Progression of irradiated mesenchymal stromal cells from early to late senescence: Changes in SASP composition and anti-tumour properties.

Genotoxic injuries converge on senescence-executive program that promotes production of a senescence-specific secretome (SASP). The study of SASP is particularly intriguing, since through it a senescence process, triggered in a few cells, can spread to many other cells and produce either beneficial or negative consequences for health. We analysed the SASP of quiescent mesenchymal stromal cells (MSCs) following stress induced premature senescence (SIPS) by ionizing radiation exposure. We performed a proteome analysis of SASP content obtained from early and late senescent cells. The bioinformatics studies evidenced that early and late SASPs, besides some common ontologies and signalling pathways, contain specific factors. In spite of these differences, we evidenced that SASPs can block in vitro proliferation of cancer cells and promote senescence/apoptosis. It is possible to imagine that SASP always contains core components that have an anti-tumour activity, the progression from early to late senescence enriches the SASP of factors that may promote SASP tumorigenic activity only by interacting and instructing cells of the immune system. Our results on Caco-2 cancer cells incubated with late SASP in presence of peripheral white blood cells strongly support this hypothesis. We evidenced that quiescent MSCs following SIPS produced SASP that, while progressively changed its composition, preserved the capacity to block cancer growth by inducing senescence and/or apoptosis only in an autonomous manner.

A subtractive proteomics approach for the identification of immunodominant Acinetobacter baumannii vaccine candidate proteins.

Background: Acinetobacter baumannii is one of the most life-threatening multidrug-resistant pathogens worldwide. Currently, 50%-70% of clinical isolates of A. baumannii are extensively drug-resistant, and available antibiotic options against A. baumannii infections are limited. There is still a need to discover specific de facto bacterial antigenic proteins that could be effective vaccine candidates in human infection. With the growth of research in recent years, several candidate molecules have been identified for vaccine development. So far, no public health authorities have approved vaccines against A. baumannii. Methods: This study aimed to identify immunodominant vaccine candidate proteins that can be immunoprecipitated specifically with patients' IgGs, relying on the hypothesis that the infected person's IgGs can capture immunodominant bacterial proteins. Herein, the outer-membrane and secreted proteins of sensitive and drug-resistant A. baumannii were captured using IgGs obtained from patient and healthy control sera and identified by Liquid Chromatography- Tandem Mass Spectrometry (LC-MS/MS) analysis. Results: Using the subtractive proteomic approach, we determined 34 unique proteins captured only in drug-resistant A. baumannii strain via patient sera. After extensively evaluating the predicted epitope regions, solubility, transverse membrane characteristics, and structural properties, we selected several notable vaccine candidates. Conclusion: We identified vaccine candidate proteins that triggered a de facto response of the human immune system against the antibiotic-resistant A. baumannii. Precipitation of bacterial proteins via patient immunoglobulins was a novel approach to identifying the proteins that could trigger a response in the patient immune system.

Antidepressant prescribing patterns in Australia.

BACKGROUND: The Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders (MDcpg2015 and MDcpg2020) provide evidence-based and consensus-based recommendations for managing mood disorders. AIMS: We examined Australian real-world prescribing habits to determine whether management in clinical practice aligned with MDcpg2015 recommendations. METHOD: A retrospective analysis of a cohort of patients ≥16 years old who had been dispensed a Pharmaceutical Benefits Scheme (PBS)-listed antidepressant between July 2013 and June 2019 was conducted using Australian Commonwealth Department of Human Services PBS 10% sample data. RESULTS: Between July 2013 and June 2019, 239 944 patients in Australia commenced antidepressant treatment. Of these, 22% (52 694 patients) received a second treatment (a new class of treatment after a period of discontinuation or additional antipsychotic therapy) and 6% (15 741 patients) received a third treatment. Patients were initially prescribed primarily selective serotonin reuptake inhibitors (SSRIs; 52% of prescriptions) or tricyclic antidepressants (TCAs; 25%), even though TCAs are not recommended for first-line treatment. Fewer than one-quarter of patients were prescribed serotonin-noradrenaline reuptake inhibitors (13%) or other agents (10%). General practitioners (GPs) were more likely to initiate TCAs than psychiatrists (22% v. 7%).Once initiated, the overall median time patients remained on treatment was 4.5 months; this was highest with SSRIs (5.8 months) and lowest with TCAs (0.9 months). CONCLUSIONS: First-line prescribing broadly follows guidelines. GP and psychiatrist prescribing patterns differ, perhaps reflecting different patient groups and the need to tailor treatment to individuals. Future guidelines should aim to capture the different presentations and complexity of depression.

