A multi-centre, randomized, controlled trial on coaching and telemonitoring in patients with cystic fibrosis: conneCT CF.

BACKGROUND: The extend of lung disease remains the most important prognostic factor for survival in patients with cystic fibrosis (CF), and lack of adherence is the main reason for treatment failure. Early detection of deterioration in lung function and optimising adherence are therefore crucial in CF care. We implement a randomized controlled trial to evaluate efficacy of telemonitoring of adherence, lung function, and health condition in combination with behavior change interventions using innovative digital technologies. METHODS: This is a multi-centre, randomized, controlled, non-blinded trial aiming to include 402 patients ≥ 12 years-of-age with CF. A standard-of-care arm is compared to an arm receiving objective, continuous monitoring of adherence to inhalation therapies, weekly home spirometry using electronic devices with data transmission to patients and caring physicians combined with video-conferencing, a self-management app and professional telephone coaching. The duration of the intervention phase is 18 months. The primary endpoint is time to the first protocol-defined pulmonary exacerbation. Secondary outcome measures include number of and time between pulmonary exacerbations, adherence to inhalation therapy, changes in forced expiratory volume in 1 s from baseline, number of hospital admissions, and changes in health-related quality of life. CF-associated medical treatment and care, and health care related costs will be assessed by explorative analysis in both arms. DISCUSSION: This study offers the opportunity to evaluate the effect of adherence interventions using telemedicine capable devices on adherence and lung health, possibly paving the way for implementation of telemedicine in routine care for patients with CF. TRIAL REGISTRATION: This study has been registered with the German Clinical Trials Register (Identifier: DRKS00024642, date of registration 01 Mar 2021, URL: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00024642 ).

Safety and pharmacokinetics of the orally available antiprionic compound PRI-002: A single and multiple ascending dose phase I study.

INTRODUCTION: PRI-002 is an orally available anti-amyloid beta (Aß) prionic compound developed for direct disassembly of toxic Aß oligomers relevant to Alzheimer's disease. METHODS: Two placebo-controlled clinical phase I trials with oral dosing of PRI-002 were conducted in healthy young subjects: A single ascending dose trial (4, 12, 36, 108, or 320 mg PRI-002 or placebo) in 40 participants followed by a multiple ascending dose study with daily 160 mg PRI-002 for 14 days or 320 mg for 28 days in 24 participants. The main objectives were safety, tolerability, and evaluation of pharmacokinetic (PK) parameters. RESULTS: PRI-002 was safe and well tolerated after single and multiple oral administration up to the highest doses. PRI-002 was absorbed rapidly and drug exposure increased proportional to dose. During repeated daily administration, the drug accumulated by a factor of about three. Steady-state conditions were reached after 1 to 2 weeks. CONCLUSIONS: The safety and PK results encourage further clinical development of PRI-002.

NLC versus nanoemulsions: Effect on physiological skin parameters during regular in vivo application and impact on drug penetration.

Nanostructured lipid carriers (NLC) and nano-sized emulsions based on monoacyl-phosphatidylcholine (MAPL) were tested for their effect on physiological skin parameters in vivo during daily application over four weeks. The influence of the basic formulations on transepidermal water loss (TEWL), skin hydration, sebum content and pH was determined once per week and after a recovery period of three weeks. In addition, confocal Raman spectroscopy was employed to evaluate natural moisturising factor and urea content. The results showed that the tested NLC systems with different MAPL content led to increased TEWL and decreased stratum corneum hydration, NMF and urea content. This effect was more pronounced for NLC with higher MAPL content and less pronounced for corresponding emulsions with increased oil phase volume. The observed effects indicate temporarily impaired barrier function; however, all effects were reversible after the treatment was finished. Additional tape stripping penetration experiments were performed on intact human forearm skin in vivo using the model substance curcumin. Higher total penetrated curcumin amounts were found for NLC-based formulations when compared to the emulsion. Comparative in vitro tape stripping data on porcine ear skin confirmed the trends observed in vivo. In summary, these findings suggest that the effect of the developed MAPL-based NLC and nano-sized emulsion on skin barrier function differs mildly in a one-time application setup, but may increase strongly during daily application over a longer treatment period.

Safety and tolerability of topically administered autologous, apoptotic PBMC secretome (APOSEC) in dermal wounds: a randomized Phase 1 trial (MARSYAS I).

