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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.We enrolled 72 individuals with primary open-angle glaucoma or ocular hypertension, on treatment with fixed combination (α agonist+β 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.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 (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.

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.

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.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.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.

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.

We investigated the success rates of eyedrop instillation and the distance between the cornea and the dropper tip in 100 volunteers using high-speed digital video recording. Past eyedrop adherence studies assumed that instillation occurred without failure. The ideal distance between the cornea and dropper tip remained unclear, although the general estimate was approximately 2.54 cm (1 inch). This study was approved by the Institutional Review Boards of all participating medical institutions, and all volunteers provided written, informed consent. Successful instillation was defined as when 1 drop fell accurately into the eye on the first attempt. The instillation of ≥2 drops or drops delivered outside the eye was considered a failure. The distance between the eye and dropper tip was measured using still images from a paused digital video camera and a digital ruler. Forty percent of the volunteers instilled eyedrops without instructions from ophthalmologists, pharmacists, or other healthcare workers. When the images were analyzed, the success rate of the first instillation was 70.1%. When the eye was arbitrarily divided into 9 sections, most of the drop sites were the iris or the center of the eye. The distance between the dropper tip and cornea was 2.62±1.75 (median 2.20) cm. These results indicate that the generally recommended distance is usually followed. The successful instillation rate based on the distance from the dropper tip to the cornea was 77% at 1.6±0.88 cm and 54.9% at 4.8±1.25 cm.

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.

Purpose: To investigate the effects of topical application of ophthalmic 5% povidone-iodine eye drops, which has been reported to cause apnea in spontaneously breathing children during general anesthesia. Methods: The authors conducted a randomized, controlled, single-blinded study comparing the effect of balanced salt solution eye drops and povidone-iodine eye drops on respiration in spontaneously breathing children during general anesthesia with sevoflurane via a laryngeal mask airway. Fifty patients received balanced salt solution eye drops and 50 patients received 5% povidone-iodine eye drops. Results: None of the control patients had a significant change in respiration. Thirty of the 50 (60%) povidone-iodine patients had a slowing of respiration within the first 6 breaths after eye drop instillation ( P < .001). The median time of respiratory pause in those 30 patients was 18.5 seconds (range: 4.36 to 96.2 seconds). Among the povidone-iodine patients, children with a history of a prior tonsillectomy and adenoidectomy and/or bilateral myringotomy had a 7.2 times greater chance of experiencing a change in respiration after instillation of the povidone-iodine eye drops. Conclusions: Topical application of 5% povidone-iodine eye drops causes a slowing and pause in spontaneous ventilation in a majority of children prior to strabismus surgery. This may represent activation of the diving reflex. [ J Pediatr Ophthalmol Strabismus . 2019;56(6):378–382.]

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.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.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.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.

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.

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.

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.

Purpose: To evaluate the effect of topical instillation of pegaptanib sodium upon inflammatory angiogenesis induced in the rabbit cornea by alkaline cauterization. Methods: Inflammatory angiogenesi...

Bronchial obstruction, caused by retained secretions, is often treated by the administration of mucoactive agents including distilled water, saline, hypertonic saline, and sodium bicarbonate. However, the inflammatory effect of these solutions on the lungs remains unclear. This study evaluated the instillation effects of different solutions on oxidative stress and lung inflammatory response in C57BL/6 mice. Fifty C57BL/6 mice were divided into 5 groups: control (CG); distilled water (DWG), hypertonic saline (HSG), saline (SG) and sodium bicarbonate (SBG). CG was exposed to ambient air while DWG, HSG, SG and SBG had 50 μl of respective solutions administered intranasally for 5 consecutive days. Twenty-four hours after the last intranasal instillation, all animals were euthanized for subsequent analysis. All solutions promoted increased recruitment of inflammatory cells to the lung compared to controls. Superoxide dismutase activity was lower in HSG compared to all other groups; catalase activity was reduced in SG, while it increased in SBG and DWG compared to CG. Finally, there was an increase in the inflammatory markers TNF-α, CCL2 and IFN-γ in DWG compared to CG, SG and HSG. In conclusions, the intranasal instillation of different solutions promotes redox imbalance and inflammation on lungs of adult mice.

