Process Optimization for the Continuous Production of a Gastroretentive Dosage Form Based on Melt Foaming.

Several drugs have poor oral bioavailability due to low or incomplete absorption which is affected by various effects as pH, motility of GI, and enzyme activity. The gastroretentive drug delivery systems are able to deal with these problems by prolonging the gastric residence time, while increasing the therapeutic efficacy of drugs. Previously, we developed a novel technology to foam hot and molten dispersions on atmospheric pressure by a batch-type in-house apparatus. Our aim was to upgrade this technology by a new continuous lab-scale apparatus and confirm that our formulations are gastroretentive. At first, we designed and built the apparatus and continuous production was optimized using a Box-Behnken experimental design. Then, we formulated barium sulfate-loaded samples with the optimal production parameters, which was suitable for in vivo imaging analysis. In vitro study proved the low density, namely 507 mg/cm3, and the microCT record showed high porosity with 40 µm average size of bubbles in the molten suspension. The BaSO4-loaded samples showed hard structure at room temperature and during the wetting test, the complete wetting was detected after 120 min. During the in vivo study, the X-ray taken showed the retention of the formulation in the rat stomach after 2 h. We can conclude that with our device low-density floating formulations were prepared with prolonged gastric residence time. This study provides a promising platform for marketed active ingredients with low bioavailability.

Ultrasound-guided hydrostatic reduction versus fluoroscopy-guided air reduction for pediatric intussusception: a multi-center, prospective, cohort study.

BACKGROUND: Intussusception is the most common abdominal emergency in children. The first line treatment of uncomplicated pediatric intussusception is enema reduction. Until now, there have been no multi-center studies comparing the effectiveness and safety of UGHR and FGAR in the treatment of pediatric intussusception. The aim of this study was to compare the effectiveness and safety of the two most commonly used enema methods of pediatric intussusception: ultrasound-guided hydrostatic reduction (UGHR) and fluoroscopy-guided air reduction (FGAR). METHODS: From November 1, 2017 to October 31, 2018, we conducted a multi-center, prospective, cohort study. Children diagnosed with intussusception in four large Children's Medical Centers in China were divided into UGHR and FGAR groups. Stratified analysis and subgroup analysis were used for further comparison. The success and recurrence rates were used to evaluate the effectiveness of enema reduction. The perforation rate was used to evaluate the safety of enema reduction. RESULTS: A total of 2124 cases met the inclusion criteria (UGHR group: 1119 cases; FGAR group: 1005 cases). The success and recurrence rates in the UGHR group were higher than in the FGAR group (95.80%, 9.28% vs. 93.13%, 10.65%) (P < 0.05, P > 0.05), respectively. The perforation rate in the UGHR group was 0.36% compared with 0.30% in the FGAR group (P > 0.05). Subgroup analysis showed the success rates in the UGHR group were higher than in the FGAR group of patients with onset time between 12 and 24 h (95.56% vs. 90.57%) (P < 0.05). Of patients aged 4 to 24 months, the success rates in the UGHR group were also higher than in the FGAR group (95.77% vs. 91.60%) (P < 0.05). Stratified analysis showed the success rates in the UGHR group were higher than in the FGAR group in patients with the symptom of bloody stool (91.91% vs 85.38%) (P < 0.05). CONCLUSIONS: UGHR and FGAR are safe, nonsurgical treatment methods for acute pediatric intussusception. UGHR is superior to FGAR, no radiation risk, its success rate is higher, without a difference in perforation rate, especially for patients aged 4-24 months. LEVEL OF EVIDENCE: Level II.

Elucidating the anatomy of a rare communicating bronchopulmonary foregut malformation (CBPFM) in a preschool child.

