Real-life experience after 3 months with tezepelumab before marketing approval / Experiencia de la vida real después de 3 meses con tezepelumab antes de la aprobación de comercialización

Background: Tezepelumab is a monoclonal antibody targeting thymic stromal lymphopoietin (TSLP), implicated in asthma pathogenesis, and that has been approved for patients with severe uncontrolled asthma in Spain in October 2023. This study evaluates our experience with Tezepelumab for those patients who received the indicated drug off-label prior to its commercialization. Methods: We conducted a real-life observational study on three patients from the Severe Asthma Unit of the Hospital Universitario de Fuenlabrada, Spain, who received Tezepelumab off-label before its official approval. We analyzed symptoms control based on ACT, exacerbations, reductions in the doses of oral corticosteroid, lung function, blood changes and safety at 3 months of treatment. Results: Tezepelumab demonstrated efficacy in improving asthma control and a notable reduction in emergency department visits. OCS use decreased, with one patient halving their prednisone dose. Lung function, particularly FEV1 and FEV1/FVC parameters, improved, but no significant changes were observed in FeNO levels, blood eosinophil counts and total IgE. The treatment exhibited a favorable safety profile with no reported adverse effects during the study period. Conclusions: In this preliminary real-world experience prior to the official approval of tezepelumab in Spain, this monoclonal antibody showed promising results and suggests its potential as a valuable alternative for the treatment of severe asthma.(AU)

Deep Eutectic Solvents for Subcutaneous Delivery of Protein Therapeutics.

Proteins are among the most common therapeutics for the treatment of diabetes, autoimmune diseases, cancer, and metabolic diseases, among others. Despite their common use, current protein therapies, most of which are injectables, have several limitations. Large proteins such as monoclonal antibodies (mAbs) suffer from poor absorption after subcutaneous injections, thus forcing their administration by intravenous injections. Even small proteins such as insulin suffer from slow pharmacokinetics which poses limitations in effective management of diabetes. Here, a deep eutectic-based delivery strategy is used to offer a generalized approach for improving protein absorption after subcutaneous injections. The lead formulation enhances absorption of mAbs after subcutaneous injections by ≈200%. The same composition also improves systemic absorption of subcutaneously injected insulin faster than Humalog, the current gold-standard of rapid acting insulin. Mechanistic studies reveal that the beneficial effect of deep eutectics on subcutaneous absorption is mediated by their ability to reduce the interactions of proteins with the subcutaneous matrix, especially collagen. Studies also confirm that these deep eutectics are safe for subcutaneous injections. Deep eutectic-based formulations described here open new possibilities for subcutaneous injections of therapeutic proteins.

Treatment and biologic maintenance-dosing patterns among pediatric patients with ulcerative colitis or Crohn's disease.

OBJECTIVES: To assess treatment patterns and initial and maintenance dosing of biologics over 3 years in pediatric patients with ulcerative colitis (UC) or Crohn's disease (CD), utilizing data from the ImproveCareNow registry. METHODS: Pediatric patients diagnosed with UC or CD and aged 2-17 years were included in the study. Descriptive statistics were employed to summarize baseline demographics. The proportion of patients on medication for UC or CD were analyzed at the baseline visit, 1-year, and 3-year time points (Cohort 1). Biologic maintenance dosage was calculated only for patients who had data for dose and weight at all-time points (Cohort 2). RESULTS: In Cohort 1 (UC = 1784; CD = 4720), baseline treatment in UC included corticosteroid, 5-ASA, and 6-MP/AZA; at 1-year and 3-year time points, treatment with 5-ASA and corticosteroid decreased, whereas 6-MP/AZA and anti-TNFs increased. In CD, baseline treatment included corticosteroid, anti-TNF, 6-MP/AZA, and methotrexate; use of corticosteroids decreased, whereas the use of methotrexate and anti-TNFs increased over 3 years. In Cohort 2 (UC = 350; CD = 1537), at first maintenance dose, UC patients on infliximab received a mean dose of 10.5 mg/kg/8 wk, adalimumab (weight < 40 kg and ≥40 kg) 1.3 mg/kg/2 wk and 0.8 mg/kg/2 wk, and vedolizumab 6.9 mg/kg/8 wks. At the first maintenance dose, CD patients on infliximab received a mean dose of 8.1 mg/kg/8 wk, adalimumab (weight < 40 kg) 1.1 mg/kg/2 wk, adalimumab (weight ≥ 40 kg) 0.8 mg/kg/2 wk, and vedolizumab 10.5 mg/kg/8 wks. CONCLUSION: The use of corticosteroids was common at the initial visit in patients. Anti-TNFs remain the most used class of biologics, however, reported doses in our study were substantially higher than the standard dosing guidelines.