Clinical and radiologic evaluation of a Turkish family with hypochondroplasia and a rare FGFR3 variant.

OBJECTIVES: Hypochondroplasia (HCH) is characterized by disproportionate short stature and regarded as a milder form of achondroplasia (ACH), which is another skeletal dysplasia, both caused by variants in fibroblast growth factor receptor 3 (FGFR3) gene. HCH diagnosis is based on the clinical features and skeletal survey findings. The most common FGFR3 variant in HCH affects the codon 540, leading to substitution of asparagine with lysine in about 70% of patients. CASE PRESENTATION: Herein, we described the clinical and radiographical manifestations of HCH in affected members of a Turkish family with very rare Asn540Thr (c.1619A>C) variant within hot spot of the gene for this condition. CONCLUSIONS: This is a very rarely reported variant in the literature and this report is the first case with this variant in Turkish population. The report also presents the phenotypic variability within a family with the same variant, which is inherent to HCH.

Phenotypic and molecular characterization of five patients with PIK3CA-related overgrowth spectrum (PROS).

Somatic and germline PI3K-AKT-mTOR pathway pathogenic variants are involved in several segmental overgrowth phenotypes such as the PIK3CA-related overgrowth spectrum (PROS), Proteus syndrome, and PTEN hamartoma tumor syndrome. In this study, we describe five patients with PROS. We identified by high-throughput sequencing four different somatic PIK3CA pathogenic variants in five individuals. The Glu726Lys variant, which was previously reported in megalencephaly-capillary malformation-polymicrogyria (MCAP) syndrome, was identified in two patients with unclassified PROS. The Cys420Arg substitution, which was previously reported in CLOVES, was found in a patient with fibroadipose hyperplasia. Additionally, relatively rare pathogenic variants, His1047Tyr and Tyr1021Cys, were detected in two patients with MCAP. Therefore, we suggest performing deep sequencing of PIK3CA in all patients with suspected PROS, instead of targeted polymerase chain reaction for hotspot pathogenic variants.

Antipsychotic prescribing patterns in Australia: a retrospective analysis.

BACKGROUND: To examine real-world patterns of antipsychotic use in patients with schizophrenia Australia. METHODS: This retrospective cohort analysis was conducted using the Australian Commonwealth Department of Human Services Pharmaceutical Benefits Scheme (PBS) 10% sample data. Included data were for patients aged 16-years or older who initiated treatment for the first time with a PBS-reimbursed antipsychotic medication for schizophrenia between July 2013 and September 2017. Patterns of treatment usage were summarised descriptively. Differences in prescribing patterns by age and prescribing year were reported. Treatment persistence was estimated using Kaplan-Meier methods, with differences explored using log-rank tests. Values of p < 0.05 were considered statistically significant. RESULTS: 6,740 patients, representing 8,249 non-unique patients, received prescriptions for antipsychotic medications. Patients were aged 16 years to over 85 years (54.5% were < 55 years) and two-thirds of patients were male (61%). The majority of treatment episodes (62%, n = 5,139/8,249) were prescribed an atypical oral antipsychotic. Typical long-acting antipsychotic therapies (LATs) were prescribed 19% of the treatment episodes (n = 1,608/8,249. There was a small increase in prescribing of atypical LAT and typical LAT and a small decrease in atypical oral and clozapine prescribing over the study period. Treatment persistence was greatest in patients treated with clozapine, than in those treated with atypical LATs. CONCLUSIONS: While the majority of patients receive atypical antipsychotic medications, one in five continue to use older typical LAT therapies. Patient age and time on therapy may be associated with choice of therapy. Persistence to atypical LAT therapy is better than for other treatment modalities in this real-world cohort.

Protocol for cell surface biotinylation of magnetic labeled and captured human peripheral blood mononuclear cells.

