Process evaluation of a maintenance pulmonary rehabilitation trial for people with chronic obstructive pulmonary disease.

BACKGROUND: The ComEx3 community-based extended maintenance pulmonary rehabilitation (PR) randomised controlled trial (RCT) aimed to determine the optimal strategy for maintaining the benefits of exercise for people with chronic obstructive pulmonary disease (COPD). We conducted a process evaluation of this RCT to determine if the trial was implemented per protocol, and to explore the barriers and facilitators of the trial, and mechanisms of impact. METHODS: This was a mixed methods study consisting of analysis of PR class records, study diaries and interviews of those involved in the trial. We developed a reporting framework from available literature and performed a content analysis. RESULTS: Eleven of the 12 participants in the intervention group attended ≥70% of available classes before the trial was terminated due to the COVID-19 pandemic. Analysis of the study diaries found that adherence to the home exercise program was higher in the intervention than the control group. Analyses of interviews (n = 21) highlighted the complexity of standardising the processes across multiple sites, but revealed behaviour change amongst class physiotherapists who were able to conform with the required processes. Facilitators of participation included the desire to improve function and quality of life, while barriers included illnesses and lack of motivation. Mechanisms of impact included confidence in exercising and benefits from the education sessions. CONCLUSIONS: The ComEx3 RCT was implemented as planned largely due to commitment by the research team and the desire by patients to improve their quality of life by attending a PR program that they are familiar with. Successful implementation of PR RCTs requires good organisational skills, clear and consistent trial documentation, broad understanding of participant needs while being conscious of challenges experienced by people with COPD, and dedication by everyone involved in the RCT. SO WHAT?: This article shows the importance of running a process evaluation alongside an RCT. Although this RCT did not progress to completion, this process evaluation which was guided by a robust framework, will provide guidance for future interventions in this area.

Scaffold modifications to the 4-(4,4-dimethylpiperidinyl) 2,6-dimethylpyridinyl class of HIV-1 allosteric integrase inhibitors.

Allosteric integrase inhibitors (ALLINIs) of HIV-1 may hold promise as a novel mechanism for HIV therapeutics and cure. Scaffold modifications to the 4-(4,4-dimethylpiperidinyl) 2,6-dimethylpyridinyl class of ALLINIs provided a series of potent compounds with differentiated 5/6 fused ring systems. Notably, inhibitors containing the 1,2,4-triazolopyridine and imidazopyridine core exhibited single digit nM antiviral potency and low to moderate clearance after intravenous (IV) dosing in rat pharmacokinetic (PK) studies. The 1,2,4-triazolopyridines showed a higher oral exposure when compared to the imidazopyridines. Further modifications to the C5 substituent of the 1,2,4-triazolopyridines resulted in a new lead compound, which had improved rat IV/PO PK compared to the former lead compound GSK3739936, while maintaining antiviral potency. Structure-activity relationships (SAR) and rat pharmacokinetic profiles of this series are discussed.

Design and exploration of C-3 benzoic acid bioisosteres and alkyl replacements in the context of GSK3532795 (BMS-955176) that exhibit broad spectrum HIV-1 maturation inhibition.

GSK3532795 (formerly BMS-955176) is a second-generation HIV-1 maturation inhibitor that has shown broad spectrum antiviral activity and preclinical PK predictive of once-daily dosing in humans. Although efficacy was confirmed in clinical trials, the observation of gastrointestinal intolerability and the emergence of drug resistant virus in a Phase 2b clinical study led to the discontinuation of GSK3532795. As part of the effort to further map the maturation inhibitor pharmacophore and provide additional structural options, the evaluation of alternates to the C-3 phenyl substituent in this chemotype was pursued. A cyclohexene carboxylic acid provided exceptional inhibition of wild-type, V370A and ΔV370 mutant viruses in addition to a suitable PK profile following oral dosing to rats. In addition, a novel spiro[3.3]hept-5-ene was designed to extend the carboxylic acid further from the triterpenoid core while reducing side chain flexibility compared to the other alkyl substituents. This modification was shown to closely emulate the C-3 benzoic acid moiety of GSK3532795 from both a potency and PK perspective, providing a non-traditional, sp3-rich bioisostere of benzene. Herein, we detail additional modifications to the C-3 position of the triterpenoid core that offer effective replacements for the benzoic acid of GSK3532795 and capture the interplay between these new C-3 elements and C-17 modifications that contribute to enhanced polymorph coverage.