Autoadministración domiciliaria de biológicos. Una encuesta de satisfacción en una unidad de asma grave en tiempo de pandemia por COVID-19 / Home self-administration of biologics. A satisfaction survey in a severe asthma unit during a COVID-19 pandemic

Objetivo: Evaluar las preferencias y satisfacción de los pacientes con asma grave, relacionadas con el lugar de administración de fármacos biológicos subcutáneos: hospital, centro de salud y domicilio, durante la pandemia COVID-19. Métodos: Estudio observacional, descriptivo y transversal que analizó, mediante una encuesta telefónica realizada del 23 al 27 de noviembre de 2020, las preferencias y el grado de satisfacción con la administración de fármacos biológicos subcutáneos en pacientes asmáticos atendidos en la consulta de Alergología de un Hospital General. Resultados: Respondieron la encuesta 33 pacientes, edad media 51,5 años, 57,6% mujeres. Un 57,6% de los pacientes se administraron los fármacos (omalizumab, mepolizumab y benralizumab) en su domicilio, 21,2% en el Hospital de Día y en el Centro de Salud, respectivamente. Los motivos para la administración fuera del hospital fueron la comodidad y evitar el contagio por virus SARS-CoV-2 (30,7%).Tras la pandemia, los pacientes preferían continuar con la dispensación y autoadministración domiciliaria del biológico y tener consultas médicas presenciales. El grado de satisfacción fue 9,7 (escala 0 a 10). Conclusiones: Los pacientes prefieren autoadministrarse en su domicilio los fármacos biológicos para el AG con el apoyo de la dispensación domiciliaria de éstos, mostrando un alto grado de satisfacción por la comodidad que les aporta. Finalizada la pandemia, demandan que las visitas médicas sean presenciales pero desean continuar autoadministrándose el fármaco tras su dispensación domiciliaria por el Servicio de Farmacia. (AU)

Objective: To assess preferences and satisfaction of patients with severe asthma about the place of administration of subcutaneous biological drugs: hospital, health center and home, during the COVID-19 pandemic. Methods: Observational, descriptive and cross-sectional study that analyzed, from November 23 to 27, 2020, through a telephone survey, the preferences and degree of satisfaction with the administration of subcutaneous biological drugs in asthmatic patients treated in the Allergology consultation of a General Hospital. Results: A total of 33 patients responded to the survey, the mean age was 51.5 years, 57.6% were women. The patients that received subcutaneous biological drugs (omalizumab, mepolizumab and benralizumab) at home were 57,6%, at the Day Hospital and at the Health Center 21,2 %, in both cases. The reasons for the administration outside the hospital were comfort and to avoid the spread of the SAR-CoV-2 virus (30.7%). After the pandemic, patients prefer home deliveries, self-administration and face-to-face medical consultations. The degree of satisfaction with the treatment was very high. Conclusions: Patients prefer to self-administer biological drugs for GA at home with the support of their home dispensing, showing a high degree of satisfaction with the comfort it provides. Once the pandemic is over, they demand that medical visits be face-to-face but they want to continue self-administering the drug after it is dispensed at home by the Pharmacy Service. (AU)

Eficacia de una intervención farmacéutica basada en el modelo CMO sobre la adherencia a fármacos biológicos y la experiencia del pacientecon enfermedad reumática (Estudio ADhER-2) / Effectiveness on adherence to biological drugs and experience of a pharmaceutical intervention based on CMO model in patients with rheumatic disease (AdhER-2 study)