Analysis of the surfaceome of a blood cell subset requires cell sorting, followed by surface protein enrichment. Here, we present a protocol combining magnetically activated cell sorting (MACS) and surface biotinylation of the target cell subset from human peripheral blood mononuclear cells (PBMCs). We describe the steps for isolating target cells and their in-column surface biotinylation, followed by isolation and mass spectrometry analysis of biotinylated proteins. The protocol enables in-column surface biotinylation of specific cell subsets with minimal membrane disruption.

Persistence to Biologic Therapy Among Patients With Ankylosing Spondylitis: An Observational Study Using the OPAL Dataset.

OBJECTIVE: To describe the treatment response and persistence to biologic disease-modifying antirheumatic drug (bDMARD) therapy in patients with ankylosing spondylitis (AS) in a real-world Australian cohort. METHODS: This was a retrospective, noninterventional cohort study that extracted data for patients with AS from the Optimising Patient outcomes in Australian RheumatoLogy (OPAL) dataset for the period of August 2006 to September 2019. Patients were classified as either bDMARD initiators if they commenced a bDMARD during the sampling window, or bDMARD-naïve if they did not. Results were summarized descriptively. Treatment persistence was calculated using Kaplan-Meier methods. Differences in treatment persistence were explored using log-rank tests. RESULTS: There were 5048 patients with AS identified. Of these, 2597 patients initiated bDMARDs and 2451 remained bDMARD-naïve throughout the study window. Treatment with first-, second-, and third-line bDMARDs significantly reduced disease activity. Median persistence on first-line bDMARDs was 96 months (95% CI 85-109), declining to 19 months (95% CI 16-22) in second-line therapy, and 15 months (95% CI 11-18) in third-line therapy. Median persistence was longest for the golimumab (GOL) group in all lines of therapy and shortest for the etanercept (ETN) group. Differences in persistence rates according to the time period that bDMARDs were prescribed (pre- and post-2012) were also seen for ETN and adalimumab. CONCLUSION: In this cohort, all bDMARDs effectively reduced AS disease activity. Treatment persistence was sustained for up to 8 years for patients remaining on their first bDMARD, longer than on subsequent agents. Further research is needed to determine its influence on treatment recommendations.

Proteomic and Biological Analysis of the Effects of Metformin Senomorphics on the Mesenchymal Stromal Cells.

Senotherapeutics are new drugs that can modulate senescence phenomena within tissues and reduce the onset of age-related pathologies. Senotherapeutics are divided into senolytics and senomorphics. The senolytics selectively kill senescent cells, while the senomorphics delay or block the onset of senescence. Metformin has been used to treat diabetes for several decades. Recently, it has been proposed that metformin may have anti-aging properties as it prevents DNA damage and inflammation. We evaluated the senomorphic effect of 6 weeks of therapeutic metformin treatment on the biology of human adipose mesenchymal stromal cells (MSCs). The study was combined with a proteome analysis of changes occurring in MSCs' intracellular and secretome protein composition in order to identify molecular pathways associated with the observed biological phenomena. The metformin reduced the replicative senescence and cell death phenomena associated with prolonged in vitro cultivation. The continuous metformin supplementation delayed and/or reduced the impairment of MSC functions as evidenced by the presence of three specific pathways in metformin-treated samples: 1) the alpha-adrenergic signaling, which contributes to regulation of MSCs physiological secretory activity, 2) the signaling pathway associated with MSCs detoxification activity, and 3) the aspartate degradation pathway for optimal energy production. The senomorphic function of metformin seemed related to its reactive oxygen species (ROS) scavenging activity. In metformin-treated samples, the CEBPA, TP53 and USF1 transcription factors appeared to be involved in the regulation of several factors (SOD1, SOD2, CAT, GLRX, GSTP1) blocking ROS.

Understanding Treatment Preferences of Australian Patients Living with Treatment-Resistant Depression.