The significance of VTE in cancer: Introduction of the 'Spot the CLOT' series.

Learning needs of patients with cancer have been examined and published widely in oncology nursing literature. However, the topic of cancer-associated thrombosis (CAT) is rarely considered a necessary inclusion. Awareness by individuals with cancer about venous thromboembolism (VTE) and its association with cancer is low (Aggarwal et al., 2015). A 2015 qualitative study by Dr. Simon Noble revealed that high-risk cancer patients receiving active chemotherapy knew more about febrile neutropenia than signs and symptoms of VTE, despite a higher absolute risk of VTE. This is concerning given that CAT is the number one cause of death for patients undergoing chemotherapy treatment. Awareness of CAT is generally low not only in patients and their families, but also in healthcare providers. Research has found that many patients diagnosed with CAT perceived a significant knowledge deficit in their treating physicians because alternative diagnoses were considered before CAT, despite classic signs and symptoms of VTE (Noble et al., 2015). VTE is a common and often severe complication in cancer patients, being the leading cause of morbidity and second leading cause of mortality (Noble et al., 2015). Despite its significance, however, the awareness of CAT is low in patients, caregivers, and healthcare providers. This article is the first in a series entitled, 'Spot the CLOT', which is aimed at promoting the awareness of CAT in oncology nurses with the goal of improving patient education on this important topic.

The Pleural Effusion And Symptom Evaluation (PLEASE) study of breathlessness in patients with a symptomatic pleural effusion.

INTRODUCTION: Pathophysiology changes associated with pleural effusion, its drainage and factors governing symptom response are poorly understood. Our objective was to determine: 1) the effect of pleural effusion (and its drainage) on cardiorespiratory, functional and diaphragmatic parameters; and 2) the proportion as well as characteristics of patients with breathlessness relief post-drainage. METHODS: Prospectively enrolled patients with symptomatic pleural effusions were assessed at both pre-therapeutic drainage and at 24-36 h post-therapeutic drainage. RESULTS: 145 participants completed pre-drainage and post-drainage tests; 93% had effusions ≥25% of hemithorax. The median volume drained was 1.68 L. Breathlessness scores improved post-drainage (mean visual analogue scale (VAS) score by 28.0±24 mm; dyspnoea-12 (D12) score by 10.5±8.8; resting Borg score before 6-min walk test (6-MWT) by 0.6±1.7; all p<0.0001). The 6-min walk distance (6-MWD) increased by 29.7±73.5 m, p<0.0001. Improvements in vital signs and spirometry were modest (forced expiratory volume in 1 s (FEV1) by 0.22 L, 95% CI 0.18-0.27; forced vital capacity (FVC) by 0.30 L, 95% CI 0.24-0.37). The ipsilateral hemi-diaphragm was flattened/everted in 50% of participants pre-drainage and 48% of participants exhibited paradoxical or no diaphragmatic movement. Post-drainage, hemi-diaphragm shape and movement were normal in 94% and 73% of participants, respectively. Drainage provided meaningful breathlessness relief (VAS score improved ≥14 mm) in 73% of participants irrespective of whether the lung expanded (mean difference 0.14, 95% CI 10.02-0.29; p=0.13). Multivariate analyses found that breathlessness relief was associated with significant breathlessness pre-drainage (odds ratio (OR) 5.83 per standard deviation (sd) decrease), baseline abnormal/paralyzed/paradoxical diaphragm movement (OR 4.37), benign aetiology (OR 3.39), higher pleural pH (OR per sd increase 1.92) and higher serum albumin level (OR per sd increase 1.73). CONCLUSIONS: Breathlessness and exercise tolerance improved in most patients with only a small mean improvement in spirometry and no change in oxygenation. Breathlessness improvement was similar in participants with and without trapped lung. Abnormal hemi-diaphragm shape and movement were independently associated with relief of breathlessness post-drainage.

