Intratracheal instillation of budesonide suspension versus normal saline on oxidative stress in neonates with meconium aspiration syndrome.

BACKGROUND: Presently, the efficacy of neonatal resuscitation techniques via interventions such as oral, nasal, and endotracheal suction for preventing meconium aspiration syndrome (MAS) after delivery has not been satisfactory. OBJECTIVE: This study aimed to investigate the role of intratracheal instillation of budesonide on oxidative stress in MAS. METHODS: Sixty-two neonates with MAS admitted to Huai'an Maternity and Child Healthcare Hospital from January 2018 to June 2020 were divided into a study group (intratracheal instillation of 2 ml budesonide suspension; n = 31) and a control group (intratracheal instillation of 2 ml normal saline; n = 31). Collect data from two groups of patients and evaluate clinical outcomes, including oxygenation index (OI), as well as serum total oxidant status (TOS), total antioxidant capacity (TAC), oxidative stress index (OSI) and 8-Isoprostane before treatment and 72h after admission. RESULTS: We found no statistical differences in mortality, complication rate, total oxygen inhalation time, OI before treatment and 72h after admission between the two groups of neonates with MAS, while the duration of invasive respiratory support in the study group was significantly shorter than in the control group. Also, serum TAC, TOS, OSI and 8-isoprostane levels were not statistically different before treatment between the two groups. After 72h of admission, OSI and 8-Isoprostane in neonates with MAS in the study group were much lower than those in the control group. TOS, OSI, 8-Isoprostane in the control group and 8-Isoprostane in the study group were significantly higher than those before treatment. As for TAC and TOS, no significant differences were observed between the two groups. CONCLUSION: Intratracheal instillation of budesonide was shown to alleviate oxidative stress and shorten invasive ventilation time in neonates with MAS.

A fusion protein comprising pneumococcal surface protein A and a pneumolysin derivate confers protection in a murine model of pneumococcal pneumonia.

PspA and pneumolysin are two important vaccine candidates, able to elicit protection in different models of pneumococcal infection. The high immunogenic potential of PspA, combined with a possible adjuvant effect of pneumolysin derivatives (due to their ability to interact with TLR-4) could greatly improve the immunogenicity and coverage of a protein-based pneumococcal vaccine. A chimeric protein including the N-terminal region of PspA in fusion with the pneumolysin derivative, PlD1, has been shown to induce high antibody levels against each protein, and protect mice against invasive challenge. The aim of the present study was to investigate the cellular response induced by such vaccine, and to evaluate protection in a murine model of lobar pneumococcal pneumonia. Pneumococcal pneumonia was induced in BALB/c mice by nasal instillation of a high dose of a serotype 14 strain with low virulence. Airway inflammation was confirmed by total and differential cell counts in BAL and by histological analysis of the lungs, and bacterial loads were measured 7 days after challenge. Cytokine levels were determined in the bronchoalveolar fluid (BALF) of mice immunized with rPspA-PlD1 fusion after challenge, by flow cytometry and ELISA. After challenge, the mice developed lung inflammation with no invasion of other sites, as demonstrated by histological analysis. We detected significant production of TNF-α and IL-6 in the BALF, which correlated with protection against pneumonia in the group immunized with rPspA-PlD1. In conclusion, we found that the rPspA-PlD1fusion is protective against pneumococcal pneumonia in mice, and protection is correlated with an early and controlled local inflammatory response. These results are in agreement with previous data demonstrating the efficacy of the fusion protein against pneumococcal sepsis and reinforce the potential of the rPspA-PlD1 protein chimera as a promising vaccine strategy to prevent pneumococcal disease.

Drug instillation in the management of urinary tract urothelial carcinoma.