BACKGROUND: There is evidence of improved adherence and treatment outcomes when patients' treatment preferences are considered, and shared decision making is utilized. PURPOSE: We aimed to better understand treatment preferences among Australians with treatment-resistant depression (TRD), focusing on the specific treatment attributes that people value (such as effectiveness, risk of side effects and cost) and their relative importance. The risk-benefit trade-offs that characterize treatment choices were also examined. PATIENTS AND METHODS: An online survey of 75 patients with experience of TRD was conducted, consisting of two discrete choice experiment (DCE) components - a medication DCE and a treatment plan DCE. Participants were able to prioritize and trade off different features of medications and treatment plans. Additional questions aimed to better define this population group, which in Australia is poorly understood. RESULTS: In both DCEs, two distinct latent classes were identified. In the medication DCE, the classes were distinguished by willingness to consider new treatment alternatives. Participants in class 1 were reluctant to give up current treatment, while those in the slightly larger class 2 preferred new treatment options. In both classes, treatment effectiveness and cost were the greatest contributors to preference. Similar behavior was seen in the treatment plan DCE, with the larger class more likely to choose a new plan over their current treatment arrangement. Participants preferred medications that were low-cost, taken orally, had a high percentage improvement in mood symptoms, high rate of remission and low risk of weight gain. A similar result was found in preferences for treatment plans such that plans with the greatest effectiveness and lowest cost were most favorable. CONCLUSION: Patient preferences should routinely be considered and discussed to guide informed decisions regarding the value of new and existing medications for TRD and how they sit in the context of treatment plans.

Why Do Muse Stem Cells Present an Enduring Stress Capacity? Hints from a Comparative Proteome Analysis.

Muse cells are adult stem cells that are present in the stroma of several organs and possess an enduring capacity to cope with endogenous and exogenous genotoxic stress. In cell therapy, the peculiar biological properties of Muse cells render them a possible natural alternative to mesenchymal stromal cells (MSCs) or to in vitro-generated pluripotent stem cells (iPSCs). Indeed, some studies have proved that Muse cells can survive in adverse microenvironments, such as those present in damaged/injured tissues. We performed an evaluation of Muse cells' proteome under basic conditions and followed oxidative stress treatment in order to identify ontologies, pathways, and networks that can be related to their enduring stress capacity. We executed the same analysis on iPSCs and MSCs, as a comparison. The Muse cells are enriched in several ontologies and pathways, such as endosomal vacuolar trafficking related to stress response, ubiquitin and proteasome degradation, and reactive oxygen scavenging. In Muse cells, the protein-protein interacting network has two key nodes with a high connectivity degree and betweenness: NFKB and CRKL. The protein NFKB is an almost-ubiquitous transcription factor related to many biological processes and can also have a role in protecting cells from apoptosis during exposure to a variety of stressors. CRKL is an adaptor protein and constitutes an integral part of the stress-activated protein kinase (SAPK) pathway. The identified pathways and networks are all involved in the quality control of cell components and may explain the stress resistance of Muse cells.

Obesity induced by high-fat diet is associated with critical changes in biological and molecular functions of mesenchymal stromal cells present in visceral adipose tissue.

The mesenchymal stromal cells (MSCs) residing within the stromal component of visceral adipose tissue appear to be greatly affected by obesity, with impairment of their functions and presence of senescence. To gain further insight into these phenomena, we analyzed the changes in total proteome content and secretome of mouse MSCs after a high-fat diet (HFD) treatment compared to a normal diet (ND). In healthy conditions, MSCs are endowed with functions mainly devoted to vesicle trafficking. These cells have an immunoregulatory role, affecting leukocyte activation and migration, acute inflammation phase response, chemokine signaling, and platelet activities. They also present a robust response to stress. We identified four signaling pathways (TGF-ß, VEGFR2, HMGB1, and Leptin) that appear to govern the cells' functions. In the obese mice, MSCs showed a change in their functions. The immunoregulation shifted toward pro-inflammatory tasks with the activation of interleukin-1 pathway and of Granzyme A signaling. Moreover, the methionine degradation pathway and the processing of capped intronless pre-mRNAs may be related to the inflammation process. The signaling pathways we identified in ND MSCs were replaced by MET, WNT, and FGFR2 signal transduction, which may play a role in promoting inflammation, cancer, and aging.

Obesity is associated with senescence of mesenchymal stromal cells derived from bone marrow, subcutaneous and visceral fat of young mice.