Communicating bronchopulmonary foregut malformations (CBPFMs) are complex and rare anomalies. Their characteristic feature is an anomalous communication between the respiratory system (trachea, lung or bronchus) on one side and the gastrointestinal tract (oesophagus or stomach) on the other. Though acquired CBPFMs are known, the large majority of them are congenital and single. CBPFMs often go undetected even at surgery and require more than one operation before they are successfully addressed. This is because the symptomatology of CBPFM resembles the more common oesophageal atresia (OA) with tracheoesophageal fistula, wherein it may coexist. We report a patient with OA who had a rare form of CBPFM where the upper lobe of the right lung communicated with the upper oesophagus. This account highlights a novel method of working out the uncertain anatomy, in such cases. There may be associated anomalies of the lung parenchyma and vasculature usually involving the pulmonary arterial supply to the affected lung. Clinical, radiological, endoscopic and pathological characterisation permit precise diagnosis in most instances, with an occasional case that defies definition.

Dysphagia Evaluation: The Added Value of Concurrent MBS and Esophagram.

OBJECTIVES/HYPOTHESIS: Dysphagia is associated with increased mortality and healthcare costs. The modified barium swallow study (MBS) is the gold standard in assessing oropharyngeal dysphagia, but does not evaluate the esophagus. A barium esophagram can visualize the esophagus but does not evaluate the oropharyngeal swallow, nor does it utilize the expertise of speech and language pathologists. Providers may order one or both studies yet still risk missing critical pathology. STUDY DESIGN: Retrospective cohort study. METHODS: A retrospective chart review was conducted at an academic medical center between January 2016 and June 2019 focused on patients who had both MBS and esophagram as imaging for dysphagia evaluation. Analysis determined whether MBS and esophagram performed concomitantly improved diagnostic clarity. RESULTS: A total of 5,183 patients underwent 6,066 swallow studies for dysphagia in the study period. Of which, 124 of these patients had concurrent MBS and esophagram. 10.5% of concurrent studies demonstrated a congruent negative evaluation. 59.7% of patients had an unremarkable MBS or esophagram paired with abnormal findings within the corresponding esophagram or MBS, respectively. 29.8% had both MBS and esophagrams that demonstrated an abnormality, but with unique pathologies identified by each study. In total, 85.1% of unremarkable MBS or esophagrams were paired with abnormal findings in the corresponding esophagram or MBS, respectively. CONCLUSION: Selection of diagnostic testing is variable among providers and may be influenced by healthcare systems. This analysis revealed that MBS and esophagrams provide unique diagnoses. Concurrent MBS and esophagrams may improve diagnostic accuracy, yet minimize additional studies. National practices around dysphagia diagnostics are inconsistent and would benefit from standardization. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:2666-2670, 2021.

Radiation exposure in modified barium swallow studies.

PURPOSE OF REVIEW: The modified barium swallow study (MBSS) is an X-ray examination of swallowing used to detect the presence and type impairment, aspiration risk, and to develop intervention plans. In this review, we will cover the use of ionizing radiation in MBSSs and review recent literature concerning radiation exposure and cancer risks to patients undergoing MBSSs. Lastly, we will discuss the clinical implications of these findings. RECENT FINDINGS: Recent literature confirms that the MBSS is a low-dose examination and that reducing pulse rate negatively impacts diagnostic accuracy. Importantly, cancer risks to adults undergoing MBSSs were also reported to be low. SUMMARY: An adult undergoing MBSS using a standardized, valid protocol, like the Modified Barium Swallow Impairment Profile (MBSImP), has low-radiation exposure and very low associated cancer risks. MBSSs should be used whenever relevant to adult patient care without undue concern regarding radiation exposure. Children also have low radiation exposure from MBSSs; however, cancer risks from that exposure remain unknown. Best practices in radiation safety must always be followed. Reducing pulse rates in the adult or pediatric population to reduce radiation exposure is not a valid strategy because of the resulting reduction in diagnostic accuracy.

Swallowing Patterns in the HNC Population: Timing of Penetration-Aspiration Events and Residue.