Design, synthesis and SAR study of novel C2-pyrazolopyrimidine amides and amide isosteres as allosteric integrase inhibitors.

The design, synthesis and structure-activity relationships associated with a series of C2-substituted pyrazolopyrimidines as potent allosteric inhibitors of HIV-1 integrase (ALLINIs) are described. Structural modifications to these molecules were made in order to examine the effect on potency and, for select compounds, pharmacokinetic properties. We examined a variety of C2-substituted pyrazolopyrimidines and found that the C2-amide derivatives demonstrated the most potent antiviral activity of this class against HIV-1 infection in cell culture.

Heterocycle amide isosteres: An approach to overcoming resistance for HIV-1 integrase strand transfer inhibitors.

A series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors was prepared and screened for activity against purified integrase enzyme and/or viruses modified with the following mutations within integrase: Q148R, Q148H/G140S and N155H. These are mutations that result in resistance to the first generation integrase inhibitors raltegravir and elvitegravir. Based on consideration of drug-target interactions, an approach was undertaken to replace the amide moiety of the first generation pyrimidinedione inhibitor with azole heterocycles that could retain potency against these key resistance mutations. An imidazole moiety was found to be the optimal amide substitute and the observed activity was rationalized with the use of calculated properties and modeling. Rat pharmacokinetic (PK) studies of the lead imidazole compounds demonstrated moderate clearance and moderate exposure.

Structure-based amelioration of PXR transactivation in a novel series of macrocyclic allosteric inhibitors of HIV-1 integrase.

Previous studies have identified a series of imidazo[1,2-a]pyridine (IZP) derivatives as potent allosteric inhibitors of HIV-1 integrase (ALLINIs) and virus infection in cell culture. However, IZPs were also found to be relatively potent activators of the pregnane-X receptor (PXR), raising the specter of induction of CYP-mediated drug disposition pathways. In an attempt to modify PXR activity without affecting anti-HIV-1 activity, rational structure-based design and modeling approaches were used. An X-ray cocrystal structure of (S,S)-1 in the PXR ligand binding domain (LBD) allowed an examination of the potential of rational structural modifications designed to abrogate PXR. The introduction of bulky basic amines at the C-8 position provided macrocyclic IZP derivatives that displayed potent HIV-1 inhibitory activity in cell culture with no detectable PXR transactivation at the highest concentration tested.

Design, synthesis and SAR study of bridged tricyclic pyrimidinone carboxamides as HIV-1 integrase inhibitors.

The design, synthesis and structure-activity relationships associated with a series of bridged tricyclic pyrimidinone carboxamides as potent inhibitors of HIV-1 integrase strand transfer are described. Structural modifications to these molecules were made in order to examine the effect on potency towards wild-type and clinically-relevant resistant viruses. The [3.2.2]-bridged tricyclic system was identified as an advantageous chemotype, with representatives exhibiting excellent antiviral activity against both wild-type viruses and the G140S/Q148H resistant virus that arises in response to therapy with raltegravir and elvitegravir.

Dentistry: Studying for a chosen career and the role of family, friends and support in that journey.

