Recent Advances in Drug Repurposing for Parkinson's Disease.

Curr Med Chem. 2018 Jul 19;:

Authors: Chen X, Gumina G, Virga KG

Abstract
As a long-term degenerative disorder of the central nervous system that mostly affects older people, Parkinson's disease is a growing health threat to our ever-aging population. Despite remarkable advances in our understanding of this disease, all therapeutics currently available only act to improve symptoms but cannot stop the disease progress. Therefore, it is essential that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson's disease. Drug repurposing, also known as drug repositioning, or the process of finding new uses for existing or abandoned pharmaceuticals, has been recognized as a cost-effective and time-efficient way to develop new drugs, being equally promising as de novo drug discovery in the field of neurodegeneration and, more specifically for Parkinson's disease. The availability of several established libraries of clinical drugs and fast evolvement in disease biology, genomics and bioinformatics has stimulated the momentums of both in silico and activity-based drug repurposing. With the successful clinical introduction of several repurposed drugs for Parkinson's disease, drug repurposing has now become a robust alternative approach to the discovery and development of novel drugs for this disease. In this review, recent advances in drug repurposing for Parkinson's disease will be discussed.

PMID: 30027839 [PubMed - as supplied by publisher]

Health-related quality of life among adults with diverse rare disorders.

Orphanet J Rare Dis. 2017 12 07;12(1):177

Authors: Bogart KR, Irvin VL

Abstract
BACKGROUND: Twenty-five to 30 million Americans live with a rare disease (RD) and share challenges unique to RD. The majority of research on RDs has focused on etiology, treatment and care, while the limited health-related quality of life (HRQL) research has been restricted to single RDs, small samples, or non-validated measures. This study reports HRQL among adults with diverse RDs, and compares their scores to those of the U.S. population and people with common chronic health conditions.
METHODS: We conducted a cross-sectional survey of adults living in the U.S. diagnosed with any RD. Participants were recruited through RD organizations and completed the online survey between December 2016 and May 2017 (n = 1218). HRQL was assessed using the standardized Patient-Reported Outcomes Measurement Information System (PROMIS). RDs were classified into categories defined by Orphanet. Means and 95% confidence intervals were calculated for the main sample and for RD categories and were compared to published U.S. population norms and common chronic disease norms. Intercorrelations were conducted between HRQL, demographics, and RD experiences.
RESULTS: When compared to the norms for the U.S. population and for those with common chronic diseases, mean HRQL scores were significantly poorer across all six PROMIS domains for the main sample, and were usually poorer when analyzed by sub-sets of specific RD classifications. People with rare systemic and rheumatologic, neurological, and immune diseases had the poorest HRQL. Participants had poorer HRQL if they had multiple RDs, lower income, were female, or older. Having symptoms longer was associated with worse HRQL, however, having a formal diagnosis longer was associated with better HRQL.
CONCLUSIONS: This study is the first to examine HRQL in a large, heterogeneous sample of RDs using validated measures. There is a significant disparity in HRQL among people with RD compared to the general population and people with common chronic diseases. Poor HRQL could be attributed to challenges accessing diagnoses, medical information, treatment, psychosocial support, and coping with stigma and uncertainty. As most individuals with RDs will not be cured in their lifetimes, identifying ways to improve HRQL is crucial to patient-centered care and should be a funding priority.

PMID: 29212508 [PubMed - indexed for MEDLINE]

Measuring what matters to rare disease patients - reflections on the work by the IRDiRC taskforce on patient-centered outcome measures.

