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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., (© 2024 The Authors. Health Promotion Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of Australian Health Promotion Association.)

Age and sex have a profound effect on cytosine methylation levels in humans and many other species. Here we analyzed DNA methylation profiles of 2400 tissues derived from 37 primate species including 11 haplorhine species (baboons, marmosets, vervets, rhesus macaque, chimpanzees, gorillas, orangutan, humans) and 26 strepsirrhine species (suborders Lemuriformes and Lorisiformes). From these we present here, pan-primate epigenetic clocks which are highly accurate for all primates including humans (age correlation R = 0.98). We also carried out in-depth analysis of baboon DNA methylation profiles and generated five epigenetic clocks for baboons (Olive-yellow baboon hybrid), one of which, the pan-tissue epigenetic clock, was trained on seven tissue types (fetal cerebral cortex, adult cerebral cortex, cerebellum, adipose, heart, liver, and skeletal muscle) with ages ranging from late fetal life to 22.8 years of age. Using the primate data, we characterize the effect of age and sex on individual cytosines in highly conserved regions. We identify 11 sex-related CpGs on autosomes near genes (POU3F2, CDYL, MYCL, FBXL4, ZC3H10, ZXDC, RRAS, FAM217A, RBM39, GRIA2, UHRF2). Low overlap can be observed between age- and sex-related CpGs. Overall, this study advances our understanding of conserved age- and sex-related epigenetic changes in primates, and provides biomarkers of aging for all primates., (© 2023. The Author(s).)

Long-acting (LA) human immunodeficiency virus-1 (HIV-1) antiretroviral therapy characterized by a ≥1 month dosing interval offers significant advantages over daily oral therapy. However, the criteria for compounds that enter clinical development are high. Exceptional potency and low plasma clearance are required to meet dose size requirements; excellent chemical stability and/or crystalline form stability is required to meet formulation requirements, and new antivirals in HIV-1 therapy need to be largely free of side effects and drug-drug interactions. In view of these challenges, the discovery that capsid inhibitors comprising a quinazolinone core tolerate a wide range of structural modifications while maintaining picomolar potency against HIV-1 infection in vitro , are assembled efficiently in a multi-component reaction, and can be isolated in a stereochemically pure form is reported herein. The detailed characterization of a prototypical compound, GSK878, is presented, including an X-ray co-crystal structure and subcutaneous and intramuscular pharmacokinetic data in rats and dogs.

An investigation of the structure-activity relationships of a series of HIV-1 maturation inhibitors (MIs) based on GSK3640254 ( 4 ) was conducted by incorporating novel C-17 amine substituents to reduce the overall basicity of the resultant analogues. We found that replacement of the distal amine on the C-17 sidechain present in 4 with a tertiary alcohol in combination with either a heterocyclic ring system or a cyclohexyl ring substituted with polar groups provided potent wild-type HIV-1 MIs that also retained excellent potency against a T332S/V362I/prR41G variant, a laboratory strain that served as a surrogate to assess HIV-1 polymorphic virus coverage. Compound 26 exhibited broad-spectrum HIV-1 activity against an expanded panel of clinically relevant Gag polymorphic viruses and had the most desirable overall profile in this series of compounds. In pharmacokinetic studies, 26 had low clearance and exhibited 24 and 31% oral bioavailability in rats and dogs, respectively.

Purpose: The impact of the COVID-19 pandemic on healthcare providers includes physical, psychological, financial, and childcare issues. The purpose of this qualitative study was to explore the experiences of dental hygienists returning to clinical practice after the March 2020 closure due to the COVID-19 pandemic. Methods: A qualitative phenomenological research design was used with virtual focus groups. Clinical dental hygienists who had worked a minimum of 3 days a week prior to dental practice closures in March 2020 and had returned to work in May 2020 were invited to participate through purposive sampling on dental hygiene social media sites. Demographic data was collected prior to a one-hour focus group session. Two investigators independently analyzed and coded the data using a qualitative data analysis software program. The themes identified were used to generate a description of the major findings. Results: Data saturation was achieved with (n=35) participants for a total of 13 focus groups. Most participants were female (89%), and the average age was 40 years. The following major themes were identified: physical issues; emotional; adherence to infection control protocols; fear of contracting/transmitting COVID-19; financial stress; our career was marginalized; and let's get back and make money. Conclusion: Dental hygienists experienced similar physical and mental health stressors as other health care professionals upon returning to work during the COVID-19 pandemic, however dental hygienists also reported feeling marginalized and undervalued. Results from this study suggest that dental hygienists need both personal and workplace support to manage the issues resulting from the COVID-19 pandemic in order to retain them in the workforce., (Copyright © 2022 The American Dental Hygienists’ Association.)