PURPOSE OF REVIEW: This article aimed to investigate the efficacy of drug instillation therapy in preventing the recurrence of postsurgical upper urinary tract urothelial carcinoma (UTUC) by reviewing recently published research articles. RECENT FINDINGS: Several clinical trials have shown new potential forms of postsurgical intracavitary and intravesical drug instillation methodologies with better efficacy and less toxicity for use in UTUC. With the improvement of endoscopic imaging techniques and laser sciences, diverse attempts in drug instillation have shown an improved recurrence rate after kidney-sparing surgery in low-grade, low-tumor burden cancers in the upper urinary tract. A gel-form type of mitomycin-C in intracavitary instillation further reduced recurrence rates in UTUC. Other studies have compared different drug instillation methodologies with varying initiation times and timed instillation. They have shown that early instillation with multiple rounds resulted in better protective effects for recurrence rates before, during, and after surgery. SUMMARY: A new gel-form of intracavitary instillation of mitomycin-C, the timing of drug instillation, and refining techniques can result in better recurrence-free survival of patients with UTUC after surgery. Further large-scale prospective clinical trials are needed to validate these new forms of drugs and methodologies to change the therapeutic guidelines of UTUC.

Airway Delivery of Hydrogel-Encapsulated Niclosamide for the Treatment of Inflammatory Airway Disease.

Repurposing of the anthelminthic drug niclosamide was proposed as an effective treatment for inflammatory airway diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease. Niclosamide may also be effective for the treatment of viral respiratory infections, such as SARS-CoV-2, respiratory syncytial virus, and influenza. While systemic application of niclosamide may lead to unwanted side effects, local administration via aerosol may circumvent these problems, particularly when the drug is encapsulated into small polyethylene glycol (PEG) hydrospheres. In the present study, we examined whether PEG-encapsulated niclosamide inhibits the production of mucus and affects the pro-inflammatory mediator CLCA1 in mouse airways in vivo, while effects on mucociliary clearance were assessed in excised mouse tracheas. The potential of encapsulated niclosamide to inhibit TMEM16A whole-cell Cl- currents and intracellular Ca2+ signalling was assessed in airway epithelial cells in vitro. We achieved encapsulation of niclosamide in PEG-microspheres and PEG-nanospheres (Niclo-spheres). When applied to asthmatic mice via intratracheal instillation, Niclo-spheres strongly attenuated overproduction of mucus, inhibited secretion of the major proinflammatory mediator CLCA1, and improved mucociliary clearance in tracheas ex vivo. These effects were comparable for niclosamide encapsulated in PEG-nanospheres and PEG-microspheres. Niclo-spheres inhibited the Ca2+ activated Cl- channel TMEM16A and attenuated mucus production in CFBE and Calu-3 human airway epithelial cells. Both inhibitory effects were explained by a pronounced inhibition of intracellular Ca2+ signals. The data indicate that poorly dissolvable compounds such as niclosamide can be encapsulated in PEG-microspheres/nanospheres and deposited locally on the airway epithelium as encapsulated drugs, which may be advantageous over systemic application.

A Randomized Controlled Clinical Trial to Compare Conventional Drug Instillation to A Device Dropper Method in Medical Treatment of Glaucoma.

PURPOSE: To compare and analyze the performance of a device dropper (DD) over conventional drop instillation (CDI) method on ease of administration, compliance, patient satisfaction, and intraocular pressure (IOP) control in persons with glaucoma on ocular hypotensive medications. METHODS: We enrolled 72 individuals with primary open-angle glaucoma or ocular hypertension, on treatment with fixed combination (α agonist+ß blocker) drugs for at least 6 months. These were randomized into two groups (36 in each arm). Group 1 administered the drug with a DD and Group 2 used CDI method. Recruited individuals were interviewed for subjective difficulties using a formatted questionnaire at first month follow-up and IOP change from baseline was evaluated. RESULTS: Baseline demographic and ocular characteristics were similar in both groups. 57.1% in the conventional instillation and none in the DD had reported difficulty in using the eye drops on follow-up visit. DD group had significantly less spillage and contamination of eye surface or dropper tips, required minimal assistance, accurately targeted on first drop placement directly into the eye compared to CDI group (p-value<0.001). Mean IOP was comparable between the two groups. CONCLUSION: DD instillation method was observed to be easier to administer, more accurate in targeting the conjunctival cul-de-sac, reduced wastage with lesser contamination compared to the CDI technique. DDs may be expected to have better compliance and effectiveness in medical management of glaucoma.