Orphanet J Rare Dis. 2017 11 02;12(1):171

Authors: Morel T, Cano SJ

Abstract
Our ability to evaluate outcomes which genuinely reflect patients' unmet needs, hopes and concerns is of pivotal importance. However, much current clinical research and practice falls short of this objective by selecting outcome measures which do not capture patient value to the fullest. In this Opinion, we discuss Patient-Centered Outcomes Measures (PCOMs), which have the potential to systematically incorporate patient perspectives to measure those outcomes that matter most to patients. We argue for greater multi-stakeholder collaboration to develop PCOMs, with rare disease patients and families at the center. Beyond advancing the science of patient input, PCOMs are powerful tools to translate care or observed treatment benefit into an 'interpretable' measure of patient benefit, and thereby help demonstrate clinical effectiveness. We propose mixed methods psychometric research as the best route to deliver fit-for-purpose PCOMs in rare diseases, as this methodology brings together qualitative and quantitative research methods in tandem with the explicit aim to efficiently utilise data from small samples. And, whether one opts to develop a brand-new PCOM or to select or adapt an existing outcome measure for use in a rare disease, the anchors remain the same: patients, their daily experience of the rare disease, their preferences, core concepts and values. Ultimately, existing value frameworks, registries, and outcomes-based contracts largely fall short of consistently measuring the full range of outcomes that matter to patients. We argue that greater use of PCOMs in rare diseases would enable a fast track to Patient-Centered Care.

PMID: 29096663 [PubMed - indexed for MEDLINE]

Touraine-Solente-Gole syndrome.

Orbit. 2018 Apr;37(2):97-101

Authors: Doshi D

Abstract
Touraine-Solente-Gole syndrome, also known as Pachydermoperiostosis (PDP) or Primary Hypertrophic Osteoarthropathy, is a rare hereditary disorder, which affects both bones and skin. It is characterized by a combination of dermatologic changes (pachydermia or thickening of the skin) and rheumatologic manifestations (periostosis and finger clubbing). Eyelid ptosis which is caused by thickened eyelids (blepharoptosis) is a less common symptom. We report the case of a patient with a complete form of Touraine-Solente-Gole syndrome with bilateral blepharoptosis as presenting feature.

PMID: 29040027 [PubMed - indexed for MEDLINE]

Orbital T-cell lymphoma versus lupus panniculitits: a T-cell-mediated spectrum of orbital lymphoproliferative disease.

Orbit. 2018 Apr;37(2):102-104

Authors: Huggins AB, Kim C, Rabinowitz MP

Abstract
This is a case description of a single male patient found to have T-cell-mediated inflammation and lymphoproliferation of the orbit. Chronic T-cell-mediated inflammatory disease can pose a diagnostic challenge particularly in its differentiation from a neoplastic process. The histopathology in this case demonstrated features of both lupus erythematosus panniculitis and features of orbital T-cell lymphoma. While both are rare, lupus erythematosus panniculitis of the orbit is even more exceptional; this patient's indolent, chronic relapsing course distinguished itself from the typical aggression of orbital T-cell lymphoma. We believe this rare case may actually represent an example of a newly described disease spectrum that incorporates lupus erythematosus panniculitis as well as subcutaneous panniculitis-like T-cell lymphoma.

PMID: 29039997 [PubMed - indexed for MEDLINE]

KH176 under development for rare mitochondrial disease: a first in man randomized controlled clinical trial in healthy male volunteers.

Orphanet J Rare Dis. 2017 10 16;12(1):163

Authors: Koene S, Spaans E, Van Bortel L, Van Lancker G, Delafontaine B, Badilini F, Beyrath J, Smeitink J

Abstract
BACKGROUND: Mitochondrial disorders are a clinically, biochemically and genetically heterogeneous group of multi-system diseases, with an unmet medical need for treatment. KH176 is an orally bio-available small molecule under development for the treatment of mitochondrial(-related) diseases. The compound is a member of a new class of drugs, acting as a potent intracellular redox-modulating agent essential for the control of oxidative and redox pathologies. The aim of this randomized, placebo controlled, double-blinded phase 1 study was to test safety, tolerability and pharmacokinetics of single and multiple doses of KH176 in healthy male volunteers. Putative effects on redox related biomarkers were explored.
RESULTS: KH176 was well tolerated up to and including a single dose of 800 mg and multiple doses of 400 mg b.i.d. for 7 Days. However, when the QT interval was corrected for heart rate, administration of single doses of 800 and 2000 mg and at a multiple dose of 400 mg KH176 had marked effects. Post-hoc analysis of the ECGs showed clear changes in cardiac electrophysiology at single doses of 800 and 2000 mg and multiple doses of 400 mg b.i.d.. At lower doses, detailed ECG analysis showed no changes in electrophysiology compared to placebo. Exposure-response modelling of the cardiac intervals revealed an exposure range of KH176 without effects on cardiac conduction and provided a threshold of 1000 ng/mL above which changes in intervals could occur. After single- and multiple-dose administration, the pharmacokinetics of KH176 was more than dose proportional. KH176 accumulated to a small extent and food only slightly affected the pharmacokinetics of KH176, which was considered clinically irrelevant. Renal excretion of unchanged KH176 and its metabolite represents a minor pathway in the elimination of KH176. As expected in healthy volunteers no effects on redox biomarkers were observed.
CONCLUSION: The study deemed that KH176 is well tolerated up to single doses of 800 mg and multiple doses of 400 mg b.i.d. and has a pharmacokinetic profile supportive for a twice daily dosing. Only at high doses, KH176 causes clinically relevant changes in cardiac electrophysiology, including prolonged QTc interval and changes in T wave morphology. A Phase 2 clinical trial (100 mg b.i.d., orally) has been conducted recently of which the final results are expected Q1 2018.
TRIAL REGISTRATION: NCT02544217 . Registered. ISRCTN43372293 . Retrospectively registered.