INTRODUCTION: Well-being issues are increasing amongst dental students. Social relationships can be important for student support during their studies. The aim of the study was to explore dental students' feelings towards studying dentistry, social networks and chosen support during this journey. MATERIALS AND METHODS: An anonymous electronic cross-sectional survey was carried out. All dental students in a single dental school were invited to participate. Participation and answering questions was voluntary. Descriptive analyses were used for categorical data, and qualitative data were analysed thematically. RESULTS: In total, 109 students responded. One third reported having a family member from a healthcare profession but most were not related to dental professionals. The majority of students 83% liked the course, 14% said they felt "neutral", and 5% said they did not like it. The following three themes explained this: (a) demands of the course, (b) being suited to dentistry (eg patient care) and (c) passion for dentistry as a career (or lack of). Most felt their peers were friendly (92%) and supportive (78%) but also competitive (64%). Irrespective of stress, 70% of participants sought help from family and two thirds sought help from student peers. DISCUSSION: Most students enjoy studying dentistry despite the demands of the course. Support, workload, feeling suited to the course and a passion for dentistry as a career can affect the experience. CONCLUSIONS: Family and friends are an important source of support in this process. Further work is needed to explore mechanisms to help family and friends support students.

Effect of maternal baboon (Papio sp.) dietary mismatch in pregnancy and lactation on post-natal offspring early life phenotype.

BACKGROUND: Non-human primate models of developmental programing by maternal mismatch between pregnancy and lactation diets are needed for translation to human programing outcomes. We present baboon offspring morphometry from birth to 3 years, and blood cortisol and adrenocorticotropin (ACTH) from 2 to 24 months. METHODS: Control mothers ate chow; mismatch mothers ate 30% less than controls during pregnancy and high-fat high-energy diet through lactation. RESULTS: Mismatch mothers lost weight during pregnancy. At birth, there were trends toward lower weight in mismatch offspring of both sexes (P = 0.06). From 0-3 years, catch-up growth occurred. Mismatch offspring male and female body weight increased faster than controls (P < 0.001). Mismatch female offspring showed greater increase in BMI (P < 0.001) and abdominal circumference (P = 0.008) vs controls. ACTH and cortisol slopes from 2 to 24 months of age were similar between groups in both sexes. Cortisol and ACTH increased after weaning in all groups. CONCLUSIONS: Mismatch produces sexually dimorphic post-natal growth phenotypes.

Effect of maternal obesity on fetal and postnatal baboon (Papio species) early life phenotype.

BACKGROUND: Non-human primate models of developmental programming by maternal obesity (MO) are needed for translation to human programming outcomes. We present baboon offspring (F1) morphometry, blood cortisol, and adrenocorticotropic hormone (ACTH) from 0.9 gestation to 0-2 years. METHODS: Control mothers ate chow; MO mothers ate high-fat high-energy diet pre-pregnancy through lactation. RESULTS: Maternal obesity mothers weighed more than controls pre-pregnancy. Maternal obesity gestational weight gain was lower with no correlation with fetal or placenta weights. At 0.9 gestation, MO and control F1 morphometry and ACTH were similar. MO-F1 0.9 gestation male cortisol was lower, rising slower from 0-2 years vs control-F1. At birth, male MO-F1 and control-F1 weights were similar, but growth from 0-2 years was steeper in MO-F1; newborn female MO-F1 weighed more than control-F1 but growth from 0-2 years was similar. ACTH did not change in either sex. CONCLUSIONS: Maternal obesity produced sexually dimorphic fetal and postnatal growth and hormonal phenotypes.

Work, Stress and Play: Students' perceptions of factors impacting on their studies and well-being.

INTRODUCTION: This study gathered information about life outside of the course for undergraduates studying at the School of Dentistry, Cardiff University. The aim was to explore how these external factors to the course may affect an individual's academic performance and well-being. MATERIALS AND METHODS: A cross-sectional study design was used. An online questionnaire designed for the purpose of the study was used to capture (quantitative and qualitative) data. Questions with dichotomous options, a range of statements with Likert scales (level of agreement) and open (free-text) questions were used. Data were analysed in SPSS using simple descriptive statistics and frequency distributions. Spearman's Rho was used to explore relationships for scaled categorical data. Content analysis was used for qualitative data. RESULTS: Two-thirds (n = 69, 63%) of participants reported being very stressed about their studies in the previous 12 months. The majority felt that external factors to their course (eg, lack of sleep, health issues, financial concerns, hobbies and issues with friends) had impacted on their academic lives with only 9% (n = 10) stating that their lives outside dentistry had no effect. DISCUSSION: Those who felt able to pursue hobbies and activities reported a better work-life balance and less stress. Questions about pursuing hobbies and sleep may help identify students at risk of being stressed or who may benefit from additional support in order to achieve a better work-life balance. CONCLUSION: This study has highlighted key areas for further investigation and opportunities for improving support to reduce student stress and improve well-being.