Economic model to estimate cost of negative pressure wound therapy with instillation vs control therapies for hospitalised patients in the United States, Germany, and United Kingdom.

An economic model was developed to estimate the cost of negative pressure wound therapy with instillation and dwelling of a topical wound solution vs control therapies. Economic model inputs were means derived from the results of a recently published systematic review and meta-analysis of 13 comparative studies of negative pressure wound therapy with instillation. Means across studies comprising complex acute and chronic wounds for negative pressure wound therapy-instillation vs control (negative pressure wound therapy without instillation, gauze dressings, or gentamicin polymethylmethacrylate beads) groups were 1.77 vs 2.69 operating room visits (P = .008) and 9.88 vs 21.80 therapy days (P = .02), respectively. These inputs plus hospital cost data were used to model costs for the United States, Germany, and the United Kingdom. For the United States, Germany, and United Kingdom, respectively, economic model estimates of total potential per patient savings were $33 338, €8467, and £5626 for negative pressure wound therapy-instillation group vs control, based on assumed number of OR visits during therapy, cost of therapy system, and length of therapy. Model results showed an overall potential cost-savings with negative pressure wound therapy-instillation vs control, based on fewer OR visits and shorter therapy duration as reported in the published systematic review and meta-analysis.

The necessity and effect of prophylactic quinolone ear drops after ventilation tube insertion for otitis media with effusion.

BACKGROUND: Otitis media with effusion (OME) is a condition where non-infective fluid builds up in the middle ear. Long-term OME can cause damage to the middle ear and hearing impairment. Ventilation tube insertion (VTI) is an efficient procedure to drain persistent OME. However, the effect of prophylactic ear drops after VTI remains controversial because no infection is present. This study investigated the need for and effect of quinolone ear drops in patients with OME after VTI. METHODS: Between July 2018 and July 2021, 272 patients (436 ears with OME) who underwent VTI were enrolled. Prophylactic quinolone ear drops (ofloxacin) were used in 271 OME ears and not used in 165. The clinical findings and effect of the ear drops were assessed. RESULTS: The group with postoperative ofloxacin had less postoperative otorrhea (p < 0.001). In univariate analysis, age ≥ 13 years (odds ratio [OR] = 1.499, 95% confidence interval [CI]: 1.003-2.238, p = 0.046) was significantly associated with recovery to normal middle ear functioning (type A on postoperative tympanometry). No adenoid hypertrophy (OR = 1.692, 95% CI: 1.108-2.585, p = 0.014) and no postoperative otorrhea (OR = 2.816, 95% CI: 1.869-4.237, p < 0.001) were significant independent factors associated with middle ear recovery in both univariate and multivariate analysis. After VTI, 65% of tympanic membranes in the group with postoperative ofloxacin recovered to normal, while in 67% of tympanic membranes in the group without ofloxacin scarring remained. CONCLUSIONS: Patients who received prophylactic postoperative ofloxacin had less postoperative otorrhea. No adenoid hypertrophy and no postoperative otorrhea were significant independent predictors of middle ear recovery to normal function in both univariate analysis and multivariate analysis. However, prophylactic ofloxacin was not an independent predictor of normal middle ear functioning after VTI. After VTI, most OME patients who had used ofloxacin postoperatively had eardrums that were in better condition than those of patients who had not used ofloxacin. In this study, we confirmed the advantages and limitations of OME after VTI with prophylactic ofloxacin, thus providing clinicians with some guidance regarding the decision to administer prophylactic ofloxacin.