GSK3640254 is an HIV-1 maturation inhibitor (MI) that exhibits significantly improved antiviral activity toward a range of clinically relevant polymorphic variants with reduced sensitivity toward the second-generation MI GSK3532795 (BMS-955176). The key structural difference between GSK3640254 and its predecessor is the replacement of the para -substituted benzoic acid moiety attached at the C-3 position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic acid substituted with a CH 2 F moiety at the carbon atom α- to the pharmacophoric carboxylic acid. This structural element provided a new vector with which to explore structure-activity relationships (SARs) and led to compounds with improved polymorphic coverage while preserving pharmacokinetic (PK) properties. The approach to the design of GSK3640254, the development of a synthetic route and its preclinical profile are discussed. GSK3640254 is currently in phase IIb clinical trials after demonstrating a dose-related reduction in HIV-1 viral load over 7-10 days of dosing to HIV-1-infected subjects.

Structure-property relationships associated with a series of (carbonyl)oxyalkyl amino acid ester prodrugs of the marketed HIV-1 protease inhibitor atazanavir ( 1 ), designed to enhance the systemic drug delivery, were examined. Compared to previously reported prodrugs, optimized candidates delivered significantly enhanced plasma exposure and trough concentration ( C min at 24 h) of 1 in rats while revealing differentiated PK paradigms based on the kinetics of prodrug activation and drug release. Prodrugs incorporating primary amine-containing amino acid promoieties offered the benefit of rapid bioactivation that translated into low circulating levels of the prodrug while delivering a high C max value of 1 . Interestingly, the kinetic profile of prodrug cleavage could be tailored for slower activation by structural modification of the amino terminus to either a tertiary amine or a dipeptide motif, which conferred a circulating depot of the prodrug that orchestrated a sustained release of 1 along with substantially reduced C max and a further enhanced C min .

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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Allosteric HIV-1 integrase inhibitors (ALLINIs) have been of interest recently because of their novel mechanism of action. Strategic modifications to the C5 moiety of a class of 4-(4,4-dimethylpiperidinyl)-2,6-dimethylpyridinyl ALLINIs led to the identification of a tetrahydroisoquinoline heterocycle as a suitable spacer element to project the distal hydrophobic aryl ring. Subsequent optimization of the aryl substitutions identified 12 as an ALLINI with single-digit nanomolar inhibitory potency and low clearance across preclinical species. In preclinical toxicology studies with 12 in rats, lipid hepatocellular vacuolation was observed. Removal of the C6 methyl group resulted in GSK3839919 ( 22 ), which exhibited a reduced incidence and severity of lipid vacuolation in both in vitro assays and in vivo studies while maintaining the potency and pharmacokinetic (PK) properties of the prototype. The virology, PK, and toxicology profiles of 22 are discussed., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)

Allosteric HIV-1 integrase inhibitors (ALLINIs) have garnered special interest because of their novel mechanism of action: they inhibit HIV-1 replication by promoting aberrant integrase multimerization, leading to the production of replication-deficient viral particles. The binding site of ALLINIs is in a well-defined pocket formed at the interface of two integrase monomers that is characterized by conserved residues along with two polymorphic amino acids at residues 124 and 125. The design, synthesis, and optimization of pyridine-based allosteric integrase inhibitors are reported here. Optimization was conducted with a specific emphasis on the inhibition of the 124/125 polymorphs such that the designed compounds showed excellent potency in vitro against majority of the 124/125 variants. In vivo profiling of promising preclinical lead 29 showed that it exhibited a good pharmacokinetic (PK) profile in preclinical species, which resulted in a low predicted human efficacious dose. However, findings in rat toxicology studies precluded further development of 29 .

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., (© 2021 Canadian Association of Nurses in Oncology (CANO).)

