and a favorable surgical outcome was defined as Engel I-II. Of the eight patients who underwent VNS implantation, three (37.5%) were initially responders, but this was not sustained in two. Of the nine patients who underwent surgical resection, three (33.3%) had a favorable outcome; however, only one patient was seizure-free at last follow-up. Pathology was available in six patients, and only one had evidence of inflammation; this patient had seizure onset 1 year prior to surgery. Favorable seizure outcome correlated with older age at time of resective surgery, with a trend favoring later age of seizure onset. Taken together, surgical resection and VNS implantation may have limited efficacy in this patient population but can be considered in carefully selected cases.

The effect of dietary emulsifiers and thickeners on intestinal barrier function and its response to acute stress in healthy adult humans: A randomised controlled feeding study.

Although dietary emulsifiers are implicated in the pathogenesis of Crohn's disease, their effect has not been studied in humans. To determine the effects of high- and low-emulsifier diets (HED, LED) on intestinal barrier function in healthy subjects in unstressed and acutely stressed states. We conducted a single-blinded, cross-over, controlled feeding trial in 22 healthy adults. After recording 7 days of their habitual diet, we randomised participants to HED or LED with ≥3-week washout between diets. On dietary completion, acute stress was induced via intravenous corticotrophin-releasing hormone. We assessed dietary adherence, effects on 2-h urinary lactulose: rhamnose ratio (LRR), serum concentrations of lipopolysaccharide-binding protein, soluble-CD14 and markers of epithelial injury and inflammation. Dietary adherence was excellent. In an unstressed state, median (interquartile range) LRR during HED was 0.030 (0.018-0.042); on LED, this was 0.042 (0.029-0.078; p = 0.04). LPB concentrations were lower on HED than LED (p = 0.026), but no differences were observed for epithelial injury or inflammation. Under acute stress, LRR increased by 89% (-1% to 486%) on HED (p = 0.004), differing (p = 0.001) from 39% (1%-90%) decrease on LED (p = 0.009). Soluble-CD14 also increased (p < 0.001). The LED had a prolonged carry-over effect on suppressing HED-induced changes during stress. Similar changes in LRR and soluble-CD14 were observed when HED was used as the first diet (both p < 0.01). High intake of emulsifiers improved barrier function in the unstressed state, but increased intestinal permeability to stress, without evidence of inflammation. A LED was protective of the stress effect.

Review of Urinary Tract Infections and Pyelonephritis

Urinary tract infections (UTIs) are serious bacterial infections affecting children of all ages. An understanding of the methods of urine collection is important to prevent the contamination of urine specimens and to interpret results. The diagnosis of a UTI requires appropriate interpretation of both urinalysis and urine culture results because testing must indicate evidence of inflammation and the presence of bacteria. Rapid treatment of UTIs is imperative to prevent acute decompensation and systemic illness. Empiric antibiotics should be narrowed as soon as possible to tailor antibiotic treatment and limit antibiotic overuse. Imaging with a renal ultrasound scan is recommended for all infants with first febrile UTIs rather than a voiding cystourethrogram. An additional goal of UTI treatment is to prevent renal scarring, which can lead to lifelong health consequences. Children with anatomic abnormalities of the urinary tract and those who have recurrent UTIs are at increased risk of renal scarring. [ Pediatr Ann . 2024;53(6):e217–e222.]

Histopathological findings from the investigation of paediatric acute hepatitis of unknown aetiology, United Kingdom 2022.

In 2022, there were global reports of increased numbers of acute hepatitis not explained by hepatitis A-E virus infection in children. This manuscript summarises histopathology results from 20 patients in the United Kingdom who underwent liver transplantor had a liver biopsy as part of aetiological investigations. All available histopathological samples were reviewed centrally as part of the outbreak investigation. A working group comprised of infection specialists, hepatologists and histopathologists met virtually to review the cases, presentation, investigations and histopathology. All 20 liver samples had evidence of inflammation without significant interface activity, and submassive confluent pan-lobular or multilobular hepatocellular necrosis. Overall, the predominant histopathological findings were of acute nonspecific hepatitis with submassive hepatic necrosis and central vein perivenulitis and endothelitis. Histopathological findings were a poor indicator of aetiology.

Evidence for inflammation in normal-appearing brain regions in patients with growing sporadic vestibular schwannoma: A PET study.