PMID: 29037240 [PubMed - indexed for MEDLINE]

User Centered Neuro-Fuzzy Energy Management Through Semantic-Based Optimization.

IEEE Trans Cybern. 2018 Jul 17;:

Authors: Howell SK, Wicaksono H, Yuce B, McGlinn K, Rezgui Y

Abstract
This paper presents a cloud-based building energy management system, underpinned by semantic middleware, that integrates an enhanced sensor network with advanced analytics, accessible through an intuitive Web-based user interface. The proposed solution is described in terms of its three key layers: 1) user interface; 2) intelligence; and 3) interoperability. The system's intelligence is derived from simulation-based optimized rules, historical sensor data mining, and a fuzzy reasoner. The solution enables interoperability through a semantic knowledge base, which also contributes intelligence through reasoning and inference abilities, and which are enhanced through intelligent rules. Finally, building energy performance monitoring is delivered alongside optimized rule suggestions and a negotiation process in a 3-D Web-based interface using WebGL. The solution has been validated in a real pilot building to illustrate the strength of the approach, where it has shown over 25% energy savings. The relevance of this paper in the field is discussed, and it is argued that the proposed solution is mature enough for testing across further buildings.

PMID: 30028719 [PubMed - as supplied by publisher]

Speed-Dial: A Surrogate Mouse for Non-Visual Web Browsing.

ASSETS. 2017 Oct-Nov;2017:110-119

Authors: Billah SM, Ashok V, Porter DE, Ramakrishnan IV

Abstract
Sighted people can browse the Web almost exclusively using a mouse. This is because web browsing mostly entails pointing and clicking on some element in the web page, and these two operations can be done almost instantaneously with a computer mouse. Unfortunately, people with vision impairments cannot use a mouse as it only provides visual feedback through a cursor. Instead, they are forced to go through a slow and tedious process of building a mental map of the web page, relying primarily on a screen reader's keyboard shortcuts and its serial audio readout of the textual content of the page, including metadata. This can often cause content and cognitive overload. This paper describes our Speed-Dial system which uses an off-the-shelf physical Dial as a surrogate for the mouse for non-visual web browsing. Speed-Dial interfaces the physical Dial with the semantic model of a web page, and provides an intuitive and rapid access to the entities and their content in the model, thereby bringing blind people's browsing experience closer to how sighted people perceive and interact with the Web. A user study with blind participants suggests that with Speed-Dial they can quickly move around the web page to select content of interest, akin to pointing and clicking with a mouse.

PMID: 30027156 [PubMed]

PD-1, PD-L1 and CD163 in pancreatic undifferentiated carcinoma with osteoclast-like giant cells: expression patterns and clinical implications.