Fundamento: Analizar la eficacia de una intervención farmacéutica basada en el modelo CMO sobre la adherencia a fármacos biológicos modificadores de la enfermedad (FAME-b) y sobre la experiencia con los profesionales y servicios sanitarios de pacientescon artritis reumatoide, artritis psoriásica y espondilitis anquilosante estratificados según sus necesidades de atención. Material y métodos: Estudio experimental prospectivo, unicéntrico y controlado de once meses de duración. Se incluyeron pacientes con artritis reumatoide, artritis psoriásica y espondilitis anquilosante no adherentes a FAME-b. Se aleatorizaron en grupo control (GC) e intervención (GI), que recibieron atención farmacéutica habitual o basada en CMO, respectivamente. La adherencia basaly final se calculó mediante la ratio media de posesión de medicamentos y las puntuaciones obtenidas en Compliance Questionnaire on Rheumatology y en Morisky Medication Adherence Scale. Para valorar la experiencia basal y final de los pacientes con los profesionales y servicios sanitarios se utilizó el instrumento de Evaluaciónde la Experiencia del Paciente Crónico (IEXPAC). Resultados: En el GI (n=18), solo un paciente fue estratificado como prioridad 1 (5,6%), nueve se estratificaron como prioridad2 (50,0%) y ocho como prioridad 3 (44,4%). Se realizaron 90 intervenciones farmacéuticas (5,1±1,8 intervenciones por paciente). Al finalizar el estudio, el GI mostró respecto del GC más pacientes adherentes (77,8 vs 18,8%; p=0,002) y mayor puntuación IEXPAC (7,6±1,3 vs 5,8±1,1; p <0,001). Conclusiones: La intervención farmacéutica basada en el modelo CMO mejoró significativamente la adherencia a FAME-b y la experiencia de los pacientes con los profesionales y el sistema sanitario.(AU)

Background: We aimed to assess the effectiveness on adherence to treatment with biologic disease modifying antirheumatic drugs (b-DMARD) and experience with providers of healthcare of a CMO pharmaceutical intervention care model in subjects with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis stratified according to their needs. Method: Prospective, single centre randomized controlled study. The study period was eleven months. Non compliant patients withrheumatoid arthritis, psoriatic arthritis, and ankylosing spondy litis treated with b-DMARD were included. Patients were randomized to a control (CG) or intervention group (IG) who receivedregular or the CMO pharmaceutical intervention model treatment, respectively. Baseline and final adherence were determined using medication possession ratio, the Compliance Questionnaire onRheumatology, and Morisky Medication Adherence Scale. To assess baseline and final patient experience with providers of healthcare we applied the Chronic Patient Experience Assessment Instrument (IEXPAC). Results: For the IG, one patient (5.6%) was categorized as priority1, nine (50.0%) as priority 2, and eight (44.4%) as priority 3. Ninety pharmaceutical interventions were carried out (5.1±1.8 interventions / patient). At the end of the study, the IG showed higherfrequency of patients who adhered to the pharmaceutical intervention (77.8 vs 18.8%; p=0.002) and higher mean IEXPAC score (7.6±1.3 vs 5.8±1.1; p <0.001) in comparison to the CG. Conclusion: The CMO pharmaceutical intervention model significantly improves patient adherence to b-DMARD and their experience with the providers of healthcare.(AU)

Multiple Evanescent White Dot Syndrome Following Medigen Vaccine Biologics Corporation COVID-19 Vaccination.