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, sp 3 -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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The discovery of a pan-genotypic hepatitis C virus (HCV) NS3/4A protease inhibitor based on a P1-P3 macrocyclic tripeptide motif is described. The all-carbon tether linking the P1-P3 subsites of 21 is functionalized with alkyl substituents, which are shown to effectively modulate both potency and absorption, distribution, metabolism, and excretion (ADME) properties. The CF 3 Boc-group that caps the P3 amino moiety was discovered to be an essential contributor to metabolic stability, while positioning a methyl group at the C1 position of the P1' cyclopropyl ring enhanced plasma trough values following oral administration to rats. The C7-fluoro, C6-CD 3 O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD 3 O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH 3 O prototype.

We describe the design, synthesis and pharmacokinetic (PK) evaluation of a series of amino acid-based prodrugs of the HIV-1 protease inhibitor atazanavir (1) derivatized on the pharmacophoric secondary alcohol using a (carbonyl)oxyalkyl linker. Prodrugs of 1 incorporating simple (carbonyl)oxyalkyl-based linkers and a primary amine in the promoiety were found to exhibit low chemical stability. However, chemical stability was improved by modifying the primary amine moiety to a tertiary amine, resulting in a 2-fold enhancement of exposure in rats following oral dosing compared to dosing of the parent drug 1. Further refinement of the linker resulted in the discovery of 22 as a prodrug that delivered the parent 1 to rat plasma with a 5-fold higher AUC and 67-fold higher C 24 when compared to oral administration of the parent drug. The PK profile of 22 indicated that plasma levels of this prodrug were higher than that of the parent, providing a more sustained release of 1 in vivo., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Nonhuman primate (NHP) studies are crucial to biomedical research. NHPs are the species most similar to humans in lifespan, body size, and hormonal profiles. Planning research requires statistical power evaluation, which is difficult to perform when lacking directly relevant preliminary data. This is especially true for NHP developmental programming studies, which are scarce. We review the sample sizes reported, challenges, areas needing further work, and goals of NHP maternal nutritional programming studies. The literature search included 27 keywords, for example, maternal obesity, intrauterine growth restriction, maternal high-fat diet, and maternal nutrient reduction. Only fetal and postnatal offspring studies involving tissue collection or imaging were included. Twenty-eight studies investigated maternal over-nutrition and 33 under-nutrition; 23 involved macaques and 38 baboons. Analysis by sex was performed in 19; minimum group size ranged from 1 to 8 (mean 4.7 ± 0.52, median 4, mode 3) and maximum group size from 3 to 16 (8.3 ± 0.93, 8, 8). Sexes were pooled in 42 studies; minimum group size ranged from 2 to 16 (mean 5.3 ± 0.35, median 6, mode 6) and maximum group size from 4 to 26 (10.2 ± 0.92, 8, 8). A typical study with sex-based analyses had group size minimum 4 and maximum 8 per sex. Among studies with sexes pooled, minimum group size averaged 6 and maximum 8. All studies reported some significant differences between groups. Therefore, studies with group sizes 3-8 can detect significance between groups. To address deficiencies in the literature, goals include increasing age range, more frequently considering sex as a biological variable, expanding topics, replicating studies, exploring intergenerational effects, and examining interventions.

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 (FEV 1 ) 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., Competing Interests: Conflict of interest: S. Muruganandan has nothing to disclose. Conflict of interest: M. Azzopardi has nothing to disclose. Conflict of interest: R. Thomas has nothing to disclose. Conflict of interest: D.B Fitzgerald has nothing to disclose. Conflict of interest: Y.J. Kuok has nothing to disclose. Conflict of interest: H.M. Cheah has nothing to disclose. Conflict of interest: C.A. Read has nothing to disclose. Conflict of interest: C.A. Budgeon has nothing to disclose. Conflict of interest: P.R. Eastwood has nothing to disclose. Conflict of interest: S. Jenkins has nothing to disclose. Conflict of interest: B. Singh has nothing to disclose. Conflict of interest: K. Murray has nothing to disclose. Conflict of interest: Y.C.G. Lee has served on the advisory board of CareFusion/BD Ltd and has previously led clinical trials for which Rocket Medical plc (UK) provided the drainage kits for study participants without charge, as well as providing an unrestricted educational grant to assist the running of the trial., (Copyright ©ERS 2020.)