What is the impact of granulocyte colony-stimulating factor (G-CSF) in subcutaneous injection or intrauterine infusion and during both the fresh and frozen embryo transfer cycles on recurrent implantation failure: a systematic review and meta-analysis?

BACKGROUND: Among recurrent implantation failure (RIF) patients, the rate of successful implantation remains relatively low due to the complex etiology of the condition, including maternal, embryo and immune factors. Effective treatments are urgently needed to improve the outcomes of embryo transfer for RIF patients. In recent years, many researchers have focused on immunotherapy using granulocyte colony-stimulating factor (G-CSF) to regulate the immune environment. However, the study of the G-CSF for RIF patients has reached conflicting conclusions. The aim of this systematic review and meta-analysis was performed to further explore the effects of G-CSF according to embryo transfer cycle (fresh or frozen) and administration route (subcutaneous injection or intrauterine infusion) among RIF patients. METHOD: The PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for literature published from the initial to October 2020. The meta-analysis, random-effects model and heterogeneity of the studies with I2 index were analyzed. Stata 15 was used for statistical analysis. RESULTS: A total of 684 studies were obtained through the databases mentioned above. Nine RCTs included 976 RIF patients were enrolled in this meta-analysis. Subgroup analysis indicated that G-CSF improved the clinical pregnancy rate for both the fresh and frozen embryo transfer cycles (fresh RR: 1.74, 95% CI: 1.27-2.37, I2 = 0.0%, n = 410; frozen RR: 1.44, 95% CI: 1.14-1.81, I2 = 0.0.%, n = 366), and for both subcutaneous injection and intrauterine infusion (subcutaneous RR: 1.73, 95% CI: 1.33-2.23, I2 = 0.0%, n = 497; intrauterine RR: 1.39, 95% CI: 1.09-1.78, I2 = 0.0%, n = 479), but the biochemical pregnancy rate of the RIF group was also higher than that of the control group (RR: 1.85, 95% CI: 1.28-2.68; I2 = 20.1%, n = 469). There were no significant differences in the miscarriage rate (RR: 1.13, 95% CI: 0.25-5.21: I2 = 63.2%, n = 472) and live birth rate (RR: 1.43, 95% CI: 0.86-2.36; I2 = 52.5%; n = 372) when a random-effects model was employed. CONCLUSION: The administration of G-CSF via either subcutaneous injection or intrauterine infusion and during both the fresh and frozen embryo transfer cycles for RIF patients can improve the clinical pregnancy rate. However, whether G-CSF is effective in improving livebirth rates of RIF patients is still uncertain, continued research on the utilization and effectiveness of G-CSF is recommended before G-CSF can be considered mainstream treatment for RIF patients.

Accuracy and patient perceived difficulty of utilizing ototopical antibiotic therapy.

PURPOSE: To examine how patients self-administer ear drops, ascertain their perceived difficulty in performing the task and determine if they are able to deliver the correct dosage. MATERIALS AND METHODS: This is a prospective cohort study performed in an otology outpatient clinic with twenty-one subjects with a condition requiring ototopical antibiotics. The number of ear drops applied as well as skills performed during ear drop application was measured. Patient reported difficulty and confidence in application of ear drops data was also obtained. RESULTS: The mean number of drops applied was 2.91 ± 2.1 (target = 3 drops) with a large variance in drop application, range of 0.6 to 9.2 drops. If "correct dosage" is considered 85-115% of the intended dose, then almost half of patients, 47.6%, underdosed with 23.8% that over dosed. Patients reported that the average difficulty in applying drops to themselves was 3.6 (1 being easy and 10 being difficult). Patients reported a high confidence level in applying the correct dose of ear drops of 6.7 (1 being not confident and 10 being very confident). CONCLUSIONS: In our study of 21 patients self-administering ear drops, only 28.6% of patients were able to correctly apply the appropriate treatment dose, with almost half of patients underdosing. Questionnaire data indicated that most patients were unaware they were administering an incorrect dose. Inaccurate administration of ear drops could be problematic and lead to longer durations of symptoms, false treatment failures, and increased costs.