OBJECTIVE: This study described swallowing patterns in a large head/neck cancer (HNC) cohort. STUDY DESIGN: In a retrospective review of data from a randomized controlled trial, we studied timing of penetration events as they related to aspiration and oral/pharyngeal residue. SETTING: Retrospective review of a multicenter randomized controlled trial. SUBJECTS AND METHODS: In total, 168 patients who were >3 months postradiation received baseline modified barium swallow evaluations. Retrospective analyses of data from these exams were studied, including Penetration-Aspiration Scale (PAS) scores and timing of these events (before, during, or after the swallow), as well as percentage of oral and pharyngeal residue. RESULTS: Aspiration occurred more frequently after than before or during the swallow (P < .05). There were significantly more events of penetration that led to aspiration after the swallow (n = 260) when compared to events before (n = 6) or after (n = 81) the swallow. There was more pharyngeal (16%-25%) than oral residue (5%-20%). Weak correlations were found between thin liquid, nectar-thick liquid, pudding residue, and PAS scores, with varying significance (pharyngeal residue/PAS rs: .26*, .35*, .07*; oral residue/PAS rs: .21*, .16, .3; *P < .05). CONCLUSION: The predominant pattern for this sample of postradiation patients with HNC with dysphagia was aspiration that occurred after the swallow, rather than before or during the swallow. The aspiration was directly caused by penetration events that occurred during the swallow, resulting in aspiration as the airway reopened. Patients demonstrated more pharyngeal residue than oral residue, but a weak relationship was found between residue and penetration/aspiration events. These results guide clinicians in targeting appropriate swallowing interventions.

Virtual Dysphagia Evaluation: Practical Guidelines for Dysphagia Management in the Context of the COVID-19 Pandemic.

With encouraging signs of pandemic containment nationwide, the promise of return to a full range of clinical practice is on the horizon. Clinicians are starting to prepare for a transition from limited evaluation of emergent and urgent complaints to resumption of elective surgical procedures and routine office visits within the next few weeks to months. Otolaryngology as a specialty faces unique challenges when it comes to the COVID-19 pandemic due to the fact that a comprehensive head and neck examination requires aerosol-generating endoscopic procedures. Since the COVID-19 pandemic is far from being over and the future may hold other highly communicable infectious threats that may require similar precautions, standard approaches to the clinical evaluation of common otolaryngology complaints will have to be modified. In this communication, we present practical recommendations for dysphagia evaluation with modifications to allow a safe and comprehensive assessment.

Predicting dissolution and transformation of inhaled nanoparticles in the lung using abiotic flow cells: The case of barium sulfate.

Barium sulfate (BaSO4) was considered to be poorly-soluble and of low toxicity, but BaSO4 NM-220 showed a surprisingly short retention after intratracheal instillation in rat lungs, and incorporation of Ba within the bones. Here we show that static abiotic dissolution cannot rationalize this result, whereas two dynamic abiotic dissolution systems (one flow-through and one flow-by) indicated 50% dissolution after 5 to 6 days at non-saturating conditions regardless of flow orientation, which is close to the in vivo half-time of 9.6 days. Non-equilibrium conditions were thus essential to simulate in vivo biodissolution. Instead of shrinking from 32 nm to 23 nm (to match the mass loss to ions), TEM scans of particles retrieved from flow-cells showed an increase to 40 nm. Such transformation suggested either material transport through interfacial contact or Ostwald ripening at super-saturating conditions and was also observed in vivo inside macrophages by high-resolution TEM following 12 months inhalation exposure. The abiotic flow cells thus adequately predicted the overall pulmonary biopersistence of the particles that was mediated by non-equilibrium dissolution and recrystallization. The present methodology for dissolution and transformation fills a high priority gap in nanomaterial hazard assessment and is proposed for the implementation of grouping and read-across by dissolution rates.

Dysphagia in Myositis: A Study of the Structural and Physiologic Changes Resulting in Disordered Swallowing.