Hyposecretion of aqueous humor has been postulated to adversely affect the health of the trabecular meshwork and outflow resistance. However, the effect of medications that reduce aqueous humor production on outflow facility in living human eyes is unclear. This study evaluated the effect of timolol, an aqueous humor flow suppressant, on outflow facility in healthy eyes.Prospective, before-and-after study.In a multicenter study, 113 healthy participants over 40 years of age were included. Intraocular pressure (IOP) was measured with the participant in the sitting position by using a pneumatonometer. The outflow facility was measured with the participant in the supine position by 2-minute pneumatonography. After participants self-administered drops of timolol 0.5% for 1 week, twice daily in each eye, both measurements were repeated.Mean IOP decreased from 15.1 ± 3.0 mm Hg at baseline to 12.4 ± 2.4 mm Hg (P0.001) after 1 week of timolol use. Mean outflow facility decreased from 0.23 ± 0.08 μL/min/mm Hg at baseline to 0.18 ± 0.08 μL/min/mm Hg (P0.001) after timolol. The change in outflow facility was negatively correlated with baseline outflow facility (r = -0.51; P 0.001).Timolol reduces outflow facility in healthy human eyes, and this effect is greater in eyes with higher baseline outflow facility. This phenomenon may be related to reduced aqueous humor flow, but the precise mechanism remains to be determined.

Purpose: To evaluate strabismus surgery with intraoperative adjustment of sutures under topical anesthesia in children. Methods: Nineteen children with horizontal deviation underwent a one-stage surgical technique performed under topical anesthesia. Surgery consisted of unilateral or bilateral recession and/or resection of horizontal muscles or the medial or lateral rectus muscles, with intraoperative adjustment of sutures based on alternate prism cover test. Follow-up was done at 1 day and 1, 3, and 6 months postoperatively. Results: Mean age at surgery was 12.68 ± 2.50 years (range: 8 to 16 years). Mean preoperative angle of deviation was 24.21 ± 11.20 prism diopters (PD) (range: −50 to +30 PD) at distance. Mean postoperative angle of deviation at 6 months was 4.11 ± 2.87 PD (range: −10 to +10 PD) at distance. In esotropic patients, the average angle of deviation decreased from +23.80 ± 5.89 PD preoperatively to +4.80 ± 3.35 PD at 6 months, whereas in exotropic patients it decreased from −24.36 ± 12.76 to −3.86 ± 2.77 PD. Seventeen of 19 patients (89%) remained comfortable during surgery, whereas 2 needed an intravenous injection of propofol. The success rate, defined by a postoperative residual angle of deviation of ±8 PD or less, was 89% at 6 months. Conclusions: Strabismus surgery with intraoperative suture adjustment under topical anesthesia in children is a tolerable procedure with encouraging outcomes, representing an alternative to general anesthesia in well-selected children. Clinical evaluation of children and parents is fundamental to predict a likely poor collaboration of the child during surgery, which, if present, would require surgery under general anesthesia. [ J Pediatr Ophthalmol Strabismus . 2019;56(3):173–177.]

Background We describe 3 cases where negative-pressure wound therapy with instillation and dwell time (NPWTi-d) was used as an adjunctive therapy for 3 chronic wounds. Cases Three patients (2 males and 1 female), ranging in age from 28 to 53 years, presented with complex, infected wounds: (1) a diabetic foot ulcer with underlying infection, (2) a dehisced abdominal wound with enterocutaneous fistula, and (3) a large wound of the upper torso and axillary region resulting from soft tissue necrosis. Negative-pressure wound therapy with instillation and dwell time was initiated by instilling normal saline or an antiseptic solution; the solution was left in place for 3 to 10 minutes. Continuous negative pressure was then applied at -125 or -150 mm Hg; cycles were repeated every 1 or 3 hours. Treatment was applied for 5 to 44 days, and dressings were changed every 2 to 3 days. Granulation tissue developed in all 3 wounds; all closed after subsequent skin grafting. Conclusions Outcomes of these cases suggest that NPWTi-d may be used as an adjunctive treatment modality for a variety of chronic wounds.