PURPOSE: To report a case of multiple evanescent white dot syndrome (MEWDS) following severe acute respiratory syndrome coronavirus 2 vaccination. STUDY DESIGN: Case report. RESULTS: A 36-year-old healthy Taiwanese female was presented with flashing lights in the right eye two days after the first dose of Medigen Vaccine Biologics Corporation (MVC) coronavirus disease 19 (COVID-19) vaccine. Examination of the retina revealed multiple white dots in the posterior pole extending to the mid-periphery. Disruption of ellipsoid zone on optical coherence tomography, early hyperfluorescence on fluorescein angiography, late hypo-cyanescence on indocyanine green angiography, and paracentral scotoma on visual field test were consistent with MEWDS. At four-week follow-up, the patient's fundus lesions resolved, and symptoms subsided without treatment. CONCLUSION: Resembling previous post-vaccine MEWDs cases, the symptoms are self-limited, and the visual prognosis is excellent. The presented case demonstrates MEWDS following MVC COVID-19 vaccine and suggests the immune-mediated basis for MEWDS in predisposed patients.

Impacto de una intervención educativa en el conocimiento y manejo de residuos peligrosos biológico-infecciosos / Impact of an educational intervention on the knowledge and management of infectious biological hazardous waste

Introducción: el personal de enfermería tiene una participación fundamental en el manejo de los residuos peligrosos biológico-infecciosos (RPBI) durante la atención en salud, situación que hace indispensable el conocimiento respecto a la peligrosidad y riesgo en el manejo de estos residuos. Objetivo: evaluar el impacto de una intervención educativa acerca del conocimiento y manejo de RPBI, en el personal de enfermería de un hospital general regional. Metodología: estudio cuasi experimental, pretest/postest, prospectivo y longitudinal. Se realizó una intervención educativa, y antes y después de esta se aplicó un cuestionario para evaluar conocimientos relacionados con RPBI y una lista de cotejo del Modelo Institucional para la Prevención de Infecciones Nosocomiales (MIPRIN) para evaluar el manejo de RPBI. Resultados: la intervención educativa demostró un efecto positivo en los conocimientos del personal de enfermería en relación con el manejo de RPBI. En la evaluación pretest se obtuvo un porcentaje de conocimientos de 65.2% y en la postest fue de 78.3% (p < 0.001). Respecto al cumplimiento en el manejo de RPBI, hubo un incremento; sin embargo, no se puede atribuir a la intervención, puesto que se evaluó por servicio y no de manera directa con los participantes. Conclusión: la intervención educativa mostró cambios significativos en los conocimientos y el manejo de RPBI del personal de enfermería.

Introduction: Nursing staff represent an important percentage in the management of biological hazardous waste (BHW) during health care, a situation that makes this knowledge essential regarding the danger and risk in handling these wastes. Objective: To evaluate the impact of an educational intervention about the knowledge and management of BHW in the nursing staff of a regional general hospital. Methods: quasi-experimental, pre-test/post-test, prospective and longitudinal study. An educational intervention was carried out; before and after this intervention, a questionnaire was administered to evaluate knowledge related to BHW and a checklist of the Institutional Model for the Prevention of Nosocomial Infections (MIPRIN, according to its initials in Spanish) to evaluate the management of BHW. Results: The educational intervention showed a positive effect in the nursing staff's knowledge in relation to BHW. In the pre-test evaluation a knowledge percentage of 65.2% was obtained and in the post-test evaluation it was 78.3% (p < 0.001). Regarding compliance in the management of BHW there was an increase; however, it cannot be attributed to the intervention, since it was evaluated by service and not directly with the participants.

Black Truffle Extract Exerts Antidiabetic Effects through Inhibition of Inflammation and Lipid Metabolism Regulation.