Audio-vestibular disorders and pregnancy: A systematic review.

PURPOSE: During pregnancy a woman's body undergoes many physiological changes that involve all systems and organs, including sensory ones. We conducted this systematic review to highlight current evidence and treatment options in pregnant women with audio-vestibular disorders. MATERIALS AND METHODS: A search was made on the following databases: PubMed, PubMed Central, Web of Science and Scopus. This research protocol was deposited in the PROSPERO Database. RESULTS: After application of inclusion-exclusion criteria, 30 manuscripts were included in the review. Many authors (14/15) found a slight alteration of audiometric tests during pregnancy, with a reported recovery postpartum in most of the studies (5/7). Regarding sudden sensorineural hearing loss (SSNHL), we found four articles for a total of 69 patients: the treatment of choice was intravenous Dextran 40 and intra-tympanic corticosteroids. Most included studies (4/6) found neither clinical nor epidemiological associations between otosclerosis and pregnancy in large-based sample studies. Few investigations regarded Eustachian tube function and vertigo. CONCLUSIONS: According to our results, many variations of hearing acuity during pregnancy are slight and transient and require only clinical observation. In large samples, otosclerosis appeared not to be associated with pregnancy. Clinicians should consider intra-tympanic steroids in managing SSNHL during pregnancy. Further more accurate research is needed to deepen and clarify the association between pregnancy and audio-vestibular disorders.

Effect of intrabronchial platelet rich plasma on the exercise-induced pulmonary hemorrhage endoscopic score in thoroughbred racehorses using furosemide: a preliminary study / [Efeito da instilação intrabronquial de plasma rico em plaquetas no escore endoscópico da hemorragia pulmonar induzida por exercício em cavalos Puro-Sangue Inglês de corrida e usuários de furosemida: um estudo preliminar]

The high prevalence of exercise-induced pulmonary hemorrhage (EIPH) in athletic horses constitutes to be a challenge to the racing industry and a source of major concern to animal welfare. Both experimental and clinical evidence indicate that the use of autologous platelet-rich plasma (PRP) is a promising effector of repair in a variety of pulmonary conditions. The present study evaluated the effect of intrabronchial instillation of PRP on EIPH endoscopic scores from 37 Thoroughbred racehorses. Inclusion criteria were for animals to be EIPH-positive in, at least, two consecutive post-exercise endoscopic exams and to receive 250mg of furosemide IV four hours before racing. Animals were randomly assigned into 3 groups: placebo, control, and PRP instillation. All 37 Thoroughbred racehorses included had EIPH endoscopic scores pre- and post- treatment compared by statistical analysis. The bleeding score from the group receiving PRP was significantly lower than in the control and placebo groups. No adverse effects were observed in any animal during or after the experiment. It was possible to conclude that the intrabronchial instillation of autologous PRP was effective in reducing EIPH scores in racehorses receiving furosemide and that this bioproduct can be considered as a promising coadjuvant in controlling EIPH in athletic horses.(AU)

A alta prevalência de hemorragia pulmonar induzida por exercício (HPIE) em cavalos atletas é um desafio de longa data para a indústria de corridas, além de figurar como grande preocupação sobre o bem-estar animal. As evidências experimentais e clínicas indicam que o uso do plasma rico em plaquetas (PRP) de fonte autógena é promissor na terapêutica de diversas lesões pulmonares. O presente estudo objetivou avaliar as mudanças após corrida no escore endoscópico de HPIE de 37 cavalos Puro-Sangue Inglês que receberam instilação intrabronquial de PRP autólogo. Os animais selecionados eram HPIE-positivos em, ao menos, dois exames endoscópicos consecutivos e recebiam 250mg de furosemida IV administrado quatro horas antes de cada corrida. Na comparação dos escores endoscópicos pré e pós-tratamento, verificou-se que o escore de HPIE do grupo tratado com PRP foi significantemente menor que o dos grupos controle e placebo. Nenhum efeito adverso foi observado nos animais durante ou após o experimento. Concluiu-se que a instilação intrabronquial de PRP autólogo foi efetiva na redução do escore de HPIE de cavalos de corrida usuários de furosemida e que este bioproduto pode ser considerado uma alternativa promissora no controle de HPIE em cavalos atletas.(AU)