Obesity is one of the greatest health problems. Bariatric surgery is more effective than non-surgical options; however, postoperative pain is bound to a greater morbidity. Control of postoperative pain is important in facilitating patient convalescence. In this study, we assessed the efficacy of intraperitoneal instillation of bupivacaine after bariatric surgery. A hundred patients who underwent bariatric procedures including sleeve gastrectomy, sleeve gastrectomy with cardioplasty, gastric bypass, and gastric mini bypass (one anastomosis gastric bypass) were included in the study. Patients were divided into two groups randomly, 50 patients for each; group I had intraperitoneal instillation of 40 ml bupivacaine 0.25% at the end of the procedure, while group II had normal saline instillation. Monitoring of pain control in the first 24 h after surgery was done using the visual analogue scale (VAS) to assess the efficacy of intraperitoneal bupivacaine instillation and its effect on the overall opioid usage, postoperative nausea and vomiting (PONV), and shoulder tip pain. Pain scores were significantly lower in group I compared to group II at recovery, 2, 4 and 6 h after surgery, P = 0.004, 0.001

BACKGROUND The aim of this study was to provide an integrated analysis of safety and efficacy data for brimonidine tartrate ophthalmic solution 0.025 per cent (low-dose; Bausch & Lomb Incorporated), a topical vasoconstrictor for relief of ocular redness. METHODS Integrated efficacy data from two randomised, double-masked, vehicle-controlled studies in subjects with ocular redness as well as safety data from the two efficacy studies, a vehicle-controlled safety study, and a pharmacokinetic study were analysed. Efficacy outcomes analysed included investigator-assessed ocular redness (scale, 0-4) before treatment instillation and at five to 240 minutes post-instillation on Day 1, at five minutes post-instillation on Days 15 and 29, and one week after treatment discontinuation (Day 36), and redness self-assessed by subjects recorded daily in diaries. Safety assessments included adverse events, ophthalmic examinations, and rebound redness upon treatment discontinuation. Drop comfort (scale, 0-10) was a tolerability measure. RESULTS The efficacy population included 117 subjects (brimonidine, n = 78; vehicle, n = 39). The safety population included 635 subjects (brimonidine, n = 426; vehicle, n = 209). Investigator-assessed ocular redness was significantly lower with brimonidine versus vehicle at all post-instillation time points on Day 1 (mean change from pre-instillation of -1.4 units for brimonidine and -0.2 units for vehicle; p

Whether alveolar liquid surface tension, T, is elevated in the acute respiratory distress syndrome (ARDS) has not been demonstrated in situ in the lungs. Neither is it known how exogenous surfactant, which has failed to treat ARDS, affects in situ T. We aim to determine T in an acid-aspiration ARDS model before and after exogenous surfactant administration. In isolated rat lungs, we combine servo-nulling pressure measurement and confocal microscopy to determine alveolar liquid T according to the Laplace relation. Administering 0.01 N (pH 1.9) HCl solution by alveolar injection or tracheal instillation, to model gastric liquid aspiration, raises T. Subsequent surfactant administration fails to normalize T. Furthermore, in normal lungs, tracheal instillation of control saline or exogenous surfactant raises T. Lavaging the trachea with saline and injecting the lavage solution into the alveolus raises T, suggesting that tracheal instillation may wash T-raising airway contents to the alveolus. Adding 0.01 N HCl or 5 mM CaCl2—either of which aggregates mucins—to tracheal lavage solution reduces or eliminates the effect of lavage solution on alveolar T. Following tracheal saline instillation, liquid suctioned directly out of alveoli through a micropipette contains mucins. Additionally, alveolar injection of gastric mucin solution raises T. We conclude that 1) tracheal liquid instillation likely washes T-raising mucins to the alveolus and 2) even exogenous surfactant that could be delivered mucin-free to the alveolus might not normalize T in acid-aspiration ARDS. NEW & NOTEWORTHY We demonstrate in situ in isolated lungs that surface tension is elevated in an acid-aspiration acute respiratory distress syndrome (ARDS) model. Following tracheal liquid instillation, also in isolated lungs, we directly sample alveolar liquid. We find that liquid instillation into normal lungs washes mucins to the alveolus, thereby raising alveolar surface tension. Furthermore, even if exogenous surfactant could be delivered mucin-free to the alveolus, exogenous surfactant might fail to normalize alveolar surface tension in acid-aspiration ARDS.

