Development of PEGylated PLGA nanoparticle for controlled and sustained drug delivery in cystic fibrosis

<p>Abstract</p> <p>Background</p> <p>The mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene results in CF. The most common mutation, ΔF508-CFTR, is a temperature-sensitive, trafficking mutant with reduced chloride transport and exaggerated immune response. The ΔF508-CFTR is misfolded, ubiquitinated, and prematurely degraded by proteasome mediated- degradation. We recently demonstrated that selective inhibition of proteasomal pathway by the FDA approved drug PS-341 (pyrazylcarbonyl-Phe-Leuboronate, a.k.a. Velcade or bortezomib) ameliorates the inflammatory pathophysiology of CF cells. This proteasomal drug is an extremely potent, stable, reversible and selective inhibitor of chymotryptic threonine protease-activity. The apprehension in considering the proteasome as a therapeutic target is that proteasome inhibitors may affect proteostasis and consecutive processes. The affect on multiple processes can be mitigated by nanoparticle mediated PS-341 lung-delivery resulting in favorable outcome observed in this study.</p> <p>Results</p> <p>To overcome this challenge, we developed a nano-based approach that uses drug loaded biodegradable nanoparticle (PLGA-PEG^PS-341) to provide controlled and sustained drug delivery. The <it>in vitro </it>release kinetics of drug from nanoparticle was quantified by proteasomal activity assay from days 1-7 that showed slow drug release from day 2-7 with maximum inhibition at day 7. For <it>in vivo </it>release kinetics and biodistribution, these drug-loaded nanoparticles were fluorescently labeled, and administered to C57BL6 mice by intranasal route. Whole-body optical imaging of the treated live animals demonstrates efficient delivery of particles to murine lungs, 24 hrs post treatment, followed by biodegradation and release over time, day 1-11. The efficacy of drug release in CF mice (<it>Cftr^-/-</it>) lungs was determined by quantifying the changes in proteasomal activity (~2 fold decrease) and ability to rescue the <it>Pseudomonas aeruginosa </it>LPS (<it>Pa</it>-LPS) induced inflammation, which demonstrates the rescue of CF lung disease in murine model.</p> <p>Conclusion</p> <p>We have developed a novel drug delivery system to provide sustained delivery of CF "correctors" and "anti-inflammatories" to the lungs. Moreover, we demonstrate here the therapeutic efficacy of nano-based proteostasis-modulator to rescue <it>Pa-LPS </it>induced CF lung disease.</p

Utilizing energy transfer in binary and ternary bulk heterojunction organic solar cells

Energy transfer has been identified as an important process in ternary organic solar cells. Here, we develop kinetic Monte Carlo (KMC) models to assess the impact of energy transfer in ternary and binary bulk heterojunction systems. We used fluorescence and absorption spectroscopy to determine the energy disorder and Förster radii for poly(3-hexylthiophene-2,5-diyl), [6,6]-phenyl-C61-butyric acid methyl ester, 4-bis[4-(N,N-diisobutylamino)-2,6-dihydroxyphenyl]squaraine (DIBSq), and poly(2,5-thiophene-<i>alt</i>-4,9-bis(2-hexyldecyl)-4,9-dihydrodithieno[3,2-c:3′,2′-<i>h</i>][1,5]naphthyridine-5,10-dione). Heterogeneous energy transfer is found to be crucial in the exciton dissociation process of both binary and ternary organic semiconductor systems. Circumstances favoring energy transfer across interfaces allow relaxation of the electronic energy level requirements, meaning that a cascade structure is not required for efficient ternary organic solar cells. We explain how energy transfer can be exploited to eliminate additional energy losses in ternary bulk heterojunction solar cells, thus increasing their open-circuit voltage without loss in short-circuit current. In particular, we show that it is important that the DIBSq is located at the electron donor–acceptor interface; otherwise charge carriers will be trapped in the DIBSq domain or excitons in the DIBSq domains will not be able to dissociate efficiently at an interface. KMC modeling shows that only small amounts of DIBSq (<5% by weight) are needed to achieve substantial performance improvements due to long-range energy transfer

Living on a flammable planet: interdisciplinary, cross-scalar and varied cultural lessons, prospects and challenges: Table 1.