White adipose tissue (WAT) is distributed in several depots with distinct metabolic and inflammatory functions. In our body there are subcutaneous (sWAT), visceral (vWAT) and bone marrow (bWAT) fat depots. Obesity affects the size, function and inflammatory state of WATs. In particular, obesity may affect the activity of mesenchymal stromal cells (MSCs) present in WAT. MSCs are a heterogeneous population containing stromal cells, progenitor cells, fibroblasts and stem cells that are able to differentiate among adipocytes, chondrocytes, osteocytes and other mesodermal derivatives.In the first study of this kind, we performed a comparison of the effects of obesity on MSCs obtained from sWAT, vWAT and bWAT. Our study showed that obesity affects mainly the biological functions of MSCs obtained from bone marrow and vWAT by decreasing the proliferation rate, reducing the percentage of cells in S phase and triggering senescence. The onset of senescence was confirmed by expression of genes belonging to RB and P53 pathways.Our study revealed that the negative consequences of obesity on body physiology may also be related to impairment in the functions of the stromal compartment present in the several adipose tissues. This finding provides new insights as to the targets that should be considered for an effective treatment of obesity-related diseases.

A comparative study on normal and obese mice indicates that the secretome of mesenchymal stromal cells is influenced by tissue environment and physiopathological conditions.

BACKGROUND: The term mesenchymal stromal cells (MSCs) designates an assorted cell population comprised of stem cells, progenitor cells, fibroblasts, and stromal cells. MSCs contribute to the homeostatic maintenance of many organs through paracrine and long-distance signaling. Tissue environment, in both physiological and pathological conditions, may affect the intercellular communication of MSCs. METHODS: We performed a secretome analysis of MSCs isolated from subcutaneous adipose tissue (sWAT) and visceral adipose tissue (vWAT), and from bone marrow (BM), of normal and obese mice. RESULTS: The MSCs isolated from tissues of healthy mice share a common core of released factors: components of cytoskeletal and extracellular structures; regulators of basic cellular functions, such as protein synthesis and degradation; modulators of endoplasmic reticulum stress; and counteracting oxidative stress. It can be hypothesized that MSC secretome beneficially affects target cells by the horizontal transfer of many released factors. Each type of MSC may exert specific signaling functions, which could be determined by looking at the many factors that are exclusively released from every MSC type. The vWAT-MSCs release factors that play a role in detoxification activity in response to toxic substances and drugs. The sWAT-MSC secretome contains proteins involved in in chondrogenesis, osteogenesis, and angiogenesis. Analysis of BM-MSC secretome revealed that these cells exert a signaling function by remodeling extracellular matrix structures, such as those containing glycosaminoglycans. Obesity status profoundly modified the secretome content of MSCs, impairing the above-described activity and promoting the release of inflammatory factors. CONCLUSION: We demonstrated that the content of MSC secretomes depends on tissue microenvironment and that pathological condition may profoundly alter its composition. Video abstract.

Effects of mesenchymal stem cell transfer on orthodontically induced root resorption and orthodontic tooth movement during orthodontic arch expansion protocols: an experimental study in rats.

OBJECTIVES: The aim was to evaluate the effects of mesenchymal stem cell (MSC) transfer to periodontal ligament (PDL) on the inhibition and/or repair of orthodontically induced root resorption (OIRR) during and after arch expansion and on the orthodontic tooth movement (OTM) rate of the maxillary first molar teeth of rats. MATERIAL AND METHODS: Sixty Wistar rats were divided into three groups as the untreated group, MSC and control injections during the expansion period group (EMSC-EC), and MSC and control injections at the retention period group (RMSC-RC). Fifty grams of orthodontic force was applied to the maxillary first molar teeth of the rats for 14 days in the vestibular direction, and then, 20 days of retention was carried out. MSCs and control injections were performed every 3 days in the EC, RC, EMSC, and RMSC groups. At the end of the experiment, samples were prepared for OTM evaluation, mRNA expression analysis, micro-computed tomography measurements, cementum thickness calculations, and structural examinations. RESULTS: The amount of OTM in EMSC group was significantly higher than in EC group (P < 0.001). MSC transfer during the expansion and retention periods reduced the number of resorption lacunae, volumetric and linear resorptive measurements, and cyclooxygenase-2 and receptor activator of nuclear factor kappa B ligand (RANKL) mRNA expression levels, and increased the osteoprotegerin (OPG) expression levels, OPG/RANKL ratio, and cementum thickness in the EMSC and RMSC groups. CONCLUSIONS: MSC transfer to PDL during expansion increased the amount of OTM. Injection of MSC during the retention period was found to be slightly more effective in prevention and/or repair of OIRR than MSC transfer during the expansion period.