Cationic amphiphilic drugs (CADs) can induce phospholipidosis (PLD) in organs/tissues. Several ophthalmic pharmaceuticals containing CADs are marketed and used in children. To investigate the effect of PLD on the developing cornea, chloroquine and amiodarone, which are representative CADs, were applied topically to the eyes of juvenile rabbits, and the effects in juvenile rabbits were compared with those in young adult rabbits. Diffuse corneal cloudiness was observed in chloroquine- and amiodarone-treated eyes. Histopathologically, vacuolation was observed in the corneal epithelium and keratocytes. On ultrastructural examination, these vacuoles contained multilamellar inclusion bodies, which are a characteristic of PLD. The size of the vacuoles in the corneal epithelium was reduced in juveniles compared with young adults. Cytoplasmic lamellar bodies and exocytosis in the corneal endothelium were observed in young adult rabbits but not in juvenile rabbits. This study revealed that topical application of chloroquine or amiodarone induces corneal PLD in juvenile and young adult rabbits. Corneal endothelial changes occurred only in young adult rabbits, but ophthalmological changes were similar between juveniles and young adults. The results of the study suggest that the effects of corneal PLD were similar among age groups based on risk assessment.

Objective The incidence of refractory chronic rhinosinusitis (CRS) associated with methicillin-resistant Staphylococcus aureus (MRSA) is rising and remains a therapeutic challenge. The goal of this study is to demonstrate the efficacy of a non-invasive topical therapy against MRSA in these patients. Methods Seventeen patients with refractory CRS caused by MRSA were treated with a topical therapy protocol. Treatment consisted of weekly endoscopic sinus debridement followed by intra-sinus installation of a hydroxyl-ethylcellulose gel that releases mometasone and a culture-directed antibiotic for a period of 6 weeks, along with daily nasal nebulization of mometasone with the same antibiotic and saline rinses. Clinical outcome was assessed using the Lund–Kennedy (LK) symptom and endoscopic appearance scores. Sinus mucosal tissue was homogenized and cultured, and microbial biofilm burden was assessed based on colony forming units (CFUs) counts. Results Rhinotopic therapy resulted in clearance of MRSA in 13 of 16 patients (81.2%). Treated patients also demonstrated significant improvement clinically as measured by the LK scores. In addition, a significant decrease in mucosal CFUs was observed post-therapy. Conclusion Our findings demonstrate that topical therapy is an effective method for treating MRSA-associated refractory CRS.

Objectives Milrinone pulmonary administration is used currently for the treatment of pulmonary hypertension. Several methods are available: simple jet nebulization, vibrating mesh nebulization, intratracheal instillation, and intratracheal atomization. The aim of this study was to explore the concentration-effect relationship of milrinone for each of these methods. Design Observational open-label pharmacokinetic/pharmacodynamics cohort study. Setting Single-center, hospital animal laboratory. Participants Twelve swine. Interventions After hypercapnia pulmonary hypertension, swine were administered equivalent inhaled milrinone doses of 15 or 50 µg/kg through simple jet nebulization, vibrating mesh nebulization, intratracheal instillation, and intratracheal atomization. Measurements and Main Results Blood and urine samples were taken up to 360 minutes postadministration. The ratio of mean systemic arterial pressure to mean pulmonary arterial pressure was monitored continuously. Right heart echographies were taken before and after hypercapnia and after drug administration. Mean elimination half-lives were similar for the 4 administrations. Mean percent changes in the ratio were of 37 (60%), 18 (31%), 17 (36%), and 20 (20%), for simple jet nebulization, vibrating mesh nebulization, intratracheal instillation, and intratracheal atomization, respectively. Mean maximum plasma concentrations for intratracheal administrations were reached at 8 and 45 min for atomization and instillation, respectively. Significant increases in right atrial diameter and right ventricular end-diastolic area were witnessed during pulmonary hypertension as well as a return to baseline values after milrinone administration. Conclusions The intratracheal methods, particularly intratracheal atomization, showed less hemodynamic effect than nebulizations and, in the case of intratracheal instillation, unpredictable drug exposure. Nebulization methods on the other hand, especially simple jet nebulization, suggest better efficacy and sensitivity but are less fit for emergency situations.