Hum Pathol. 2018 Jul 18;:

Authors: Luchini C, Cros J, Pea A, Pilati C, Veronese N, Rusev B, Capelli P, Mafficini A, Nottegar A, Brosens LAA, Noë M, Offerhaus GJA, Chianchiano P, Riva G, Piccoli P, Parolini C, Malleo G, Lawlor RT, Corbo V, Sperandio N, Barbareschi M, Fassan M, Cheng L, Wood LD, Scarpa A

Abstract
Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC), a variant of pancreatic ductal adenocarcinoma (PDAC), has striking genetic similarity to PDAC but a significantly improved overall survival. We hypothesize that this difference could be due to the immune response to the tumor, and as such, we investigated the expression of PD-1, PD-L1 and CD163 in a series of UCOGC. To this aim, 27 pancreatic UCOGCs (11 pure and 16 PDAC-associated), 5 extra-pancreatic tumors with osteoclast-like giant cells and 10 pancreatic anaplastic carcinomas (ACs) were immunostained using antibodies against PD-1, PD-L1 and CD163. In pancreatic UCOGCs, PD-L1 was expressed in neoplastic cells of 17/27 (63%) cases, more often in cases with an associated PDAC (P=.04). Expression of PD-L1 was associated with poor prognosis, confirmed by multivariate analysis: patients with PD-L1-positive UCOGCs had a risk of all-cause mortality that was 3 times higher than patients with PD-L1-negative UCOGCs (HR: 3.397, 95%CI: 1.023-18.375, P=.034). PD-L1 expression on tumor cells was also associated with aberrant P53 expression (P=.035). PD-1 was expressed on rare lymphocytes in 12 UCOGCs (44.4%), mainly located at the tumor periphery. CD163 was expressed on histiocytes, with a diffuse and strong staining pattern in all UCOGCs. Extra-pancreatic tumors with osteoclast-like giant cells showed very similar staining patterns for the same proteins. ACs have some similarities to UCOGCs, but PD-L1 has no prognostic roles. Our results may have important implications for immunotherapeutic strategies in UCOGCs; these tumors may also represent a model for future therapeutic approaches against PDAC.

PMID: 30031096 [PubMed - as supplied by publisher]

Frequency of tumour necrosis factor alpha receptor superfamily 1A multiple sclerosis-associated variants in patients with rheumatoid arthritis with anti-tumour necrosis factor therapy-related demyelinating complications.

Ann Rheum Dis. 2018 Jul 20;:

Authors: Bitoun S, Miceli-Richard C, Verstuyft C, Juge PA, Dieudé P, Berthelot JM, Richez C, Cauquil C, Sordet C, Melac-Ducamp S, Gossec L, Bouvard B, Dernis E, Houvenagel E, Boutry-Bacle MA, Mariette X, Seror R

PMID: 30030263 [PubMed - as supplied by publisher]

Clinical outcomes of CYP2C19 genotype-guided antiplatelet therapy: existing evidence and future directions.

Pharmacogenomics. 2018 Jul 20;:

Authors: Klein MD, Lee CR, Stouffer GA

Abstract
It is well established that the CYP2C19 nonfunctional *2 and *3 polymorphisms impair the bioactivation and antiplatelet effects of clopidogrel, and increase the risk of adverse cardiovascular events following percutaneous coronary intervention. In contrast, CYP2C19 genotype does not impact clinical response to prasugrel or ticagrelor. Recent studies have evaluated the impact of CYP2C19 genotype-guided selection of antiplatelet therapy on clinical outcomes and begun to close some of the gaps in knowledge and uncertainty that have impeded widespread clinical implementation of this precision medicine approach. This review will critically evaluate recent data and offer new insight into the potential clinical utility of genotype-guided antiplatelet therapy in the context of current clinical practice guidelines.

PMID: 30028231 [PubMed - as supplied by publisher]

Pharmacogenetics and cognitive symptoms in schizophrenia patients treated with antipsychotics.

Pharmacogenomics. 2018 Jul 20;:

Authors: Musil R, Spellmann I

PMID: 30028229 [PubMed - as supplied by publisher]

HE4 and eIF3a Expression Correlates with Surgical Outcome and Overall Survival in Ovarian Cancer Patients with Secondary Cytoreduction.