Developing effective therapies against chronic wound healing deficiencies is a global priority. Thus we evaluated the safety of two different doses of topically administered autologous APOSEC, the secretome of apoptotic peripheral blood mononuclear cells (PBMCs), in healthy male volunteers with artificial dermal wounds. Ten healthy men were enrolled in a single-center, randomized, double-blinded, placebo-controlled phase 1 trial. Two artificial wounds at the upper arm were generated using a 4-mm punch biopsy. Each participant was treated with both topically applied APOSEC and placebo in NuGel for 7 consecutive days. The volunteers were randomized into two groups: a low-dose group (A) receiving the supernatant of 12.5 × 106 PBMCs and a high-dose group (B) receiving an equivalent of 25 × 106 PBMCs resuspended in NuGel Hydrogel. Irradiated medium served as placebo. The primary outcome was the tolerability of the topical application of APOSEC. All adverse events were recorded until 17 days after the biopsy. Local tolerability assessment was measured on a 4-point scale. Secondary outcomes were wound closure and epithelization at day 7. No therapy-related serious adverse events occurred in any of the participants, and both low- and high-dose treatments were well tolerated. Wound closure was not affected by APOSEC therapy.

Effect of sexual diary keeping and self-evaluation on female sexual function and depression: A pilot study.

OBJECTIVES: The aim of the trial was to assess the effect of self-evaluation and sexual diary keeping on female sexual function and depressive symptoms in women diagnosed with sexual dysfunction. METHODS: A single-arm non-randomised trial included 30 women (53 ± 7 years of age) with female sexual dysfunction (Female Sexual Function Index [FSFI] < 27) and a stable partnership duration of 5-40 years. Female sexual function was assessed by sexual, psychological and gynaecological history taking and validated questionnaires including the FSFI, Female Sexual Distress Scale (FSDS) and Hamilton Depression Scale (HDS), before and after 4 weeks of sexual diary keeping. RESULTS: A subjective improvement in communication of sexual problems was reported by 60% of participants; no participants reported any worsening of communication. FSFI and FSDS scores were, respectively, 18.0 ± 7.7 and 22.0 ± 10.0 at baseline and 20.2 ± 7.2 and 20.6 ± 11.5 after 4 weeks. HDS score decreased from 6.0 ± 4.0 at baseline to 4.4 ± 2.7 after 4 weeks (p = 0.042). CONCLUSIONS: Self-evaluation and sexual diary keeping may improve aspects of sexual life, such as couple communication, without a direct effect on variables measured with validated questionnaires on different domains of sexual function.

Nebulization of Poractant alfa via a vibrating membrane nebulizer in spontaneously breathing preterm lambs with binasal continuous positive pressure ventilation.

BACKGROUND: Surfactant replacement therapy is the gold standard treatment of neonatal respiratory distress (RDS). Nebulization is a noninvasive mode of surfactant administration. We administered Poractant alfa (Curosurf) via a vibrating perforated membrane nebulizer (eFlow Neonatal Nebulizer) to spontaneously breathing preterm lambs during binasal continuous positive pressure ventilation (CPAP). METHODS: Sixteen preterm lambs were operatively delivered at a gestational age of 133 ± 1 d (term ~150 d), and connected to CPAP applied via customized nasal prongs. Nebulization was performed (i) with saline or (ii) with surfactant for 3 h in humidified or (iii) nonhumidified air, and with surfactant (iv) for 60 min or (v) for 30 min. We measured arterial oxygenation, lung gas volumes and surfactant pool size and deposition. RESULTS: Nebulization of surfactant in humidified air for 3 h improved oxygenation and lung function, and surfactant was preferentially distributed to the lower lung lobes. Shorter nebulization times and 3 h nebulization in dry air did not show these effects. Nebulized surfactant reached all lung lobes, however the increase of surfactant pool size missed statistical significance. CONCLUSION: Positive effects of surfactant nebulization to spontaneously breathing preterm lambs depend on treatment duration, surfactant dose, air humidity, and surfactant distribution within the lung.

Effect of long-term intranasal oxytocin on sexual dysfunction in premenopausal and postmenopausal women: a randomized trial.