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., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-1 integrase are clinically validated for the treatment of HIV-1 infection. Here we describe allosteric inhibitors of HIV-1 integrase that bind to the LEDGF/p75 interaction site and disrupt the structure of the integrase multimer that is required for the HIV-1 maturation. A series of pyrazolopyrimidine-based inhibitors was developed with a vector in the 2-position that was optimized by structure-guided compound design. This resulted in the discovery of pyrazolopyrimidine 3 , which was optimized at the 2- and 7-positions to afford 26 and 29 as potent allosteric inhibitors of HIV-1 integrase that exhibited low nanomolar antiviral potency in cell culture and encouraging PK properties.

Introduction: Pulmonary rehabilitation is a core component of the treatment of people with chronic obstructive pulmonary disease (COPD); however, the benefits gained diminish in the ensuing months. The optimal strategy for maintaining the benefits is unclear with weekly supervised maintenance exercise programmes proposed as one strategy. However, the long-term future of maintenance programs is dependent on quality evidence., Methods and Analysis: The ComEx3 randomised controlled trial will investigate the efficacy of extending a weekly supervised maintenance programme for an additional 6 months following an initial 10-week maintenance programme (intervention) by comparing with a control group who receive the same 10-week maintenance programme followed by 6 months of usual care. 120 participants with COPD will be recruited. Primary objective is to determine health-related quality of life over 12 months. Secondary objectives are to determine functional exercise capacity trajectory and to perform an economic evaluation of the intervention to the health system. Outcomes will be analysed for superiority according to intention-to-treat and per-protocol approaches., Ethics and Dissemination: Approval has been received from the relevant ethics committees. Findings will be disseminated in peer-reviewed journals and conferences, targeting those involved in managing people with COPD as well as those who develop policies and guidelines., Clinical Trial Registration: ANZCTR 12618000933257., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The number of international students coming to the U.S. for post-secondary education has been steadily increasing. Prior research has found that international students encounter many barriers to academic success, but this topic has not been previously studied for the discipline of dental hygiene. The aims of this study were to investigate the barriers and challenges to academic success faced by international students in U.S. dental hygiene programs and to explore the students' thoughts on the value they bring to those programs. The overlapping qualitative methods of semi-structured focus groups and one-on-one interviews with 12 students in three U.S. dental hygiene programs were used for this phenomenological study. In the results, six themes emerged: language proficiency, communication challenges with faculty and patients, ability to adapt to a new educational system, adjusting to cultural differences, feelings of belonging, and the value of diversity. The most significant barrier for the participants was comprehension of the English language. Didactically, these students reported that they needed additional time to study and to process examination questions. This study found that these international students studying dental hygiene in the U.S. had academic challenges similar to international students studying in other disciplines. Dental hygiene educators may need to evaluate their didactic and test-taking strategies to ensure the academic success of international students., (© 2019 American Dental Education Association.)

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., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Women threatening premature delivery receive synthetic glucocorticoids (sGC) to accelerate fetal lung maturation, reducing neonatal mortality and morbidity. Few investigations have explored potential long-term offspring side effects. We previously reported increased pericardial fat and liver lipids in 10-year-old (human equivalent 40 years) male baboons exposed to 3 antenatal sGC courses. We hypothesized middle-aged sGC male offspring show obesity-related morphometric changes., Methods: Pregnant baboons received courses of 2 betamethasone injections (175 μg·kg -1 ·d -1 intramuscular) at 0.6, 0.64, and 0.68 gestation. At 10 to 12.5 years, we measured morphometrics and serum lipids in 5 sGC-exposed males and 10 age-matched controls. We determined whether morphometric parameters predicted amount of pericardial fat or lipids. Life-course serum lipids were measured in 25 males (7-23 years) providing normal regression formulas to compare sGC baboons' lipid biological and chronological age., Results: Birth weights were similar. When studied, sGC-exposed males showed a steeper weight increase from 8 to 12 years and had increased waist and hip circumferences, neck and triceps skinfolds, and total and low-density lipoprotein cholesterol. Triceps skinfold correlated with apical and midventricular pericardial fat thickness, hip and waist circumferences with insulin., Conclusions: Triceps skinfold and waist and hip circumferences are useful biomarkers for identifying individuals at risk for obesity and metabolic dysregulation following fetal sGC exposure. Prenatal sGC exposure predisposes male offspring to internal adiposity, greater body size, and increased serum lipids. Results provide further evidence for developmental programming by fetal sGC exposure and call attention to potential emergence of adverse life-course effects.