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.

SUMMARY The use of negative-pressure wound therapy (NPWT) has become an established therapy for wound management. There have been many advancements in the technology of NPWT including NPWT with instillation and dwell (NPWTi-d). NPWTi-d promotes wound healing by wound cleansing, irrigation, and nonexcisional debridement. NPWTi-d has been shown in comparative clinical studies to decrease the time to definitive wound healing and length of hospitalization. NPWTi-d-using a reticulated open-cell foam dressing with "through" holes (ROCF-CC)-has been postulated to facilitate solubilization, detachment, and elimination of infectious materials, such as slough and thick exudate, before or after operative debridement, and in cases where surgical debridement is not an option. The authors provide an overview on the use of NPWTi-d by reviewing the components of the system, proposed mechanism of action, clinical outcomes, and current consensus guidelines for its utilization.

SUMMARY Negative-pressure wound therapy with instillation and dwell (NPWTi-d) is an option for management of wounds with exposed orthopedic fixation hardware. The mechanical effect of the negative-pressure therapy works to contract the wound edges, and the instillation of solution and its subsequent removal help remove infectious material. NPWTi-d also promotes robust granulation tissue formation. In this article, we discuss the science behind NPWTi-d and its role in the treatment of wounds with indwelling orthopedic fixation hardware.

Background The addition of topical fluid instillation, a programmable "dwell" time and a novel foam-wound interface to the established wound healing benefits of negative-pressure wound therapy (NPWT) works synergistically to benefit patients with complex wounds. This engineering breakthrough for wound care has been termed NPWT with instillation and dwell (NPWTi-d), and the new foam dressings are reticulated open cell foam dressings specifically designed for use with NPWTi-d. This combined technology has shown promise in chronic, complex wounds and has potential for the management of sacral and ischial pressure wounds. Methods A qualitative comprehensive review was performed analyzing articles from PubMed and Medline that reported on the use of NPWTi-d in sacral or ischial pressure ulcers. Case series and case reports were predominant, and results of cases specific to sacral and ischial pressure wounds were extracted from larger studies and summarized for presentation. Results Compared with conventional NPWT alone, NPWTi-d has been shown to help irrigate the wound, remove fibrinous debris, and promote granulation tissue formation. This is associated with a decreased number of operative debridements and decreased hospital length of stay. Conclusions This technology is rapidly demonstrating expanded utilization in hospitalized patients with chronic sacral and ischial pressure ulcers. When used correctly, NPWTi-d serves as an effective "bridge to defined endpoint": whether that is a flap reconstruction, skin grafting, or discharge home with a stable chronic wound and simplified wound care.

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.

This report describes a 15-year-old with an 11.1 × 8.2 × 8.4 cm multiloculated liver abscess caused by methicillin-sensitive Staphylococcus aureus who failed extensive catheter drainage and intravenous antibiotics. Daily intra-abscess oxacillin was instilled for 7 days with rapid clinical improvement and sterilization of the abscess. One month later, an ultrasound of the abdomen revealed a normal liver.

Critical central airway obstruction has always been a dreaded complication to which interventional pulmonologist commonly encounters. There have been various modalities which are used for the management and palliation, which includes mechanical coring, laser, cryoextraction, electrocautery and airway stenting. Rigid bronchoscopy with or without jet ventilation has been corner stone of therapeutics and palliation of central airway obstruction. There are only a few conditions where it is not possible to use rigid bronchoscopy. Here we report a case of metastatic tracheal tumour which presented with critical airway obstruction in a patient who had atlantoaxial instability (AAI) due to rheumatoid arthritis. Here we used endobronchial ultrasound scope (EBUS) via esophageal route, i.e. EUS-B guided approach for sampling of the tracheal tumour, and intratumoral chemotherapy was instilled in multiple sessions, which resulted in shrinking of tumour, thus relieving the critical airway obstruction. This is the first report of using EUS-B approach for intratumoral chemotherapy for tracheal tumors. Bronchoscopic intratumoral chemotherapy therapy (BITC) in tracheal tumors is also one of the options but has not been explored much and there has been a dearth of literature for it.

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.