Nonauditory symptoms can be a prominent feature in patients with sporadic vestibular schwannoma (VS), but the cause of these symptoms is unknown. Inflammation is hypothesized to play a key role in the growth and symptomatic presentation of sporadic VS, and in this study, we investigated through translocator protein (TSPO) positron emission tomography (PET) whether inflammation occurred within the "normal appearing" brain of such patients and its association with tumor growth. Dynamic PET datasets from 15 patients with sporadic VS (8 static and 7 growing) who had been previously imaged using the TSPO tracer [11C](R)-PK11195 were included. Parametric images of [11C](R)-PK11195 binding potential (BPND) and the distribution volume ratio (DVR) were derived and compared across VS growth groups within both contralateral and ipsilateral gray (GM) and white matter (WM) regions. Voxel-wise cluster analysis was additionally performed to identify anatomical regions of increased [11C](R)-PK11195 binding. Compared with static tumors, growing VS demonstrated significantly higher cortical (GM, 1.070 vs. 1.031, P = .03) and whole brain (GM & WM, 1.045 vs. 1.006, P = .03) [11C](R)-PK11195 DVR values. The voxel-wise analysis supported the region-based analysis and revealed clusters of high TSPO binding within the precentral, postcentral, and prefrontal cortex in patients with growing VS. We present the first in vivo evidence of increased TSPO expression and inflammation within the brains of patients with growing sporadic VS. These results provide a potential mechanistic insight into the development of nonauditory symptoms in these patients and highlight the need for further studies interrogating the role of neuroinflammation in driving VS symptomatology.

Identifying genetic determinants of Streptococcus pyogenes-host interactions in a murine intact skin infection model

Streptococcus pyogenes is an obligate human pathobiont associated with many disease states. Here, we present a model of S.pyogenes infection using intact murine epithelium. We were able to perform RNA sequencing to evaluate genetic changes undertaken by both the bacterium and host at 5 and 24h post-infection. Analysis of these genomic data demonstrate that S.pyogenes undergoes genetic adaptation to successfully infect the murine epithelium, including changes to metabolism and activation of the Rgg2/Rgg3 quorum-sensing (QS) system. Subsequent experiments demonstrate that an intact Rgg2/Rgg3 QS cascade is necessary to establish a stable superficial skin infection. QS cascade activation results in increased murine morbidity and bacterial burden on the skin. This phenotype is associated with gross changes to the murine skin and with evidence of inflammation. These experiments offer a method to investigate S.pyogenes-epithelial interactions and demonstrate that a well-studied QS pathway is critical to a persistent infection.

Establishment of persistent enteric mycobacterial infection following streptomycin pre-treatment

Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent of paratuberculosis, a chronic gastrointestinal disease affecting ruminants. This disease remains widespread in part due to the limitations of available diagnostics and vaccines. A representative small animal model of disease could act as a valuable tool for studying its pathogenesis and to develop new methods for paratuberculosis control, but current models are lacking. Streptomycin pre-treatment can reduce colonization resistance and has previously been shown to improve enteric infection in a Salmonella model. Here, we investigated whether streptomycin pre-treatment of mice followed by MAP gavage could act as a model of paratuberculosis which mimics the natural route of infection and disease development in ruminants. The infection outcomes of MAP were compared to M. avium subsp. hominissuis (MAH), an environmental mycobacterium, and M. bovis and M. orygis, two tuberculous mycobacteria. Streptomycin pre-treatment was shown to consistently improve bacterial infection post-oral inoculation. This model led to chronic MAP infection of the intestines and mesenteric lymph nodes (MLNs) up to 24-weeks post-gavage, however there was no evidence of inflammation or disease. These infection outcomes were found to be specific to MAP. When the model was applied to a bacterium of lesser virulence MAH, the infection was comparatively transient. Mice infected with bacteria of greater virulence, M. bovis or M. orygis, developed chronic intestinal and MLN infection with pulmonary disease similar to zoonotic TB. Our findings suggest that a streptomycin pre-treatment mouse model could be applied to future studies to improve enteric infection with MAP and to investigate other modifications underlying MAP enteritis.

Skin Color Matters

Evaluating skin of color (SOC) demands that clinicians avoid solely relying on visual inspection, which can lead to diagnostic error. For example, redness, one of the most obvious signs of cutaneous inflammation, is subtle, appears violaceous, hyperpigmented, or is not apparent in SOC. Erythema in all skin tones is evidence of inflammation, but in darker skin, so is hyperpigmentation. Several inflammatory conditions hallmarked by erythema, such as atopic dermatitis (AD), psoriasis, or pressure injuries (PI), may be misdiagnosed in darker skin because the clinical presentation is inconsistent with textbook descriptions. Moreover, some cancers may go undiagnosed.