OBJECTIVE: To assess the effect of on-demand intranasal oxytocin administration on female sexual function and activity. DESIGN: Randomized, prospective, double-blind, placebo-controlled, crossover trial with duration of 22 weeks. SETTING: Academic medical center. PATIENT(S): Thirty pre-and postmenopausal women with sexual dysfunction. INTERVENTION(S): Over 8 weeks, intranasal oxytocin (32 IU) or placebo self-administered by women within 50 minutes before sexual intercourse; after a washout period of 2 weeks, crossover with patients switched to the alternate group for another 8 weeks. MAIN OUTCOME MEASURE(S): Primary outcome parameter: Female Sexual Function Index (FSFI); secondary outcome parameters: Female Sexual Distress Scale (FSDS), Sexual Quality of Life-Female (SQOL-F), Sexual Interest and Desire Inventory-Female (SIDI-F), and Hamilton depression scale (HDS). RESULT(S): After oxytocin and placebo, the FSFI score increased by 26% and 31%, SQOL-F score by 144% and 125%, and SIDI-F score by 29% and 23%, respectively (repeated measures analysis of variance between groups). After oxytocin and placebo, the FSDS score decreased by 36% and 45%, respectively (repeated measures analysis of variance between groups). There was no statistically significant treatment, sequence (placebo first/second), or interaction effect. CONCLUSION(S): Long-term intranasal oxytocin and placebo administration both improved sexual function and symptoms of depression in women over time with no treatment, sequence (placebo first/second), or interaction effect. CLINICAL TRIAL REGISTRATION NUMBER: NCT02229721.

Inhalation treatment with glutathione in patients with cystic fibrosis. A randomized clinical trial.

RATIONALE: Glutathione is the major antioxidant in the extracellular lining fluid of the lungs and depleted in patients with cystic fibrosis (CF). OBJECTIVES: We aimed to assess glutathione delivered by inhalation as a potential treatment for CF lung disease. METHODS: This randomized, double-blind, placebo-controlled trial evaluated inhaled glutathione in subjects with CF 8 years of age and older and FEV1 of 40-90% of predicted. Subjects were randomized to receive 646 mg glutathione in 4 ml (n = 73) or placebo (n = 80) via an investigational eFlow nebulizer every 12 hours for 6 months. MEASUREMENTS AND MAIN RESULTS: FEV1 (absolute values), both as pre-post differences (P = 0.180) and as area under the curves (P = 0.205), were the primary efficacy endpoints, and were not different between the glutathione group and the placebo group over the 6-month treatment period. Exploratory analysis showed an increase of FEV1 from baseline over placebo of 100 ml or 2.2% predicted; this was significant at 3 months, but not later. Subjects receiving glutathione had neither fewer pulmonary exacerbations, nor better scores for quality of life. Whereas increased glutathione and metabolites in sputum demonstrated significant delivery to the lungs, there was no indication of diminished oxidative stress to proteins or lipids, and no evidence for anti-inflammatory or antiproteolytic actions of glutathione supplemented to the airways. The adverse event incidence was similar between glutathione and placebo. CONCLUSIONS: Inhaled glutathione in the dose administered did not demonstrate clinically relevant improvements in lung function, pulmonary exacerbation frequency, or patient-reported outcomes. Glutathione delivery to the airways was not associated with changes in markers of oxidation, proteolysis, or inflammation. Clinical trial registered with www.clinicaltrials.gov (NCT00506688) and https://eudract.ema.europa.eu/index.html (EudraCT 2005-003870-88).

Neurocognitive outcome in pediatric liver transplant recipients.

Studies have shown that children with liver transplants demonstrate deficits on intellectual, academic, and language measures. However, limited information is known about the long-term cognitive development of these children. In this study, 15 children who were at least 2 yr post-liver transplantation (LT) were compared on cognitive measures to an equated group of 15 children with cystic fibrosis (CF). Children with CF were selected as a clinical control given similarities in disease onset and chronicity, as well as physical growth and development. Results indicated that children with LT tended to have lower verbal intelligence quotient scores and performed significantly lower than CF children on language measures, particularly on receptive language tasks. No significant differences were obtained on measures of academic achievement or visual-spatial performance. In the LT group, days in the intensive care unit, total number of days spent in the hospital during the first year following the transplant, and elevated pretransplant bilirubin levels significantly predicted the speech and language delays.