Purpose: To explore safety and therapeutic efficacy of a topical ophthalmic triamcinolone acetonide-loaded liposome formulation (TA-LF) as primary therapy in patients with macular edema (ME) second...

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).

Background Although massive bleeding following transbronchial lung biopsies (TBLB) is rare, even minor hemorrhage may prolong the procedure and result in inadequate sampling. Tranexamic acid (TXA) is an antifibrinolytic agent, which reduces bleeding in numerous scenarios, however, its prophylactic use in mitigating post-TBLB bleeding has not been investigated. We conducted a prospective, randomized, double-blind, placebo-controlled trial to determine whether topical infusion of TXA prior to TBLB would reduce bleeding, shorten procedure duration and increase the number of biopsies obtained. Methods We blindly randomized patients undergoing TBLB to receive topical TXA or placebo in the lobar bronchus prior to biopsies. Vital signs, procedure length, fluid balance (as a measure of the amount of bleeding), operator's assessment of bleeding, and number of biopsies obtained were measured. Data was analyzed using the two-tailed Student's T-Test, Chi-square or Mann-Whitney tests as appropriate. Results Fifty patients were randomized, 26 to the TXA arm. The bleeding in the TXA group was significantly lower (P = 0.0037), with more specimens being obtained (placebo 7 (6, 9) (median and interquartile range) vs. TXA 9 (8, 10), P = 0.023) and no difference in procedure length (placebo 30 min (29.3, 34.3) vs. TXA 30 (24.8, 36), P = 0.90). There were no clinically significant adverse events in any of the groups up to one month of follow up. Conclusion Endobronchial installation of TXA prior to obtaining TBLB results in less bleeding and allows more biopsies to be obtained with no additional adverse events. The prophylactic use of TXA during TBLB may be considered as standard.

Peritoneal metastases arise in patients with a variety of primary cancers, and are associated with a poor prognosis. Systemic chemotherapy is the mainstay of treatment; however, the morbidity is considerable and the survival benefit is modest. Cytoreductive surgery and heated intraperitoneal chemotherapy is a potentially curative treatment available to a minority of patients; however, most develop recurrent disease. A novel palliative treatment for peritoneal metastases, pressurized intraperitoneal aerosol chemotherapy, has recently been introduced. Pressurized intraperitoneal aerosol chemotherapy utilizes an aerosol of chemotherapy in carbon dioxide gas. It is instilled into the abdomen under pressure via laparoscopic ports. No cytoreduction is performed. Pressurized intraperitoneal aerosol chemotherapy can be repeated at 6-week intervals. Oxaliplatin or cis-platinum and doxorubicin have been used to date.This study aims to systematically review and evaluate the method, and the preclinical and early clinical results of pressurized intraperitoneal aerosol chemotherapy.Medline and the Cochrane Library were the data sources for the study.Peer-reviewed series of greater than 10 patients, with sufficient patient data, through April 2019, were selected.Patients with peritoneal metastases underwent pressurized intraperitoneal aerosol chemotherapy.Patient dropout, histologic tumor response, adverse events, and 30-day mortality were the primary outcomes measured.A total of 921 patients with peritoneal metastases were brought to the operating room for pressurized intraperitoneal aerosol chemotherapy. The number of pressurized intraperitoneal aerosol chemotherapy treatments administered was as follows: 1 treatment, 862 (94%); 2 treatments, 645 (70%); and 3 treatments, 390 patients (42%). Initial laparoscopic access was not possible in 59 patients (6.4%). Common Terminology Criteria for Adverse Events grade 3 or higher were noted in 13.7% of the patients who, collectively, underwent a total of 2116 treatments. The 30-day mortality was 2.4% (22/921).This study was limited by the heterogeneity of reported data and primary tumor types and by the lack of long-term survival data.Early clinical results are encouraging, but tumor-specific, prospective, randomized trials are needed to compare pressurized intraperitoneal aerosol chemotherapy to systemic chemotherapy. This method has yet to be introduced to the United States. It is another therapeutic option for patients with peritoneal metastases and will broaden the patient base for future clinical trials.

The reviews of this paper are available via the supplemental material section.