A review of stem cell therapy in ischemic heart disease, where are we now?

Background: Regenerative therapies to rejuvenate the heart have a significant appeal for researchers. Preliminary findings from pre-clinical studies suggest that bone marrow cells may have reparative and regenerative effects on heart muscles, creating a ripe area for research. Many generations of stem cells used in pre-clinical and early clinical studies have shown promising but variable results. Objective: The current review article discusses the dilemmas in applying stem cell therapy to cardiovascular diseases and possible strategies to make it feasible. Methods: The field of regenerative therapies continued to progress with second-generation cells, third-generation cells, combination cell therapy, and the use of cell products alone. Research showed promising positive results in multiple randomized phases 1, 2, and 3 clinical trials in addition to numerous meta-analyses. The gaps in knowledge included stem-cell sources, their delivery routes, dosing, types of cells, and the indicated cardiac conditions. Results: The results from the latest randomized clinical trials, namely the Dream-HF, showed improved left ventricle function, symptoms, and overall survival. Studied patient populations include post-myocardial infarction (MI), ischemic/non-ischemic cardiomyopathy, intractable/microvascular angina, and cardiac surgery for congenital and valvular heart disease. The phase 3 DREAM-HF trial did not meet the primary heart failure endpoint of reducing hospital admission. Still, it showed a clinically significant reduction in major adverse cardiovascular events (MACE), including recurrent MI and stroke, by 60%. A 60% reduction in cardiovascular mortality and a 79% reduction in cardiovascular mortality in patients with evidence of inflammation (high CRP). The latter finding suggests a more anti-inflammatory effect. This effect was much higher than that observed in the PARADIGM-HF trial, which showed a 20% relative risk reduction in cardiovascular mortality. By combining the results of the DREAM-HF trial with MSC-HF, ixCELL-DCM, CONCERT-HF, and REGENERATE-DCM, the potential for clinical applications of cell therapy is promising. Conclusion: There is a promising role for cell therapy in the management of cardiovascular diseases. Results of trials in the setting of heart failure are more encouraging in both ischemic and non-ischemic cardiomyopathy. This is in contrast with acute myocardial infarction, where the results have been variable. Amongst all the various cell types tested MSCs show the most significant promise for treating HF.

1520-P: Metabolic Dysregulation in Probable Alzheimer’s Disease

Insulin resistance, T2D, and chronic inflammation increase risk of developing mild cognitive impairment and Alzheimer’s disease (AD). We report here baseline data from a multicenter, randomized, placebo-controlled Phase 3 study (NCT04669028) in patients with mild to moderate AD evaluating the effects of NE3107, an oral small molecule, blood-brain permeable anti-inflammatory insulin sensitizer that binds extracellular signal-regulated kinase. Inclusion criteria are diagnosis and progression of AD, supportive brain scan and Hachinski scale to exclude vascular dementia, Clinical Dementia Rating (CDR) score of 1-2, and Mini Mental State Exam (MMSE) score of 14-24. Primary outcomes are changes in cognition and function from baseline to 30 wks. Secondary outcomes include changes in neuropsychological deficits, functional performance, and regulation of glycemia. Aβ+ subjects were older and had worse MMSE, ADAS-Cog12 and AD Composite Scores than Aβ-patients, but had less evidence of inflammation (lower CRP) and less insulin resistance (lower fasting glucose, less IFG and T2D, lower fasting insulin and HOMA2-IR, and less hypertension) (Table). Metabolic dysregulation (elevated C1q, increased CGM mean and MAGE, increased cholesterol, triglycerides, and waist-hip ratio) was also observed independent of Aβ and APOEε4 status. Inflammation and insulin resistance may contribute to AD even in the absence of classical risk markers for AD. Disclosure C.L.Reading: Employee; BioVie, Inc. C.Ahlem: Employee; Biovie, Inc. J.M.Palumbo: Employee; BioVie, Zynerba, Other Relationship; Merck Sharp &amp; Dohme Corp. M.A.Testa: Stock/Shareholder; Phase V Technologies, Inc. D.C.Simonson: Stock/Shareholder; Phase V Technologies, Inc., GI Windows.