Black truffle, a culinary and medical fungus, is highly valued worldwide for its nutritional and therapeutic importance. To enhance the existing knowledge about the beneficial properties, this study investigates the antioxidant, antihyperlipidemic, and anti-inflammatory effects of black truffle extract in in vitro biochemical assays and animal study. Briefly, black truffle extract was administered orally to treat streptozotocin- (STZ-) induced diabetic Wistar rats for 45 days. At the end of the experimental duration, rats were sacrificed to perform biochemical and gene expression analyses related to lipid regulatory and inflammatory pathways. Our results indicated that total cholesterol, triglycerides, free fatty acids, phospholipids, and low-density lipoprotein in different tissues and circulation were significantly increased in diabetic rats. Furthermore, the ß-hydroxy ß-methylglutaryl-CoA enzyme was also significantly increased; lipoprotein lipase and lecithin-cholesterol acyltransferase enzymes were significantly decreased in diabetic rats. However, the above conditions were reversed upon black truffle extract feeding. Furthermore, black truffle extract was also found to downregulate the expression of proinflammatory cytokines (tumor necrosis factor-α and interleukin-6) and lipid regulatory genes (serum regulatory element-binding protein-1 and fatty acid synthase). The truffle extract-treated effects were comparable to glibenclamide and medication commonly used to treat diabetes mellitus. Overall, our results suggested that black truffle possesses strong antihyperlipidemic and anti-inflammatory effects on diabetic rats. These findings will enhance the current knowledge about the therapeutic importance of black truffles. They might be exploited as a possible food supplement or even as a natural source of pharmaceutical agents for diabetes prevention and treatment.

Luteolin Protects Chondrocytes from H2O2-Induced Oxidative Injury and Attenuates Osteoarthritis Progression by Activating AMPK-Nrf2 Signaling.

Osteoarthritis (OA) is a chronic degenerative disease featured by cartilage erosion and inflammation. Luteolin, a member of the flavonoid family, has been shown to exert anti-inflammatory and antioxidative activities. However, the potential biological effects and underlying mechanism of luteolin on chondrocytes and OA progression remain largely elusive. In this study, the potential effect and mechanism of luteolin on OA were investigated in vitro and in vivo. Our data revealed that luteolin inhibited H2O2-induced cell death, apoptosis, oxidative stress, programmed necrosis, and inflammatory mediator production in primary murine chondrocytes. In addition, luteolin could activate the AMPK and Nrf2 pathways, and AMPK serves as a positive upstream regulator of Nrf2. In vivo results demonstrated the therapeutic effects of luteolin on OA in the DMM mouse model. Collectively, our findings showed that luteolin might serve as a novel and effective treatment for OA and provided a new research direction for clinical OA therapies.

Pharmacokinetics and Safety Studies in Rodent Models Support Development of EPICERTIN as a Novel Topical Wound-Healing Biologic for Ulcerative Colitis.

The novel wound-healing biologic EPICERTIN, a recombinant analog of cholera toxin B subunit, is in early development for the management of ulcerative colitis. This study established for the first time the pharmacokinetics (PK), bioavailability (BA), and acute safety of EPICERTIN in healthy and dextran sodium sulfate-induced colitic mice and healthy rats. For PK and BA assessments, single administrations of various concentrations of EPICERTIN were given intravenously or intrarectally to healthy and colitic C57BL/6 mice and to healthy Sprague-Dawley rats. After intravenous administration to healthy animals, the drug's plasma half-life (t 1/2) for males and females was 0.26 and 0.3 hours in mice and 19.4 and 14.5 hours in rats, respectively. After intrarectal administration, drug was detected at very low levels in only four samples of mouse plasma, with no correlation to colon epithelial integrity. No drug was detected in rat plasma. A single intrarectal dose of 0.1 µM (0.6 µg/mouse) EPICERTIN significantly facilitated the healing of damaged colonic epithelium as determined by disease activity index and histopathological scoring, whereas 10-fold higher or lower concentrations showed no effect. For acute toxicity evaluation, healthy rats were given a single intrarectal administration of various doses of EPICERTIN with sacrifice on Day 8, recording body weight, morbidity, mortality, clinical pathology, and gross necropsy observations. There were no drug-related effects of toxicological significance. The no observed adverse effect level (intrarectal) in rats was determined to be 5 µM (307 µg/animal, or 5.2 µg drug/cm2 of colorectal surface area), which is 14 times the anticipated intrarectally delivered clinical dose. SIGNIFICANCE STATEMENT: EPICERTIN is a candidate wound-healing biologic for the management of ulcerative colitis. This study determined for the first time the intravenous and intrarectal pharmacokinetics and bioavailability of the drug in healthy and colitic mice and healthy rats, and its acute safety in a dose-escalation study in rats. An initial therapeutic dose in colitic mice was also established. EPICERTIN delivered intrarectally was minimally absorbed systemically, was well tolerated, and induced epithelial wound healing topically at a low dose.