Mycobacterium abscessus is an extensively drug-resistant opportunistic pathogen that can cause chronic otomastoiditis. There are no evidence-based treatment regimens for this severe infection. We treated four children with M. abscessus otomastoiditis with a structured regimen of topical imipenem and tigecycline, intravenous imipenem and tigecycline, and oral clofazimine and azithromycin and adjunctive surgery. This structured approach led to cure, with 1 year of follow-up after treatment.

To compare the bacterial cultures of the lower eyelid margins and lower fornices between ocular irrigations with and without eyelid margin cleaning before intraocular surgery.A prospective study was carried out that included 102 eyes from 51 patients undergoing intraocular surgery between December 2016 and April 2017. In each patient, the surgical eye (control group) only received ocular irrigation and the opposite eye (study group) received ocular irrigation with eyelid margin cleaning. Normal saline solution was used in all procedures. In each group, samples from the lower eyelid margins and lower fornices were cultured before and after cleaning. Povidone iodine and antibiotic eye drops were instilled after specimen collection.The most common bacterial isolate of all groups was Staphylococcus spp. There were no statistically significant differences of positive cultures between the control and study groups in either lower eyelid margins (Odds ratio [OR], 2.19; 95% CI, 0.84-5.72) nor lower fornices (OR, 0.93; 95% CI, 0.43-2.00). In addition, there were no statistically significant differences of positive cultures between before and after eyelid cleanings from both lower eyelid margins (OR, 2.74; 95% CI, 0.53-14.24) and lower fornices (OR, 0.73; 95% CI, 0.21-2.57).Eyelid margin cleaning with normal saline solution immediately before intraocular surgery did not help to decrease microbial loading on the ocular surfaces. The rate of bacterial contamination, however, was not increased which could be due to not performing eyelid compression.

The ophthalmic application is the main route for the therapy of glaucoma, and is well-accepted by glaucoma patients. Therefore, it is important to measure the drug behavior in lacrimal fluid after instillation of eye drops. In this study, we used ophthalmic formulation (eye drops) containing timolol maleate (TM), in anti-glaucoma eye drops, and attempted to measure the drug behavior after instillation of TM eye drops. First, we collected the lacrimal fluid (5 μL) every 10 time after instillation using micropipette, and measured by the HPLC method. The TM concentration in lacrimal fluid was 21.2 μg/mL at 5 min after the instillation, and the TM was remained for 30 min after the instillation. Next, we collected the lacrimal fluid via the dialysis prove, and measured by the HPLC method. The retention of TM in lacrimal fluid was observed for 45 min after the instillation, and the measurement accuracy was enhanced by system with an automatic injection of TM solution via dialysis prove (microdialysis-HPLC method). In addition, the measurement accuracy increased more by using a capillary liquid chromatography (CLC) instead of an HPLC (microdialysis-CLC method), and the retention time of TM in lacrimal fluid was extended to 75 min after the instillation. In conclusion, we showed that the microdialysis-CLC method was suitable to measure the drug behavior in lacrimal fluid after instillation. These findings provide significant information that can be used in the design and evaluation of ophthalmic formulation.

To determine the efficacy of platelet rich plasma applied early initialization after urethral trauma for preventing inflammation and spongiofibrosis.Twenty-three rats were randomized and divided into 3 groups, with 10 rats in 2 groups. Only sham group had 3 rats. The urethras of all rats were traumatized with a pediatric urethrotome knife at 6- and 12-o'clock. For 15 days, group I was given platelet rich plasma (PRP) once a day without urethral injury (sham group), group II (n = 10) was not given any medical treatment only urethral injury group (UI-PRP), group III (n = 10) was given PRP once a day intraurethrally as instillation using a 22 ga catheter sheath with urethral injury (UI+PRP). On day 15, the penises of the rats were degloved to perform penectomy.A significant difference was detected in all parameters when the sham, UI-PRP, UI+PRP groups were compared (respectively, P = .001, /.001, / .008 / .007) and a significant difference was observed among mucosal inflammation, fibrosis, and edema parameters when UI-PRP and UI+PRP groups were compared. (Respectively; P.001, /.001 / .006).In this study, it was shown that intraurethral PRP applied after urethral trauma significantly decreased mucosal inflammation, spongiofibrosis, and edema. Depending on the results we acquired in this study, we think that PRP may be a promising option in urethral stricture treatment.