#2715 AN EXPLORATORY STUDY OF GUT PERMEABILITY IN SUBJECTS ON HAEMODIALYSIS: RESPONSE TO AN ORAL BETA-D-GLUCAN LOAD

Abstract Background and Aims End stage kidney disease (ESKD) is associated with chronic inflammation. A combination of increased gut permeability and impaired hepatic clearance of gut-derived toxins are likely contributory factors to chronic inflammation in ESKD. Gut permeability assessment in kidney impairment is complex as traditional gut permeability probe concentrations are significantly influenced by residual kidney function. (1-3)-β-D glucans (BDG) are glucose polymers found in dietary plant material and also fungi and bacteria. BDG predominantly undergo reticuloendothelial (primarily hepatic) clearance. BDG ingested in the form of fibre are not well absorbed from the small intestine. Elevated serum BDG levels have been previously observed in chronic kidney disease and may reflect systemic translocation of dietary and gut derived microbial fragments from the portal system. This study aimed to establish if there were differences in serum BDG concentrations in individuals with normal kidney function and ESKD following ingestion of a BDG rich meal. Method 20 participants with ESKD receiving haemodialysis via an arteriovenous fistula with evidence of inflammation (a median baseline serum C-reactive protein (CRP) ≥5mg/L over the previous 3 months) and 20 participants with normal kidney function (NKF) were studied. Participants with active infection, autoimmune disease, gastrointestinal disease and hyperkalaemia were excluded. All participants followed a low fibre diet for 48 hours and fasted for 12 hours prior consuming a BDG-rich drink that delivered approximately 10μg/gram of BDG. In the ESKD cohort, the drink was consumed immediately prior to a dialysis session following a 1-day interdialytic gap. In addition to standard of care blood tests, serum BDG levels were measured at baseline, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours and 48 hours. Serum BDG measurements were analysed with the Fungitell® assay (Associates of Cape Cod, Inc). Faecal calprotectin and faecal alpha-1-antitrypsin were also analysed. Results 20 participants with ESKD receiving haemodialysis (mean age 66.8 years) and 20 participants with NKF (mean age 44.6 years) were recruited. Serum BDG levels were significantly higher at baseline in the ESKD group (29.6pg/ml in the NKF group versus 67.1pg/ml in the ESKD group, p = 0.001) and at all other timepoints throughout the study period (see Fig. 1). There were no significant difference in change from baseline BDG levels between groups. Individual BDG levels taken post meal ingestion are shown in Fig. 2. Baseline serum BDG levels correlated strongly with median baseline high sensitivity CRP over 3 months (p = 0.001) however this relationship was not present when the two groups were examined separately. Faecal calprotectin and faecal alpha-1-antitrypsin did not correlate with baseline serum BDG measurements (p = 0.93, p = 0.78, respectively). Conclusion Elevated BDG levels are observed in ESKD and increase both during and immediately following dialysis after ingestion of a BDG load. In addition to dietary BDG, translocation of gut-derived microbial BDG into the systemic circulation may play an important role in contributing to systemic inflammation observed in advanced kidney disease. Elevated BDG may reflect increased gut permeability which may be secondary to uraemic toxin related gut barrier dysfunction or splanchnic ischaemia related to ultrafiltration.

Non-Alcoholic Fatty Liver Disease: Current Insights

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. It affects approximately 3 out of 10 patients and, if not treated promptly, it could lead to cirrhosis and progress to hepatocellular carcinoma (HCC). NAFLD is defined as &gt;5% fatty infiltration of liver parenchyma documented by biopsy; if there is also evidence of inflammation and lobar degeneration, it is called non-alcoholic steatohepatitis (NASH). The main risk factors associated with this condition are being overweight or obese, diets rich in refined carbohydrates and ultra-processed foods, type 2 diabetes mellitus, sedentary lifestyle, and metabolic syndrome. This promotes an increase in the visceral adipose compartment, insulin resistance and a disproportionate increase in fatty acid deposits in the liver. Patients are generally asymptomatic and are diagnosed taking into account risk factors, documentation of hepatic steatosis by imaging or biopsy, exclusion of other causes of hepatic steatosis and absence of pre-existing chronic liver disease. Treatment is based on a multidisciplinary approach seeking weight loss, regular physical activity and a healthy diet; however, in certain selected cases, vitamin E should be started. Some patients who have not received adequate treatment will require liver transplantation, especially if there is end-stage liver disease.