What do Australian patients with inflammatory arthritis value in treatment? A discrete choice experiment.

BACKGROUND AND OBJECTIVES: The purpose of this study was to develop an understanding of treatment preferences in patients with inflammatory arthritis (IA) [rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA)] focussing on treatment attributes that patients' value, their relative importance, and the risk-benefit trade-offs that characterise patients' choices around treatment. METHODS: A discrete choice experiment (DCE) approach was used. Attributes of interest were clinical efficacy; slowing of disease progression; risk of mild-moderate side effects; risk of severe side effects; frequency of administration; real-world product evidence; management of related conditions; and availability of a patient support programme. Using data from the DCE component, a restricted latent class model (LCM) was estimated to determine discrete 'classes' of treatment preferences. RESULTS: In this analysis, 206 participants were included (AS n = 59; PsA n = 62; RA n = 85). Two classes were identified. For 'class 1' (59.9%), the most important attributes (across all treatment modalities) were preventing disease progression, clinical efficacy and risk of mild-to-moderate side effects. For 'class 2' (40.1%), clinical and non-clinical attributes were important, and attribute importance depended on treatment modality. Patient demographic and treatment characteristics did not predict class membership. CONCLUSION: For most patients with IA, clinical efficacy, stopping disease progression and risks of mild-to-moderate side effects are important treatment attributes. Patients with prior biologic DMARD experience had greater preference for injection treatments. For a subset of patients, patient support programmes and the frequency of administration were important. Clinicians should be mindful of preferences when prescribing treatment to patients with IA.Key Points• Most patients consider clinical efficacy, stopping disease progression and the risk of mild-to-moderate side effects as important treatment attributes• Patients with prior biologic DMARD experience have greater preference for injection treatments.• For a subset of patients, patient support programmes, and the frequency of administration were important.• Clinicians should be mindful of preferences when prescribing treatment to patients with IA.

Side-to-side asymmetry in lower limb strength and hamstring-quadriceps strength ratio among collegiate American football players.

[Purpose] The present study aimed to investigate the lower limbs injury risk factors that are based on conventional Hamstring to Quadriceps ratio and limb asymmetry index in varsity American football players. [Participants and Methods] Twenty-six varsity American football players aged 19-27 years and with 2.31 ± 1.29 years of American football experience from Dogu Akdeniz University volunteered to undergo measurements of average peak torque for isokinetic flexion and extension of dominant limb and non-dominant limb at 60°·s-1 and 300°·s-1. Hamstring to Quadriceps ratio and limb asymmetry index were also calculated for Hamstring and Quadriceps muscles. [Results] Statistical analysis revealed that dominant Quadriceps is stronger than non-dominant Quadriceps at 60°·s-1 speed. No statistical difference was found between dominant and non-dominant Hamstring peak torque at 60°·s-1 . Hamstring to Quadriceps ratio determined as normal both for 60°·s-1 and 300°·s-1according to the currently reported cut off value (H:Q ratio >60). Hamstring and Quadriceps limb asymmetry index also determined as normal (cut off value for LSI 10%) at 60°·s-1. However, for both Hamstring and Quadriceps, side- to- side strength asymmetry at 300°·s-1 was observed. [Conclusion] To prevent possible lower limb injury and to increase performance, varsity American football players who are actively training and competing might consider taking strength asymmetry into account to tailor their strength training program accordingly.

Synthesis, in vivo anticonvulsant testing, and molecular modeling studies of new nafimidone derivatives.