Living with fire is a challenge for human communities because they are influenced by socio-economic, political, ecological and climatic processes at various spatial and temporal scales. Over the course of 2 days, the authors discussed how communities could live with fire challenges at local, national and transnational scales. Exploiting our diverse, international and interdisciplinary expertise, we outline generalizable properties of fire-adaptive communities in varied settings where cultural knowledge of fire is rich and diverse. At the national scale, we discussed policy and management challenges for countries that have diminishing fire knowledge, but for whom global climate change will bring new fire problems. Finally, we assessed major fire challenges that transcend national political boundaries, including the health burden of smoke plumes and the climate consequences of wildfires. It is clear that to best address the broad range of fire problems, a holistic wildfire scholarship must develop common agreement in working terms and build across disciplines. We must also communicate our understanding of fire and its importance to the media, politicians and the general public. This article is part of the themed issue ‘The interaction of fire and mankind’

The effects of implementing a point-of-care electronic template to prompt routine anxiety and depression screening in patients consulting for osteoarthritis (the Primary Care Osteoarthritis Trial): A cluster randomised trial in primary care

Background This study aimed to evaluate whether prompting general practitioners (GPs) to routinely assess and manage anxiety and depression in patients consulting with osteoarthritis (OA) improves pain outcomes. Methods and findings We conducted a cluster randomised controlled trial involving 45 English general practices. In intervention practices, patients aged ≥45 y consulting with OA received point-of-care anxiety and depression screening by the GP, prompted by an automated electronic template comprising five questions (a two-item Patient Health Questionnaire–2 for depression, a two-item Generalized Anxiety Disorder–2 questionnaire for anxiety, and a question about current pain intensity [0–10 numerical rating scale]). The template signposted GPs to follow National Institute for Health and Care Excellence clinical guidelines for anxiety, depression, and OA and was supported by a brief training package. The template in control practices prompted GPs to ask the pain intensity question only. The primary outcome was patient-reported current pain intensity post-consultation and at 3-, 6-, and 12-mo follow-up. Secondary outcomes included pain-related disability, anxiety, depression, and general health. During the trial period, 7,279 patients aged ≥45 y consulted with a relevant OA-related code, and 4,240 patients were deemed potentially eligible by participating GPs. Templates were completed for 2,042 patients (1,339 [31.6%] in the control arm and 703 [23.1%] in the intervention arm). Of these 2,042 patients, 1,412 returned questionnaires (501 [71.3%] from 20 intervention practices, 911 [68.0%] from 24 control practices). Follow-up rates were similar in both arms, totalling 1,093 (77.4%) at 3 mo, 1,064 (75.4%) at 6 mo, and 1,017 (72.0%) at 12 mo. For the primary endpoint, multilevel modelling yielded significantly higher average pain intensity across follow-up to 12 mo in the intervention group than the control group (adjusted mean difference 0.31; 95% CI 0.04, 0.59). Secondary outcomes were consistent with the primary outcome measure in reflecting better outcomes as a whole for the control group than the intervention group. Anxiety and depression scores did not reduce following the intervention. The main limitations of this study are two potential sources of bias: an imbalance in cluster size (mean practice size 7,397 [intervention] versus 5,850 [control]) and a difference in the proportion of patients for whom the GP deactivated the template (33.6% [intervention] versus 27.8% [control]). Conclusions In this study, we observed no beneficial effect on pain outcomes of prompting GPs to routinely screen for and manage comorbid anxiety and depression in patients presenting with symptoms due to OA, with those in the intervention group reporting statistically significantly higher average pain scores over the four follow-up time points than those in the control group. Trial registration ISRCTN registry ISRCTN4072198

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Man with Penile Pain

Case Presentation: We describe a case of spontaneous partial segmental thrombosis of the corpus cavernosum (PSTCC).Discussion: PSTCC is a rare condition in which thrombus formation occurs in the corpus cavernosum. This condition is managed in conjunction with a urologist, and management typically includes anticoagulation and pain control

Man with Penile Pain

Case Presentation: We describe a case of spontaneous partial segmental thrombosis of the corpus cavernosum (PSTCC).Discussion: PSTCC is a rare condition in which thrombus formation occurs in the corpus cavernosum. This condition is managed in conjunction with a urologist, and management typically includes anticoagulation and pain control