J Cancer. 2018;9(14):2472-2479

Authors: Luo CH, Zhao M, Chen XY, Shahabi S, Qiang W, Zeng L, Wang J, Zhou HH

Abstract
For recurrent ovarian cancer (ROC), secondary cytoreductive surgery (SCS) is recommended as one optional treatment. However, little is known about the expression and clinical significance of biomarkers during SCS. Human epididymis protein 4 (HE4) is a clinical biomarker for ovarian cancer. Eukaryotic translation initiation factor 3a (eIF3a) is investigated extensively as a potential biomarker for malignancy. The purpose of this study was to investigate the expressions of HE4 and eIF3a at SCS, as well as their associations with surgical outcome and survival in ROC patients. Immunohistochemistry was performed to determine the expressions of HE4 and eIF3a in ovarian tumors taken from both initial and secondary cytoreductive surgery of 35 ROC patients. eIF3a levels were significantly increased at SCS, compared to those at initial cytoreductive surgery (ICS), while HE4 levels were similar. Both HE4 and eIF3a expressions were associated with surgical outcome, in terms of residual tumor. For ICS, patients with high HE4 expression achieved a higher incidence of optimal cytoreduction than those with low HE4 expression (81.0% vs. 33.3%, P = 0.015). A similar result happened in SCS, indicated by higher incidence of no residual tumor in patients with high HE4 expression (76.4% vs. 44.4%, P = 0.046). And high HE4 expression at SCS was more likely to enhance surgical outcome of SCS (77.8% vs. 29.4%, P = 0.038). Therefore, high HE4 expression at either surgery is a predictor of better overall survival (OS) (P = 0.011 and 0.002). Furthermore, patients with an elevated total score (TS) of HE4 between the two surgeries tended to have prolonged OS, compared to those with a non-elevated TS of HE4 (P = 0.076). For eIF3a, initial eIF3a expression was associated with secondary residual tumor (P = 0.035), and the difference in eIF3a expression between the two surgeries correlated with OS (P = 0.052). The expressions of HE4 and eIF3a in tumor specimens correlated with surgical outcome and predicted OS in ROC patients with SCS, thus meriting further investigation.

PMID: 30026845 [PubMed]

A systematic review of the effects of CYP2D6 phenotypes on risperidone treatment in children and adolescents.

Child Adolesc Psychiatry Ment Health. 2018;12:37

Authors: Dodsworth T, Kim DD, Procyshyn RM, Ross CJ, Honer WG, Barr AM

Abstract
The second generation antipsychotic drug risperidone is widely used in the field of child and adolescent psychiatry to treat conditions associated with disruptive behavior, aggression and irritability, such as autism spectrum disorders. While risperidone can provide symptomatic relief for many patients, there is considerable individual variability in the therapeutic response and side-effect profile of the medication. One well established biological factor that contributes to these individual differences is genetic variation in the cytochrome P450 enzyme 2D6. The 2D6 enzyme metabolizes risperidone and therefore affects drug levels and dosing. In the present review, we summarize the current literature on 2D6 variants and their effects on risperidone responses, specifically in children and adolescents. Relevant articles were identified through systematic review, and after irrelevant articles were discarded, ten studies were included in the review. Most prospective studies were well controlled, but often did not have a large enough sample size to make robust statements about rarer variants, including those categorized as ultra-rapid and poor metabolizers. Individual studies demonstrated a role for different genetic variants in risperidone drug efficacy, pharmacokinetics, hyperprolactinemia, weight gain, extrapyramidal symptoms and drug-drug interactions. Where studies overlapped in measurements, there was typically a consensus between results. These findings indicate that the value of 2D6 genotyping in the youth population treated with risperidone requires further study, in particular with the less common variants.

PMID: 30026806 [PubMed]

Bush mint (Hyptis suaveolens) and spreading hogweed (Boerhavia diffusa) medicinal plant extracts differentially affect activities of CYP1A2, CYP2D6 and CYP3A4 enzymes.