Iatrogenic atlantoaxial rotatory subluxation after thyroidectomy in a pediatric patient: A case report

Atlantoaxial rotatory subluxation (AARS) is an uncommon disease with a greater prevalence among children than adults, and it is mostly associated with trauma. Iatrogenic spinal injury accounts for a low percentage of injuries. However, in AARS, 20%-40% of cases are associated with surgery, and 48% are caused by infection. Here, we describe our experience with a case of iatrogenic AARS after general anesthesia. A 12-year-old girl presented with right-sided torticollis and cervical motion limit. The patient had undergone thyroidectomy 2 mo ago. Computed tomography revealed AARS with bilateral locked facets. Following the failure of repeated external reduction under general anesthesia, the patient underwent an open surgical reduction. The patient gained atlantoaxial alignment without any complications. Follow-up radiographs showed a normal appearance without instability. The cervical spine of children is more predisposed to injury due to anatomical and biomechanical differences. AARS secondary to infection and surgery is known as Grisel's syndrome, which involves non-traumatic AARS. Several cases of AARS after surgery and other procedures with no evidence of inflammation have been reported. Our experience shows that surgery requiring hyperextension of the neck after general anesthesia should also be included as a risk factor. Surgeons and anesthesiologists should be careful not to excessively extend the neck during pediatric surgery. Moreover, clinicians caring for pediatric patients with recent head and neck procedures must be aware of common AARS presentations.

The role of Nod-like receptors in modulating the microbiota-gut-brain axis following neonatal bacterial infection

Objective: Pediatric infection with diarrheal pathogens causes cognitive deficits in adulthood via an unknown mechanism. Neonatal infection with a bacterial enteric pathogen disrupts the development of the microbiota-gut-brain (MGB) axis in adult mice. Given the role of pattern recognition receptors, including Nucleotide Oligomerization Domain 1 (Nod1) in innate immune responses to infection, our objective was to establish their role in disrupted MGB axis communication following neonatal enteropathogenic Escherichia coli (EPEC) infection. Hypothesis: Intestinal epithelial cell (IEC) Nod1 modulates disrupted MGB axis communication following neonatal EPEC infection. Methods: C57BL/6 (male/female) IEC Nod1 conditional knockout mice (IEC cKO; Cre+) and wild type (WT) littermate controls (Cre-) were used. Neonatal mice were infected on postnatal day 7 (P7) with EPEC (10 5 CFU; strain e2348/69; orogastric gavage), or vehicle control (Luria broth). Colonization was assessed at P14 and P21 (MacConkey agar plating) and disease monitored via weight loss and ileal inflammation (qPCR). Behavior and neuroinflammation were assessed in adulthood (6-8 weeks). Behavioral tests included the novel object recognition task (NOR) for cognitive function, the light/dark (L/D) box for anxiety-like behavior, and open field test (OFT) for general and locomotor behavior. Results: Neonatally EPEC-infected Nod1 cKO mice demonstrated blunted ileal inflammation, with similar decreased expression of Il6, Tlr2, Tlr4, and Nod2 in cKO vs WT EPEC-infected mice ( P = NS, n = 4-6 ), with no evidence of inflammation in uninfected controls (WT or cKO). In contrast, evidence of hippocampal neuroinflammation was present in EPEC-infected Nod1 cKO mice, with increased expression of Iba1, Il6, and Il22 ( P &lt; 0.0001, n = 4-6), compared to sham-infected Nod1 cKO mice or uninfected control mice. In addition, EPEC-infected Nod1 cKO mice demonstrated decreased hippocampal expression of the neurogenesis marker Bdnf ( P &lt; 0.0001, n ≥ 4) compared to EPEC-infected WT mice, or uninfected mice. With respect to behavior, EPEC-infected WT mice had a lower exploration ratio (49.5 ± 1.7% vs. 54.6 ± 1.7%, P = 0.0035, n ≥ 8), whereas EPEC-infected Nod1 cKO mice displayed normal exploration of a novel object compared to uninfected Nod1 cKO mice ( P = NS, n = 10-12), without impacting anxiety-like behavior ( P = NS, n = 10-12). Conclusions: IEC Nod1 is important for maintaining MGB axis communication following neonatal EPEC infection. We speculate that decreased ileal inflammation due to absence of Nod1 IEC expression prevents cognitive deficits in adulthood, despite the evidence of neuroinflammation and impaired neurogenesis. Inflammation in the gut and brain will be further characterized by immunofluorescence in ongoing studies. NIH R01AT009365; NIH R21MH108154. Olivia Orahood is an active-duty member of the United States Space Force. The views expressed in this article are those of the author and do not reflect the official policy or position of the United States Space Force, United States Air Force, Department of Defense, or the U.S. Government This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effectiveness of T2 biologics in patients with common variable immune deficiency and allergic respiratory disease