Short-term clinical outcomes of onasemnogene abeparvovec treatment for spinal muscular atrophy.

INTRODUCTION: Spinal muscular atrophy (SMA) is a degenerative neuromuscular disorder long recognized as the most common genetic cause of infantile mortality described so far. However, the emergence of some innovative therapies, such as nusinersen and onasemnogene abeparvovec (AVXS-101), have made it possible to change the disease course of SMA. METHODS: In this study, five SMA type 1 and one SMA type 2 patients who received AVXS-101 were enrolled (7-24 months of age when administered). They were all previously treated with nusinersen, 4-5 times including loading doses, but stopped nusinersen maintenance after injection of AVXS-101. Patients were regularly followed up with laboratory tests and functional assessments after administration. RESULTS: Liver enzymes (aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase) and monocyte count tended to be elevated but normalized after several weeks. Platelets and white blood cells were transiently decreased for a few weeks after injection. Prolonged elevation of liver enzymes was associated with steroid tapering earlier than 1 month post treatment. During the follow-up period (ranging from 5 to 17 months after injection), all patients showed improved motor function and there was no case of mortality or requirement for permanent ventilatory support. For one patient, use of bilevel positive airway pressure could be reduced from 16 h to 8 h a day during sleep at 6 months post treatment. CONCLUSION: Our experience of AVXS-101 treatment has shown that a single intravenous dose could be safe and effective for SMA patients without the need for any maintenance treatment.

Clinical translation of advanced colonic drug delivery technologies.

Targeted drug delivery to the colon offers a myriad of benefits, including treatment of local diseases, direct access to unique therapeutic targets and the potential for increasing systemic drug bioavailability and efficacy. Although a range of traditional colonic delivery technologies are available, these systems exhibit inconsistent drug release due to physiological variability between and within individuals, which may be further exacerbated by underlying disease states. In recent years, significant translational and commercial advances have been made with the introduction of new technologies that incorporate independent multi-stimuli release mechanisms (pH and/or microbiota-dependent release). Harnessing these advanced technologies offers new possibilities for drug delivery via the colon, including the delivery of biopharmaceuticals, vaccines, nutrients, and microbiome therapeutics for the treatment of both local and systemic diseases. This review details the latest advances in colonic drug delivery, with an emphasis on emerging therapeutic opportunities and clinical technology translation.

Toward the next-generation phyto-nanomedicines: cell-derived nanovesicles (CDNs) for natural product delivery.

Phytochemicals are plant-derived bioactive compounds, which have been widely used for therapeutic purposes. Due to the poor water-solubility, low bioavailability and non-specific targeting characteristic, diverse classes of nanocarriers are utilized for encapsulation and delivery of bio-effective agents. Cell-derived nanovesicles (CDNs), known for exosomes or extracellular vesicles (EVs), are biological nanoparticles with multiple functions. Compared to the artificial counterpart, CDNs hold great potential in drug delivery given the higher stability, superior biocompatibility and the lager capability of encapsulating bioactive molecules. Here, we provide a bench-to-bedside review of CDNs-based nanoplatform, including the bio-origin, preparation, characterization and functionalization. Beyond that, the focus is laid on the therapeutic effect of CDNs-mediated drug delivery for natural products. The state-of-art development as well as some pre-clinical applications of using CDNs for disease treatment is also summarized. It is highly expected that the continuing development of CDNs-based delivery systems will further promote the clinical utilization and translation of phyto-nanomedicines.

The natural product berberine synergizes with osimertinib preferentially against MET-amplified osimertinib-resistant lung cancer via direct MET inhibition.