J Ethnopharmacol. 2018 Jan 30;211:58-69

Authors: Ekow Thomford N, Dzobo K, Adu F, Chirikure S, Wonkam A, Dandara C

Abstract
ETHNO-PHARMACOLOGICAL RELEVANCE: Hyptis suaveolens (L) Poit and Boerhavia diffusa Linn are medicinal herbal plants commonly found in the tropics and sub-tropics. They are used to treat various conditions among them boils, dyslipidaemia, eczema, malaria, jaundice and gonorrhoea. Thus, the herbal medicinal extracts are now found as part of some commercial herbal formulations. There has not been adequate characterization of these medicinal herbs on their effects on drug metabolising enzymes.
AIM OF THE STUDY: To investigate the effects of extracts of Hyptis suaveolens (HS) and Boerhavia diffusa (BD) on activity of drug metabolising enzymes, CYP1A2, CYP2D6 and CYP3A4, as well predict their potential for herb-drug interaction. A secondary aim was to identify constituent compounds such as polyphenolics, in the crude extract preparations of Hyptis suaveolens and Boerhavia diffusa and measure them for activity.
MATERIALS AND METHODS: CYP450 inhibition assays using recombinant CYP450 (rCYP) and fluorescence screening employing individual isozymes (CYP1A2, CYP2D6 and CYP3A4) were used to determine reversible- and time-dependent inhibition (TDI) profiles of extracts of Hyptis suaveolens and Boerhavia diffusa. Inhibition kinetic parameters, Ki and Kinact were also estimated. UPLC-MS employing a Synapt G2 (ESI negative) coupled to a PDA detector was used to identify polyphenolic compounds in crude extracts of Hyptis suaveolens and Boerhavia diffusa.
RESULTS: The inhibitory potency of Hyptis suaveolens and Boerhavia diffusa extracts varied among the different enzymes, with CYP1A2 (3.68 ± 0.10µg/mL) being the least inhibited by HS compared to CYP2D6 (1.39 ± 0.01µg/mL) and CYP3A4 (2.36 ± 0.57µg/mL). BD was most potent on CYP3A4 (7.36 ± 0.94µg/mL) compared to both CYP2D6 (17.79 ± 1.02µg/mL) and CYP1A2 (9.48 ± 0.78µg/mL). Extracts of Hyptis suaveolens and Boerhavia diffusa exhibited TDIs on all CYPs. The most prominent phenolic candidates identified in both medicinal herbs using UPLC-MS analysis included caffeic acid, rutin, quercetin, citric acid, ferulic acid and gluconic acid. These phenolic compounds are thought to potentially give HS and BD their therapeutic effects and inhibitory characteristics affecting CYP450 activities. In vivo predictions showed the potential for HS and BD extracts to cause significant interactions if co-administered with other medications.
CONCLUSIONS: The study reveals that crude aqueous extracts of HS and BD potentially inhibit drug metabolising isozymes CYP1A2, CYP2D6 and CYP3A4 in a reversible and time-dependent manner. Thus care should be taken when these extracts are co-administered with drugs that are substrates of CYP1A2, CYP2D6 and CYP3A4.

PMID: 28942133 [PubMed - indexed for MEDLINE]

Interventions for the eradication of meticillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis.