OBJECTIVES: Dysphagia in patients with myositis is associated with an increased risk of aspiration pneumonia. However, the pathophysiology of dysphagia is poorly understood. The aim of this study was to understand how myositis affects swallowing physiology on videofluoroscopic swallow study. DESIGN: This is a retrospective review of video fluoroscopic swallowing studies on 23 myositis patients with dysphagia from 2011 to 2016. Swallow studies were analyzed by timing of swallowing events and duration of swallowing events, diameter of upper esophageal sphincter opening, Modified Barium Swallow Impairment Profile, and Penetration-Aspiration Scale. The outcome measures for patients were compared with an archived videofluoroscopic swallow study from healthy, age-matched participants by Wilcoxon rank-sum tests. RESULTS: Patients with myositis had a shorter duration of upper esophageal sphincter opening (P < 0.0001) and laryngeal vestibule closure (P < 0.0001) than healthy subjects. The diameter of upper esophageal sphincter opening did not differ between groups. Patients with myositis presented with higher scores on the MBSIMP than healthy subjects, indicating great impairment particularly during the pharyngeal phase of swallowing, and a higher frequency of penetration and aspiration. CONCLUSIONS: Dysphagia in patients with myositis may be attributed to reduced endurance of swallowing musculature rather than mechanical obstruction of the upper esophageal sphincter.

In vivo evaluation of targeted delivery of biological agents using barium sulfate.

This study was aimed to monitor the transit through the intestine by X-ray imaging using barium sulfate (BS) as tracer. The in vitro features of monolithic tablets were correlated with their in vivo behavior in order to provide a tool for the development of targeted formulations containing macromolecular bioactive agents. The impact of BS on various matrices (neutral, ionic) was studied in simulated fluids using the disintegration time (DT) as main parameter. Dry tablets were characterized by spectroscopic methods (X-ray diffraction and Infra-Red) and scanning electron microscopy (SEM). The selected formulations were followed in a beagle dog model. The in vivo and in vitro DT of tablets formulated with BS were compared. Results: anionic excipients carboxymethylcellulose (CMC) and carboxymethylstarch (CMS) protected the active ingredient from the gastric acidity, ensuring its targeted delivery in the intestine. The SEM analysis, before and after transit in simulated fluids, showed that BS remained in the tablets allowing their good follow-up in vivo. The incorporation of 30% protein in tablets with 40% BS had no impact on their behavior. In conclusion, BS and X-ray imagery could be a good alternative to scintigraphy for development of targeted formulations containing high molecular weight bioactive agents.

The assessment of placental sharing using X-ray angiogram versus digital photograph: A prospective study.

INTRODUCTION: We aim to compare two different methods for the assessment of placental sharing in monochorionic diamniotic twins: X-ray-angiogram and digital photograph of the placenta. METHOD: We included the placentas of a prospective series of twins that were followed from the first trimester onward and resulted in a double live birth or double stillbirth between April 2016 and February 2019. Injection was performed after delivery and an X-ray angiogram was made, as well as a digital photograph. On both of these, the territory of each twin was measured two investigators (IC and LL). Placental sharing discordance was determined using the following formula: (larger territory - smaller territory)/larger territory. We calculated the intra-class correlation coefficients for intra-observer and inter-observer reliability and used Bland-Altman analysis to compare both methods. RESULTS: 77 placentas were included in the analysis. For both methods, there was an excellent intra- and inter-observer reliability. The mean difference in sharing (bias) on the X-ray and digital photograph using Bland-Altman analysis was 3,7% (95% CI 1,1% - 6,3%), where the digital photograph tends to overestimate the discordance. Limits of agreement were between -19% and 26%. CONCLUSION: Delineation of the placental sharing on a digital photograph slightly overestimates the discordance. Since the venous territory on X-ray angiogram physically determines where each twin gets its oxygenated blood, X-ray angiogram may be a better method to determine placental sharing, although the digital photograph constitutes a valid alternative.

Specific anatomy and radiographic illustration of the digestive tract and transit time of two orally administered contrast media in Inland bearded dragons (Pogona vitticeps).