Analysis of Rinsing Fluid during Negative Pressure Wound Therapy with Instillation: A Potential Monitoring Tool in Acute and Chronic Wound Treatment. A Pilot Study.

BACKGROUND: During negative pressure wound therapy (NPWT), open wounds are draped with a nontransparent sponge, making daily wound evaluation impossible. Sometimes, late or undetected bacterial infections and postoperative bleeding result in repetitive surgery, thus prolonging inpatient time. With the introduction of additional fluid instillation (NPWTi), the wound surface is rinsed, and bacteria, proteins and biomarkers are flushed into a collecting canister, which is later discarded. METHODS: The aim of this pilot study was to analyze rinsing fluid samples (0.9% sodium chloride) from the NPWTi device in patients with acute and chronic wounds. In 31 consecutive patients a standardized laboratory analysis was performed to evaluate cellular composition and potassium, phosphate, lactate dehydrooxygenase, pH and total protein levels. RESULTS: While there was an increase in the total cellular amount and the number of polymorphonuclear cells, the number of red blood cells (RBC) decreased after surgery. Potassium and pH showed no significant changes in the first three postoperative days, whereas total protein showed an undulant and partially significant course. CONCLUSION: We were able to quantify cellular metabolites by analyzing the rinsing fluid of NPWTi. We propose the analysis of this material as a novel and potentially promising tool to monitor wound status without removal of the dressing. The establishment of reference values might help to improve the NPWTi therapy.

Effect of Topical Instillation of Pegaptanib Sodium Upon Inflammatory Corneal Neovascularization in Rabbits.

Purpose: To evaluate the effect of topical instillation of pegaptanib sodium upon inflammatory angiogenesis induced in the rabbit cornea by alkaline cauterization. Methods: Inflammatory angiogenesis was induced by alkaline (sodium hydroxide) cauterization in the corneas of 29 male New Zealand rabbits. The animals were divided into 4 groups: a control group treated with 0.5% carboxymethylcellulose sodium eye drops, a group treated with 1.0% prednisolone acetate eye drops, a group treated with 0.5% pegaptanib sodium diluted in 15 mL 0.5% carboxymethylcellulose sodium, and a group treated with 1.0% pegaptanib sodium diluted in 15 mL 0.5% carboxymethylcellulose sodium. After cauterization, eye drops were administered every 12 hours for 21 days. The animals were evaluated every 3 days after cauterization, and the newly formed vessels were quantified from photographs. The treatment effectiveness was analyzed with 3 parameters of antiangiogenic response: neovascularization area (NA), total vascular length (TVL), and number of blood vessels (BVN). Results: Average NA, TVL, and BVN values were significantly higher in both pegaptanib groups than in the prednisolone group. A nonstatistically significant reduction in parameters on days 18 and 21 was the minimum achieved in both pegaptanib groups. The efficacy of the treatments in relation to the control was significantly greater in the prednisolone group than in the 0.5% pegaptanib group or the 1.0% pegaptanib group (P < 0.001). Conclusion: Topical instillation of 0.5% and 1.0% pegaptanib sodium diluted in 15 mL 0.5% carboxymethylcellulose sodium had no inhibitory effect on corneal neovascularization in this rabbit model.