Berberine is a natural product that has long been used in traditional Chinese medicine due to its antimicrobial, anti-inflammatory and metabolism-regulatory properties. Osimertinib is the first third-generation EGFR-tyrosine kinase inhibitor (TKI) approved for the treatment of non-small cell lung cancer (NSCLC) with activating EGFR mutations and those resistant to earlier generation EGFR-TKIs due to a T790M mutation. However, emergence of acquired resistance to osimertinib limits its long-term efficacy in the clinic. One known mechanism of acquired resistance to osimertinib and other EGFR-TKIs is MET (c-MET) gene amplification. Here, we report that berberine, when combined with osimertinib, synergistically and selectively decreased the survival of several MET-amplified osimertinib-resistant EGFR mutant NSCLC cell lines with enhanced induction of apoptosis likely through Bim elevation and Mcl-1 reduction. Importantly, this combination effectively enhanced suppressive effect on the growth of MET-amplified osimertinib-resistant xenografts in nude mice and was well tolerated. Molecular modeling showed that berberine was able to bind to the kinase domain of non-phosphorylated MET, occupy the front of the binding pocket, and interact with the activation loop, in a similar way as other known MET inhibitors do. MET kinase assay showed clear concentration-dependent inhibitory effects of berberine against MET activity, confirming its kinase inhibitory activity. These findings collectively suggest that berberine can act as a naturally-existing MET inhibitor to synergize with osimertinib in overcoming osimertinib acquired resistance caused by MET amplification.

Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial.

Importance: The benefits of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome are uncertain. Objective: To examine the effect of selective application of MIST at a low fraction of inspired oxygen threshold on survival without bronchopulmonary dysplasia (BPD). Design, Setting, and Participants: Randomized clinical trial including 485 preterm infants with a gestational age of 25 to 28 weeks who were supported with continuous positive airway pressure (CPAP) and required a fraction of inspired oxygen of 0.30 or greater within 6 hours of birth. The trial was conducted at 33 tertiary-level neonatal intensive care units around the world, with blinding of the clinicians and outcome assessors. Enrollment took place between December 16, 2011, and March 26, 2020; follow-up was completed on December 2, 2020. Interventions: Infants were randomized to the MIST group (n = 241) and received exogenous surfactant (200 mg/kg of poractant alfa) via a thin catheter or to the control group (n = 244) and received a sham (control) treatment; CPAP was continued thereafter in both groups unless specified intubation criteria were met. Main Outcomes and Measures: The primary outcome was the composite of death or physiological BPD assessed at 36 weeks' postmenstrual age. The components of the primary outcome (death prior to 36 weeks' postmenstrual age and BPD at 36 weeks' postmenstrual age) also were considered separately. Results: Among the 485 infants randomized (median gestational age, 27.3 weeks; 241 [49.7%] female), all completed follow-up. Death or BPD occurred in 105 infants (43.6%) in the MIST group and 121 (49.6%) in the control group (risk difference [RD], -6.3% [95% CI, -14.2% to 1.6%]; relative risk [RR], 0.87 [95% CI, 0.74 to 1.03]; P = .10). Incidence of death before 36 weeks' postmenstrual age did not differ significantly between groups (24 [10.0%] in MIST vs 19 [7.8%] in control; RD, 2.1% [95% CI, -3.6% to 7.8%]; RR, 1.27 [95% CI, 0.63 to 2.57]; P = .51), but incidence of BPD in survivors to 36 weeks' postmenstrual age was lower in the MIST group (81/217 [37.3%] vs 102/225 [45.3%] in the control group; RD, -7.8% [95% CI, -14.9% to -0.7%]; RR, 0.83 [95% CI, 0.70 to 0.98]; P = .03). Serious adverse events occurred in 10.3% of infants in the MIST group and 11.1% in the control group. Conclusions and Relevance: Among preterm infants with respiratory distress syndrome supported with CPAP, minimally invasive surfactant therapy compared with sham (control) treatment did not significantly reduce the incidence of the composite outcome of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age. However, given the statistical uncertainty reflected in the 95% CI, a clinically important effect cannot be excluded. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Natural and Synthetic Bioactives for Skin Health, Disease and Management.

The skin is the largest organ of the integumentary system, strategically located at the interface of the body's internal and external environment. [...].