IntroductionMany patients with common variable immune deficiency (CVID) have a history suggestive of allergic respiratory disease including chronic rhinosinusitis (CRS) and asthma. The underlying immunologic defect, the presence of comorbid conditions such as bronchiectasis or interstitial lung disease, and recurrent infections may make the diagnosis of these conditions difficult. T2 biologics targeting allergic inflammatory pathways are now the standard of care for severe persistent asthma and CRS with nasal polyposis (CRSwNP). The efficacy of these agents in patients with CVID is unknown. MethodsWe performed a retrospective analysis of patients with CVID at a single academic medical center and identified those who had ever been prescribed a T2 biologic. ResultsWe identified 8 patients with CVID who had ever been prescribed T2 biologics: 6 patients with severe persistent asthma and 2 patients with CRSwNP. All patients had CVID without inflammatory complications with therapeutic IgG levels on immune globulin replacement therapy. Comorbid bronchiectasis was identified in 3 patients and no patients had GLILD. Two patients were taking omalizumab, two on mepolizumab, 1 on benralizumab, and 1 on dupilumab for severe persistent asthma and 2 on dupilumab for CRSwNP. Only 4 patients in this group (50%) had subjective improvement of symptoms and objective clinical benefit based on ability to wean off of corticosteroids and fewer exacerbations per year. Only 1 of these patients had objective improvement in FEV1 by >200mL. Neither of the 2 patients treated with dupilumab for CRswNP reported improvement and the biologic was discontinued. Of the 2 patients with asthma who were found to have eosinophilia on bronchoalveolar fluid analysis, both of these patients had clinical improvement on eosinophil-targeted biologic therapy. All 3 patients who were tested were found to have elevated serum T2 cytokines including IL-4, but this did not predict response to therapy.Table 1(abstract: 191) Demographic and immunologic data of 8 patients with CVID on T2 biologiesAgeGenderT2 biologicIndicationBronchiectasisIncrease in FEV1 by >200mLClinical responseIgG (mg/dL)IgA (mg/dL)IgM (mg/dL)IgE (kU/L)Absolute eosinophil count(K/μL)CD19B cell count (cells/μL)Th2 Cytokine PanelBAL Eosinophils%CT ThoraxBronchoscopy-Pathology82Fomalizumabsevere persistent asthmayesnono1551522923430049Not availableNot availableBasal abnormalitycharacterized by ground glass opacities (GGO), centrilobular nodularity with small focus of consolidation posterior right lower lobe (RLL). Additional focus of patchy groundglass posterior right lung (RL).Not available74Mmepolizumabsevere persistent asthmayesnoyes11681623141681600176Not available25Resolution of right upper lobe (RUL) apical nodule and branching tubular opacity. New clustered nodularity in the posterior RLL with faint GGO in the upper lobes. Moderate bronchial wall thickening, greatest in the lower lobes.Bronchial wall with smooth muscle hypertrophy. Lung parenchyma without evidence of inflammation, fibrosis, or malignancy.57Fomalizumabsevere persistent asthmanonoyes89725221687100103Not available0Diffuse bronchial dilation without bronchial wall thickening. Mild patchy air trapping.Largely denuded and edematous bronchial wall with minima] chronic inflammation, focal subepithelial elastosis, focal expansion of the subbasal lamina, mild increase in mucous secretion.37Fdupilumabchronic rhinosinusitis with nasal Polyposisnonot applicableno787<10<20<2100187elevated IL-4, IL-6Not availableResolved patchy GGO with exception of a new tiny focus of GGO in the basal RLL. Stable mild diffuse bronchial wall thickening.Not available73Fbenralizumabsevere persistentnoyesyes84635<20<2100179Not available4Mild to moderate airway inflammation and diffuse air-trapping. Minimal left basilar linear atelectasis/scarring is new. TracheobronchomalaciaBronchial wall with moderate chronic inflammation and eosionphils (peak 12/hpf), thickened subbasal lamina, mild smooth muscle hypertrophy.43Fdupilumabsevere persistent asthmanonot availableyes12614313556.5056elevated IL-4, IL-5, IL-6Not availableBenign right oblique fissure. 2 small nodules.Not available56Fdupilumabyesnot applicableno95476602.625027Not available1chronic rhinosinusitis with nasal polyposisMultiple new areas of peribronchovascular consolidation and confluent GGO. Widespread tree-inbud nodularity. Mild cylindricalbronchiectasis. Dilated main pulmonary trunk.Bronchial wall with moderate chronic inflammation and scattered eosinophils (6/hpf), thickened subbasal lamina. No granulomas. Right lung bronchial wall with moderate chronic inflammation. Lung parenchyma with airway centered mild interstitial chronic inflammation49 Fmepolizumabsevere persistent asthmanonono166845189510049Not available0Mild bronchial wall thickening and scattered air trapping. Patchy GGO in the left upper lobe with minimal involvement of the lower lobes. Dynamic expiratory images demonstrates evidence of tracheobronchomalacia.Bronchial wall with patchy mild to moderate chronic inflammation with rare neutrophils and eosinophils. Mild smooth muscle hypertrophy. Patchy squamous metaplasia and respiratory bronchiolitis in the left lung.*Clinical response is measured by reduction in exacerbations and/or ability to wean off of corticosteroids for individuals with severe asthma and is measured by improvement in sinonasal symptoms and reduced nasal polypoid burden for CRSwNP. [Display omitted] [Display omitted] ConclusionPatients with CVID may benefit from more direct sampling of nasal mucosal and bronchial secretions (sputum, bronchoalveolar lavage) to determine the potential benefit from T2 biologics in severe allergic respiratory disease. Prospective analyses in larger cohorts following objective indices of improvement as well as changes in serum and mucosal biomarkers are necessary.