Comparison of nanoemulsion and non-emollient artificial tears on tear lipid layer thickness and symptoms / Comparación del efecto de las gotas oftálmicas de nanoemulsión vs no emolientes en el grosor de la capa lipídica lagrimal y los síntomas

PURPOSE: Dry eye disease (DED) is often managed with over-the-counter eye drops. This study evaluated the diurnal effects of a single drop of two ocular lubricants (nanoemulsion vs. non-emollient) on tear film lipid layer thickness (LLT) and symptoms of ocular dryness. Subjects were also assessed after 1 month of nanoemulsion eye drop use. METHODS: Part 1 was a cross-over comparison of a nanoemulsion and a non-emollient eye drop. LLT and dry eye symptoms were measured at baseline and at 15min, 1 h, 2 h, 4 h and 6 h after instillation of each drop. Part 2 was a 1-month observational study assessing LLT and symptoms after 30-day use of the nanoemulsion drop four times daily (qid). RESULTS: Total of 20 subjects completed the study (mean age = 45.6 ± 7.9, 15 female). Part 1 found a significant increase in average LLT 15min after nanoemulsion drop instillation in the overall and inferior third of the tear film for subjects with baseline LLT values < 50 nm. Average LLT values did not increase after use of the non-emollient. Symptoms of dryness improved up to 6h following instillation of both drops. Part 2 results found that using the nanoemulsion eye drop for 1 month improved symptoms reported on symptom surveys. CONCLUSION: Nanoemulsion eye drop use increased average LLT in subjects with low baseline levels. Statistically and clinically significant improvement in symptoms were found on symptom surveys after qid-use (four times a day) of the nanoemulsion drop. Results suggest that a nanoemulsion eye drop can benefit subjects with dry eye symptoms

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Proposal of selective wedge instillation of pulmonary surfactant for COVID-19 pneumonia based on computational fluid dynamics simulation.

BACKGROUND: The most important target cell of SARS-CoV-2 is Type II pneumocyte which produces and secretes pulmonary surfactant (PS) that prevents alveolar collapse. PS instillation therapy is dramatically effective for infant respiratory distress syndrome but has been clinically ineffective for ARDS. Nowadays, ARDS is regarded as non-cardiogenic pulmonary edema with vascular hyper-permeability regardless of direct relation to PS dysfunction. However, there is a possibility that this ineffectiveness of PS instillation for ARDS is caused by insufficient delivery. Then, we performed PS instillation simulation with realistic human airway models by the use of computational fluid dynamics, and investigated how instilled PS would move in the liquid layer covering the airway wall and reach to alveolar regions. METHODS: Two types of 3D human airway models were prepared: one was from the trachea to the lobular bronchi and the other was from a subsegmental bronchus to respiratory bronchioles. The thickness of the liquid layer covering the airway was assigned as 14 % of the inner radius of the airway segment. The liquid layer was assumed to be replaced by an instilled PS. The flow rate of the instilled PS was assigned a constant value, which was determined by the total amount and instillation time in clinical use. The PS concentration of the liquid layer during instillation was computed by solving the advective-diffusion equation. RESULTS: The driving pressure from the trachea to respiratory bronchioles was calculated at 317 cmH2O, which is about 20 times of a standard value in conventional PS instillation method where the driving pressure was given by difference between inspiratory and end-expiratory pressures of a ventilator. It means that almost all PS does not reach the alveolar regions but moves to and fro within the airway according to the change in ventilator pressure. The driving pressure from subsegmental bronchus was calculated at 273 cm H2O, that is clinically possible by wedge instillation under bronchoscopic observation. CONCLUSIONS: The simulation study has revealed that selective wedge instillation under bronchoscopic observation should be tried for COVID-19 pneumonia before the onset of ARDS. It will be also useful for preventing secondary lung fibrosis.

Steady streaming as a method for drug delivery to the inner ear.