The aim of this study was to describe the specific gross and radiographic anatomy of the digestive tract of inland bearded dragons (Pogona vitticeps). Eleven bearded dragon cadavers of both sexes (6 females, 5 males) were dissected to examine, measure, and document the specific gross anatomy of the alimentary canal. Measurements collected from the cadavers included snout-vent length, total length of the alimentary canal, and the lengths of the individual sections of the gastrointestinal tract, including the esophagus, stomach, small intestine, ampulla coli, isthmus coli, rectum, and the distance from the coprodeum to the vent opening. Twenty-two healthy adult bearded dragons (13 females, 9 males) maintained under standardized husbandry conditions underwent a physical examination, blood collection, and whole-body dorsoventral and lateral survey radiographs; these animals were used to provide the radiographic images of the complete digestive tract. For the subsequent contrast passage studies, two different contrast media, barium sulfate (BaSO4, Barilux suspension) and an iodinated ionic radiocontrast agent (Sodium meglumine amidotrizoate [SMAT], Gastrografin), were used. Water-diluted Barilux suspension (dose 9 ml/kg) was administered orally to 5 bearded dragons, while Gastrografin (dose 5ml/kg) was administered orally to 21 bearded dragons. Four animals were used for both contrast media studies, but received a break of four weeks in between. Dorsoventral and laterolateral radiographs were collected at 0 (baseline), 15, 30, and 45 minutes and 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 30, and 36 hours after each contrast medium was administered. Both contrast media were found to illustrate the alimentary tracts in the adult bearded dragons. Transit time was substantially faster with SMAT, and SMAT illustrated the entire gastrointestinal tract within 36 hours; BaSO4 did not fully illustrate the gastrointestinal tract in 36 hours. These results might serve as a guideline for the interpretation of subsequent contrast studies in this lizard species.

Trade-off between pulse rate and radiation dose during modified barium swallow examination: what is the reality?

AIM: To evaluate the effect of modification of dose mode and frame rate on patient radiation dose during modified barium swallow (MBS) examinations. MATERIALS AND METHODS: A retrospective review was undertaken of consecutive MBS examinations performed over 6 months in the inpatient setting. Patients were divided into two cohorts: pre-implementation of the MBS Impairment Profile (MBSImP; low rate, normal dose) and post-implementation (high rate, low dose). Prior to implementation, pulse rate and dose testing were performed on multiple phantoms. RESULTS: Four hundred and forty-nine patients were included in the pre-implementation cohort and 378 in the post-implementation cohort. Phantom dose testing demonstrated no significant difference in dose on either phantom between low rate/normal dose and high rate/low dose modes. Prior to MBS standardisation, the mean radiation dose was 5.86 (±4.35) mGy. Following standardisation, the mean radiation dose was 4.72 (±3.77) mGy (p<0.0001). The mean fluoroscopy time for MBS prior to standardisation was 83.8 (±44.4) seconds and the mean fluoroscopy time for MBS after standardisation was 82.3 (±39.8) seconds (p=0.62). The dose rate for MBS prior to standardisation was 4.35 (±2.42) and the dose rate for MBS after standardisation was 3.55 (±2.41) mGy/s (p<0.0001). CONCLUSION: Adjustments made to lower the dose mode and the increase in fluoroscopy frame rate decreased the patient radiation dose and did not increase fluoroscopy time.

Comparison of two small bowel distending agents for enterography in pediatric small bowel imaging.

OBJECTIVE: To evaluate the ability of pediatric patients with known or suspected inflammatory bowel disease to ingest a new oral distending agent at CT or MR enterography (CTE/MRE), and to determine the impact on small bowel (SB) distension and diagnostic confidence. MATERIALS AND METHODS: The study design is that of retrospective review of pediatric patients who underwent CTE or MRE from January 2014 to June 2016. Patients ingested low-concentration barium suspension or flavored beverage containing sorbitol and mannitol. The need for nasogastric tube (NGT) administration, amount ingested, emesis, distal extent of contrast, SB distension, terminal ileum (TI) transverse dimension, and diagnostic confidence in TI disease were assessed. Three radiologists each blindly reviewed a subset of the studies. RESULTS: Of the total 591 scans in 504 patients, 316 scans used low-concentration barium suspension and 275 scans flavored beverage. Nearly all consumed the entire amount (97% vs. 96%). Low-concentration barium suspension exams required NGT more often (7% [23/316] vs. 1% [3/275]; p < 0.0003), and tended to have more emesis (3% [9/316] vs. 1% [3/275]; p = 0.13). Diagnostic confidence score was nearly identical (p = 0.94). Qualitative and quantitative analyses showed no difference in SB distension, except for distension of mid-ileum (flavored beverage > low-concentration barium suspension; p = 0.02). Flavored beverage exams demonstrated a slight increase in distal extent of luminal distension (p = 0.02). CONCLUSIONS: A new flavored beverage distends small bowel as well as low-concentration barium suspension, with decreased requirement for NGT insertion and improved distal extent of luminal distension, and without any decrease in diagnostic confidence in the presence or the absence of TI disease.