Cochrane Database Syst Rev. 2018 Jul 21;7:CD009650

Authors: Lo DK, Muhlebach MS, Smyth AR

Abstract
BACKGROUND: Cystic fibrosis is an inherited recessive disorder of chloride transport that is characterised by recurrent and persistent pulmonary infections from resistant organisms that result in lung function deterioration and early mortality in sufferers.Meticillin-resistant Staphylococcus aureus (MRSA) has emerged as, not only an important infection in people who are hospitalised, but also as a potentially harmful pathogen in cystic fibrosis. Chronic pulmonary infection with MRSA is thought to confer people with cystic fibrosis with a worse clinical outcome and result in an increased rate of lung function decline. Clear guidance for MRSA eradication in cystic fibrosis, supported by robust evidence, is urgently needed. This is an update of a previous review.
OBJECTIVES: To evaluate the effectiveness of treatment regimens designed to eradicate MRSA and to determine whether the eradication of MRSA confers better clinical and microbiological outcomes for people with cystic fibrosis. To ascertain whether attempts at eradicating MRSA can lead to increased acquisition of other resistant organisms (including P aeruginosa) or increased adverse effects from drugs, or both.
SEARCH METHODS: Randomised and quasi-randomised controlled trials were identified by searching the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, PubMed, MEDLINE, clinical trial registries (Clinicaltrials.gov, WHO ICTRP, ISRCTN Registry), handsearching article reference lists and through contact with experts in the field.Date of the last search of the Group's Cystic Fibrosis Trials Register: 27 July 2017.Ongoing trials registries were last searched: 07 August 2017.
SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing any combinations of topical, inhaled, oral or intravenous antimicrobials with the primary aim of eradicating MRSA compared with placebo, standard treatment or no treatment.
DATA COLLECTION AND ANALYSIS: The authors independently assessed all search results for eligibility. They used the GRADE methodology to assess the quality of the evidence.
MAIN RESULTS: The review includes two trials with a total of 106 participants with MRSA infection. In both trials the active treatment was oral trimethoprim and sulfamethoxazole combined with rifampicin; however, one trial administered this combination for two weeks alongside nasal, skin and oral decontamination and a three-week environmental decontamination, while the second trial administered this drug combination for 21 days with five days intranasal mupirocin. In both trials the control arm was observation only.Both trials reported successful eradication of MRSA in people with CF as an outcome; however, the definition used for MRSA eradication differed. The first trial (n = 45) defined MRSA eradication as negative MRSA respiratory cultures at day 28, and reported that, when compared to control, oral trimethoprim and sulfamethoxazole combined with rifampicin may lead to a higher proportion of negative cultures, odds ratio (OR) 12.6 (95% confidence interval (CI) 2.84 to 55.84; low-certainty evidence); however, by day 168 of follow-up there was no difference in the proportion of participants who remained MRSA-negative in either treatment arm, OR 1.17 (95% CI 0.31 to 4.42) (low-quality evidence). In the second trial, successful eradication was defined as the absence of MRSA following treatment (oral co-trimoxazole and rifampicin with intranasal mupirocin or observation) in at least three cultures over a period of six months. At the time of reporting, 40 out of 61 participants had completed follow-up, but results showed no difference between groups. Eradication was achieved in 12 out 29 participants (41%) receiving active treatment, and in 9 out of 32 participants (28%) on the observation arm, OR 1.80 (95% CI 0.62 to 5.25) (very low-quality evidence).With regards to this review's secondary outcomes, these were reported in the first trial only. The trial reports that no differences were observed between the two arms in terms of pulmonary exacerbations (from screening to day 28), nasal colonisation, lung function, weight or participant-reported outcomes. While not a specific outcome of this review, investigators reported that the rate of hospitalisation from screening through day 168 was lower with oral trimethoprim and sulfamethoxazole combined with rifampicin compared to control, rate ratio 0.22 (95% CI 0.05 to 0.72) (P = 0.0102).
AUTHORS' CONCLUSIONS: Early eradication of MRSA is possible in people with cystic fibrosis, with one trial demonstrating superiority of active MRSA treatment compared with observation only in terms of the proportion of MRSA-negative respiratory cultures at day 28. However, by six months, the proportion of participants who remained MRSA-negative did not differ between treatment arms in either trial. Moreover, the longer-term clinical consequences in terms of lung function, mortality and cost of care, remain unclear.Using GRADE methodology, we judged the quality of the evidence provided by this review to be very low to low, due to potential biases from the open-label design and unclear detail reported in one trial. Based on the available evidence, it is the opinion of the authors that whilst early eradication of respiratory MRSA in people with cystic fibrosis is possible, there is not currently enough evidence regarding the clinical outcomes of eradication to support the use of the interventions studied.

PMID: 30030966 [PubMed - as supplied by publisher]

Energy Balance and Mechanisms of Weight Gain with Ivacaftor Treatment of Cystic Fibrosis Gating Mutations.

J Pediatr. 2018 Jul 18;:

Authors: Stallings VA, Sainath N, Oberle M, Bertolaso C, Schall JI

Abstract
OBJECTIVE: To determine if ivacaftor treatment results in weight gain and improved pulmonary function in people with cystic fibrosis transmembrane conductance regulator gating mutations.
STUDY DESIGN: Children and adults with cystic fibrosis and at least 1 cystic fibrosis transmembrane conductance regulator gating mutation were evaluated in this observational study before and after 3 months of ivacaftor treatment. Body size and composition, total energy expenditure, resting energy expenditure (REE%) as percent predicted, coefficient of fat absorption (CFA%), fecal calprotectin, fecal elastase, and quality of life were assessed. Some outcomes were explored by pancreatic status.
RESULTS: There were 23 patients (5-61 years of age) who completed the study; 70% had pancreatic insufficiency (PI). Patients gained 2.5 ± 2.2 kg (P < .001) with increased (P < .05) fat-free mass (0.9 ± 1.9 kg) and fat mass (1.6 ± 1.5 kg). REE% decreased by 5.5 ± 12.0% (P < .05), fecal calprotectin decreased by 30 ± 40 µg/g stool (P < .01), and total energy expenditure was unchanged. Improvements were greater for PI than patients who were pancreatic-sufficient. CFA% increased significantly only with PI. The change (Δ) in weight was positively correlated with the percent change in forced expiratory volume at 1 second (r = 0.46; P = .028) and ΔCFA% (r = 0.47; P = .032) and negatively with ΔREE% (r = -0.50; P = .017). Together, ΔREE%, ΔCFA%, and the percent change in forced expiratory volume at 1 second explained 58% of the variance in weight gain (adjusted R2 = 0.579; P = .0007). Growth status and muscle strength improved, as did quality of life in several domains. Fecal elastase increased in most patients with pancreatic sufficiency, with no change in those with PI.
CONCLUSIONS: Mechanisms identified for ivacaftor-associated weight gain were decreased REE, gut inflammation, and fat malabsorption (CFA).
TRIAL REGISTRATION: ClinicalTrials.gov: NCT02141464.

PMID: 30029855 [PubMed - as supplied by publisher]

Face Masks Reduce the Release of Pseudomonas aeruginosa Cough Aerosols when Worn for Clinically-Relevant Time Periods.

Am J Respir Crit Care Med. 2018 Jul 20;:

Authors: Stockwell RE, Wood ME, He C, Sherrard LJ, Ballard EL, Kidd TJ, Johnson GR, Knibbs LD, Morawska L, Bell SC, CF Cough Aerosol Group

PMID: 30028634 [PubMed - as supplied by publisher]

The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis lung disease.

Expert Opin Ther Targets. 2018 Jul 20;:

Authors: Moore PJ, Tarran R

Abstract
INTRODUCTION: Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that codes for the CFTR anion channel. In the absence of functional CFTR, the epithelial Na+ channel is also dysregulated. Airway surface liquid (ASL) hydration is maintained by a balance between epithelial sodium channels (ENaC)-led Na+ absorption and CFTR-dependent anion secretion. This finely-tuned homeostatic mechanism is required to maintain sufficient airway hydration to permit the efficient mucus clearance necessary for a sterile lung environment. In CF airways, the lack of CFTR and increased ENaC activity lead to ASL/mucus dehydration that causes mucus obstruction, neutrophilic infiltration and chronic bacterial infection. Rehydration of ASL/mucus in CF airways can be achieved by inhibiting Na+ absorption with pharmacological inhibitors of ENaC. Areas covered: In this review, we discuss ENaC structure and function and its role in CF lung disease and focus on ENaC inhibition as a potential therapeutic target to rehydrate CF mucus. We also discuss the failure of the first generation of pharmacological inhibitors of ENaC and recent alternate strategies to attenuate ENaC activity in the CF lung. Expert Opinion: ENaC is an attractive therapeutic target to rehydrate CF ASL that may serve as a monotherapy or function in parallel with other treatments. Given the increased number of strategies being employed to inhibit ENaC, this is an exciting and optimistic time to be in this field.

PMID: 30028216 [PubMed - as supplied by publisher]

The history of lung transplantation in Hong Kong.

J Thorac Dis. 2018 Jun;10(Suppl 16):S1899-S1904

Authors: Hsin MKY, Wong CF, Yan SW, Fan KY, Ho CKL, Bhatia I, Au TWK

Abstract
Clinical lung transplant was first performed in Hong Kong in 1995. In the early years, the volume of activity was very low. There has been a clear trend of increasing volume in the past few years. The recipient pathology is very different from the International Society for Heart and Lung Transplantation (ISHLT) database, with complete absence of cystic fibrosis and alpha-1-antitrypsin deficiency, and a predominance of diseases of the pulmonary circulation. Lymphangioleiomyomatosis (LAM) has a much higher representation on the waiting list than the ISHLT. The survival of patients who received a lung transplant in Hong Kong compares favorably with international data.

PMID: 30026977 [PubMed]