An estimated 50 million people suffer epilepsy worldwide and 30% of the cases do not respond to current antiepileptic drugs (AEDs). Here, we report synthesis and anticonvulsant screening of new derivatives of nafimidone, a well-known member of (arylakyl)azole anticonvulsants. The compounds showed promising protection against maximal electroshock (MES)-induced seizures in mice and rats when administered via intraperitoneal (ip) and oral route. Especially, 5b, 5c, and 5i displayed outstanding activity in rats in MES test when given ip (ED50 : 16.0, 15.8, and 11.8 mg/kg, respectively). Additionally, 5l was active against 6 Hz and corneal-kindled mice models. Behavioral toxicity of the compounds was very low and their therapeutic indexes were high compared to some currently available AEDs. A number of pharmaceutically relevant descriptors and properties were predicted for the compounds in silico in comparison with a set of known drugs. Favorable results were obtained such as good blood-brain barrier permeability and high oral absorption, as well as drug-likeness. 5l was found to show affinity to the benzodiazepine binding site of A-type GABA receptor via molecular docking simulations.

Treatment persistence of subcutaneous TNF inhibitors among Australian patients with immune-mediated rheumatic disease (IMRD).

INTRODUCTION: To describe the persistence of treatment with subcutaneous tumor necrosis factor inhibitors (TNFi) adalimumab, etanercept, and golimumab in immune-mediated rheumatic disease (rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis) by treatment sequence (first-line treatment, second-line or further lines of treatment). METHODS: A retrospective cohort analysis was conducted using the Australian Commonwealth Department of Human Services Pharmaceutical Benefits Scheme 10% sample data from January 1, 2010, to June 30, 2016. Pharmaceutical Benefits Scheme indications were used to identify patient prescriptions for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. A patient was considered persistent until a 3-month gap period where a prescription was not dispensed. The 3-month gap interval was chosen because only 1% of all discontinuations occurred beyond this 3-month period. RESULTS: Data from 2,612 first-line patients were included. Treatment discontinuation among first-line patients treated with etanercept or adalimumab was not significantly different from those treated with golimumab (HR 1.10, 95% CI 0.95-1.28, P=0.22; HR 1.06, 95% CI 0.93-1.22, P=0.39; respectively). Among the 1,276 patients in the second-line cohort (etanercept=41%, adalimumab=41%, golimumab=18%) discontinuation was significantly higher for patients on etanercept compared with golimumab (HR 1.24, 95% CI 1.03-1.50, P=0.03); but not for adalimumab compared with golimumab (HR 1.11, 95% CI 0.91-1.34, P=0.31). In the third-line setting, treatment persistence with etanercept was longer than golimumab (HR 0.75, 95% CI 0.59-0.96, P=0.02), but there was no difference between golimumab and adalimumab. Similar findings occurred in the propensity score matched population. CONCLUSION: Our study shows there is variance in real-world persistence to TNFi in patients with immune-mediated rheumatic disease by line of therapy, with the time on therapy decreasing by line. Australian persistence has been reported at lower overall rates than international evidence.

Patients with primary restless legs syndrome have higher prevalence of autonomic dysfunction and irritable bowel syndrome.

INTRODUCTION: Given the limited data on autonomic dysfunction in patients with primary restless legs syndrome (pRLS), we compared autonomic dysfunction and presence of irritable bowel syndrome (IBS) between patients with pRLS and control patients. METHODS: Consecutive adult drug-naïve patients with pRLS, and age- and gender-matched healthy control patients were enrolled in this study. Diagnoses, based on validated self-reported questionnaires, were made using the following guidelines: Rome III classification system for functional gastrointestinal disorders for IBS; Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) for the presence of anxiety and depression, respectively; Pittsburgh Sleep Quality Index (PSQI) for severity of sleep disturbances; and Scales for Outcomes in Parkinson's disease-Autonomic (SCOPA-AUT) for autonomic dysfunction. RESULTS: There were 88 patients with pRLS (18 male, 70 female) and 128 control patients (40 men, 88 women). The mean age of the pRLS patients and control patients was 50.3 ± 9.3 years and 49.7 ± 8.2 years, respectively. Overall, 41 (46.6%) of the patients with pRLS and 16 (12.5%) of the control patients had IBS. Among patients with pRLS, IBS was significantly more common and the total autonomic SCOPA-AUT scores were higher than those found among control patients. Among pRLS patients with IBS, total autonomic SCOPA-AUT, PSQI, BAI and BDI scores were significantly higher than among pRLS patients without IBS. The presence of IBS did not affect the severity of restless legs syndrome. CONCLUSION: The presence of autonomic nervous system impairment in patients with pRLS and the strong link between IBS and pRLS merit further, more extensive investigation.