X-ray evaluation of intestinal dysmotility induced by Eimeria pragensis infection in C57BL/6 mice.

This study was conducted to elucidate the intestinal dysmotility during coccidiosis. C57BL/6 male mice at seven weeks of age were inoculated with Eimeria pragensis sporulated oocysts (100 to 1,000 oocysts). The intestinal motility was evaluated by observing discharging time of barium sulfate (Ba2SO4) after oral administration (WITT: the whole intestinal transit time). The exact location of the dysmotility was analyzed by intermittent barium gastrography. Upper intestinal dysmotility was evaluated by charcoal propulsion study. Additionally, the occurrence of dysmotility was observed at different post-infection times (4, 7, and 14 days post-infection (d.p.i.)) and in infection-dose dependent manner (100, 300, and 1,000 oocysts). As the E. pragensis infected mice had significantly lower feed intake compared to the control group, we designed a feed apprehension study to evaluate the effect of low feed intake on the intestinal dysmotility. The WITT of infected mice at 7 d.p.i. was significantly longer (6 hr) than the uninfected mice (2.5 hr). Intestinal dysmotility was observed in the small intestine, caecum, and colorectum in the infected mice. Charcoal propulsion was slower in infected group (reaching to 40.4% of the whole small intestine) compared to control group (68.0%). The dysmotility was observed at the beginning of the patent period (7 d.p.i.) and subsided as the patency ended (14 d.p.i.). Mice with lower feed intake appeared to have similar intestinal motility as control mice. In summary, this study revealed the evidence of intestinal hypomotility during E. pragensis infection.

Detection of Airway Invasion During Flexible Endoscopic Evaluations of Swallowing: Comparing Barium, Blue Dye, and Green Dye.

Purpose The aim of this study was to assess the effects of barium, blue dye, and green dye on the frequency and reliability of detecting airway invasion (penetration and aspiration) seen during flexible endoscopic evaluations of swallowing (FEES). Method Thirty patients with neurodegenerative disease and suspected dysphagia underwent an FEES. Patients were presented with 10-cc boluses of water colored with blue dye, green dye, and barium, within the same examination, in a randomized order. Airway protection outcomes were blindly analyzed by a panel of expert raters. Outcomes included the presence of residue on airway structures (epiglottis, laryngeal vestibule, vocal folds, subglottis) and abnormal Penetration-Aspiration Scale (PAS; Rosenbek, Robbins, Roecker, Coyle, & Wood, 1996 ) scores (PAS ≥ 3). Statistical analyses were performed to determine group differences in the frequency of airway residue and abnormal PAS scores, as well as reliability. Results Airway residue was observed most frequently with barium when compared to blue dye ( p < .05) or green dye ( p < .05). Abnormal PAS scores were also observed most frequently with barium when compared to blue dye ( p < .0005) and green dye ( p < .0005). There were no significant differences in the observed frequency of airway residue nor abnormal PAS scores when comparing blue and green dye ( p > .05). Intrapanel reliability scores for airway residue and PAS scores, respectively, were very good ( k = .83) and good ( k = .67) for barium, very good ( k = 1.00) and moderate ( k = .50) for green dye, and moderate ( k = .47) and fair ( k = .33) for blue dye. Conclusion Airway invasion was detected significantly more frequently and with greater reliability with barium when compared to blue and green dye. Given these findings, standardized use of barium is recommended at some point during FEES, especially when attempting to detect subtle signs of airway invasion.