The inner ear, or cochlea, is a fluid-filled organ housing the mechanosensitive hair cells. Sound stimulation is relayed to the hair cells through waves that propagate on the elastic basilar membrane. Sensorineural hearing loss occurs from damage to the hair cells and cannot currently be cured. Although drugs have been proposed to prevent damage or restore functionality to hair cells, a difficulty with such treatments is ensuring adequate drug delivery to the cells. Because the cochlea is encased in the temporal bone, it can only be accessed from its basal end. However, the hair cells that are responsible for detecting speech-frequency sounds reside at the opposite, apical end. In this paper we show that steady streaming can be used to transport drugs along the cochlea. Steady streaming is a nonlinear process that accompanies many fluctuating fluid motions, including the sound-evoked waves in the inner ear. We combine an analytical approximation for the waves in the cochlea with computational fluid dynamic simulations to demonstrate that the combined steady streaming effects of several different frequencies can transport drugs from the base of the cochlea further towards the apex. Our results therefore show that multi-frequency sound stimulation can serve as a non-invasive method to transport drugs efficiently along the cochlea.

A Preclinical Safety Study of Thyroid Hormone Instilled into the Lungs of Healthy Rats-an Investigational Therapy for ARDS.

Acute respiratory distress syndrome (ARDS) is a severe, life-threatening form of respiratory failure characterized by pulmonary edema, inflammation, and hypoxemia due to reduced alveolar fluid clearance (AFC). Alveolar fluid clearance is required for recovery and effective gas exchange, and higher rates of AFC are associated with reduced mortality. Thyroid hormones play multiple roles in lung function, and L-3,5,3'-triiodothyronine (T3) has multiple effects on lung alveolar type II cells. T3 enhances AFC in normal adult rat lungs when administered intramuscularly and in normal or hypoxia-injured lungs when given intratracheally. The safety of a commercially available formulation of liothyronine sodium (synthetic T3) administered intratracheally was assessed in an Investigational New Drug Application-enabling toxicology study in healthy rats. Instillation of the commercial formulation of T3 without modification rapidly caused tracheal injury and often mortality. Intratracheal instillation of T3 that was reformulated and brought to a neutral pH at the maximum feasible dose of 2.73 µg T3 in 300 µl for 5 consecutive days had no clinically relevant T3-related adverse clinical, histopathologic, or clinical pathology findings. There were no unscheduled deaths that could be attributed to the reformulated T3 or control articles, no differences in the lung weights, and no macroscopic or microscopic findings considered to be related to treatment with T3. This preclinical safety study has paved the way for a phase I/II study to determine the safety and tolerability of a T3 formulation delivered into the lungs of patients with ARDS, including coronavirus disease 2019-associated ARDS, and to measure the effect on extravascular lung water in these patients. SIGNIFICANCE STATEMENT: There is growing interest in treating lung disease with thyroid hormone [triiodothyronine (T3)] in pulmonary edema and acute respiratory distress syndrome (ARDS). However, there is not any published experience on the impact of direct administration of T3 into the lung. An essential step is to determine the safety of multiple doses of T3 administered in a relevant animal species. This study enabled Food and Drug Administration approval of a phase I/II clinical trial of T3 instillation in patients with ARDS, including coronavirus disease 2019-associated ARDS (T3-ARDS ClinicalTrials.gov Identifier NCT04115514).

Challenges and Management in Wound Care.

SUMMARY: Wounds have been one of the most prominent pathologies since the beginning of humanity. For the last 5 decades, a drastic improvement of healing has been observed, thanks to new medical devices based on fluid aspiration capacities and the development of negative pressure wound therapy. Negative-pressure wound therapy was initially designed for a double action, fluid aspiration and mechanical stimulation of wound edges by a foam. Successive technical evolutions of negative pressure wound therapy were declined since 1997 when Argenta and Morykwas first presented their solution. The adjunct of instillation in 2009 was considered as the first interactive dressing, allowing topical wound solutions to sequentially reach the wound, in alternance with negative pressure. Other devices based on the same principle were designed to prevent postoperative infections when placed over a suture after surgery. This long evolution could enhance the armamentarium of possible solutions, considerably reducing the wound healing time.