The design, synthesis and structure-activity relationships associated with C28 amine-based betulinic acid derivatives as inhibitors of HIV-1 maturation.

The design and synthesis of a series of C28 amine-based betulinic acid derivatives as HIV-1 maturation inhibitors is described. This series represents a continuation of efforts following on from previous studies of C-3 benzoic acid-substituted betulinic acid derivatives as HIV-1 maturation inhibitors (MIs) that were explored in the context of C-28 amide substituents. Compared to the C-28 amide series, the C-28 amine derivatives exhibited further improvements in HIV-1 inhibitory activity toward polymorphisms in the Gag polyprotein as well as improved activity in the presence of human serum. However, plasma exposure of basic amines following oral administration to rats was generally low, leading to a focus on moderating the basicity of the amine moiety distal from the triterpene core. The thiomorpholine dioxide (TMD) 20 emerged from this study as a compound with the optimal antiviral activity and an acceptable pharmacokinetic profile in the C-28 amine series. Compared to the C-28 amide 3, 20 offers a 2- to 4-fold improvement in potency towards the screening viruses, exhibits low shifts in the EC50 values toward the V370A and ΔV370 viruses in the presence of human serum or human serum albumin, and demonstrates improved potency towards the polymorphic T371A and V362I virus variants.

Reproductive cycling in adult baboons (Papio species) that were intrauterine growth restricted at birth implies normal fertility but increased psychosocial stress.

We investigated menstrual cycles in intrauterine growth restricted (IUGR, 7-10 years, n = 8) and age-matched control (n = 10) baboons. Cycle duration and plasma anti-Mullerian hormone were similar. IUGR spent more days per cycle swollen and had elevated early morning fasted serum cortisol, suggesting normal fertility in the presence of increased psychosocial stress.

Functionalized triazines as potent HCV entry inhibitors.

A series of potent and novel acylsulfonamide-bearing triazines were synthesized and the structure-activity relationships (SARs) as HCV entry inhibitors were evaluated. This acylsulfonamide series was derived from an early lead, 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid wherein the carboxylic acid was replaced with an acylsulfonamide moiety. This structural modification provided a class of compounds which projected an additional vector off the terminus of the acylsulfonamide functionality as a means to drive activity. This effort led to the discovery of potent analogues within this series that demonstrated sub-nanomolar EC50 values in the HCV pseudotype particle (HCVpp) assay.

Effect of moderate, 30 percent global maternal nutrient reduction on fetal and postnatal baboon phenotype.

BACKGROUND: Most developmental programming studies on maternal nutrient reduction (MNR) are in altricial rodents whose maternal nutritional burden and offspring developmental trajectory differ from precocial non-human primates and humans. METHODS: Control (CTR) baboon mothers ate ad libitum; MNR mothers ate 70% global control diet in pregnancy and lactation. RESULTS: We present offspring morphometry, blood cortisol, and adrenocorticotropin (ACTH) during second half of gestation (G) and first three postnatal years. Moderate MNR produced intrauterine growth restriction (IUGR). IUGR males (n=43) and females (n=28) were smaller than CTR males (n=50) and females (n=47) in many measurements at many ages. In CTR, fetal ACTH increased 228% and cortisol 48% between 0.65G and 0.9G. IUGR ACTH was elevated at 0.65G and cortisol at 0.9G. 0.9G maternal gestational weight gain, fetal weight, and placenta weight were correlated. CONCLUSIONS: Moderate IUGR decreased body weight and morphometric measurements at key time points and altered hypothalamo-pituitary-adrenal function.