Outcomes of Surgical Resection and VNS in Patients with Medically Refractory Epilepsy and GAD65 Antibody Positivity (S40.004)

<h3>Objective:</h3> To determine effectiveness of vagus nerve stimulator (VNS) and surgical resection in patients with drug-resistant epilepsy associated with glutamic acid decarboxylase 65 (GAD65) antibodies. <h3>Background:</h3> Epilepsy associated with high-titer GAD65 antibodies is often refractory to immunotherapies and antiseizure medications (ASMs), underscoring the need for alternate treatment strategies. <h3>Design/Methods:</h3> We retrospectively identified Mayo Clinic Rochester patients (January 2003 – April 2022) with drug-resistant epilepsy and high serum GAD65-antibody titers (&gt;20 nnmol/L) who underwent surgical resection and/or VNS implantation. A “favorable” surgical outcome was defined as Engel I-II, and a responder to VNS was defined as a &gt;50% reduction in seizure frequency from baseline. <h3>Results:</h3> We identified 15 patients (13 females, 86.7%) who underwent surgical resection (n=7), VNS implantation (n=6), and both (n=2). Patients had failed a median of 5.5 anti-seizure medications. Twelve patients had GAD65 tested in the CSF, all were positive (median titer 3.8). Of the nine patients who underwent surgical intervention (all involving the temporal region), three (33.3%) had a favorable outcome, which was sustained for at least 3.5 years in one, 10 years in another, and the third was lost to follow-up after 1 year. Pathology was available in four patients, only one had evidence of inflammation. Of the 8 patients who underwent VNS implantation, 3 (37.5%) were initially considered a responder, but this was not sustained in two of the three. No clinical factors were statistically associated with favorable surgical or VNS outcomes. <h3>Conclusions:</h3> Temporal surgical resection and VNS are not highly effective in drug-resistant autoimmune-associated epilepsy related to high-titer GAD65 antibodies. Additional therapies are greatly needed for this challenging clinical scenario. <b>Disclosure:</b> Dr. Zhao-Fleming has nothing to disclose. Dr. Britton has received personal compensation in the range of $0-$499 for serving as a Online course with American Clinical Neurophysiology Society. The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. The institution of Dr. Dubey has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Astellas. The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Argenx. Dr. Dubey has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for AGRIMS. Dr. Dubey has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Advances in Neurology . Dr. Dubey has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Moffit Cancer Center . Dr. Dubey has received research support from Department of Defense . Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr. Smith has received research support from CURE Epilepsy.

A Rare Case of Cutis Aplasia Congenita in a Newborn

A Rare Case of Cutis Aplasia Congenita in a Newborn