Phosphate and amino acid prodrugs of the HIV-1 protease inhibitor (PI) atazanavir (1) were prepared and evaluated to address solubility and absorption limitations. While the phosphate prodrug failed to release 1 in rats, the introduction of a methylene spacer facilitated prodrug activation, but parent exposure was lower than that following direct administration of 1. Val amino acid and Val-Val dipeptides imparted low plasma exposure of the parent, although the exposure of the prodrugs was high, reflecting good absorption. Screening of additional amino acids resulted in the identification of an l-Phe ester that offered an improved exposure of 1 and reduced levels of the circulating prodrug. Further molecular editing focusing on the linker design culminated in the discovery of the self-immolative l-Phe-Sar dipeptide derivative 74 that gave four-fold improved AUC and eight-fold higher C trough values of 1 compared with oral administration of the drug itself, demonstrating a successful prodrug approach to the oral delivery of 1.

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., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims To establish what work a sample of Overseas Registration Examination (ORE) registrants were undertaking and understand what had facilitated or impeded them from finding suitable employment as dentists. Method An online questionnaire, consisting of both closed and open questions, was used to capture data from a population of 1,106 former ORE candidates who passed the examination between 2009 and 2014 and were registered by the General Dental Council (GDC). The data were analysed and presented in the form of tables, figures and a presentation of the major themes that emerged from the responses. Results There was a 42% response rate. Seventy-one percent of respondents were employed as dentists in the UK, with the majority providing a mixture of private and NHS patient treatment. Most who were not working as dentists were actively seeking training places. Additional themes that were identified included: the availability of Dental Foundation/Vocational Training places; poor employment practices; perceptions of the strengths and weaknesses of the ORE; and some ideas about the future responsibilities of the GDC. Conclusions This survey has highlighted some difficulties that many ORE registrants face finding suitable work as dentists. Stakeholders should be aware of these challenges.

Poor nutrition during pregnancy is a worldwide public health problem. Maternal nutrient reduction (MNR) is associated with maternal and fetal stress and a sex-dependent decrease in nonhuman primate (NHP) cognitive performance. Early life stress potentiates epileptogenesis in a sex-specific manner, and temporal lobe (TL) epilepsy is associated with neurocognitive disorders. The endogenous cannabinoid system (ECS) demonstrates remarkable developmental changes and plays a key role in aging-related diseases (e.g., dementia). Baboons have been studied as a natural model of epilepsy and express all ECS system components. We therefore evaluated baboon fetal temporal cortex ECS ontogenic and MNR-dependent changes. At 120 days gestational age (dGA) (term 185 days), maternal, fetal, and placental morphometry were similar between control and MNR pregnancies. MNR maternal weight gain was decreased compared with controls at 165 dGA independent of fetal sex. In male fetuses, expression of ECS synthesizing and degrading enzymes was gestational age-dependent, with the exception of fatty acid amide hydrolase (FAAH). MNR had a sex-specific effect on the protein expression of CB1R during development: CB1R protein expression was decreased in fetal temporal cortex of male fetuses at 120 and 140 dGA. Our data reveal that the MNR has sex-specific effects on temporal cortical expression of the ECS in baboon offspring and shows vulnerability of ECS in male fetuses during gestation., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

A series of 5,6,7,8-tetrahydro-1,6-naphthyridine derivatives targeting the allosteric lens-epithelium-derived-growth-factor-p75 (LEDGF/p75)-binding site on HIV-1 integrase, an attractive target for antiviral chemotherapy, was prepared and screened for activity against HIV-1 infection in cell culture. Small molecules that bind within the LEDGF/p75-binding site promote aberrant multimerization of the integrase enzyme and are of significant interest as HIV-1-replication inhibitors. Structure-activity-relationship studies and rat pharmacokinetic studies of lead compounds are presented.

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., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC 50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.

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 EC 50 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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

HIV-1 protease inhibitors (PIs), which include atazanavir (ATV, 1), remain important medicines to treat HIV-1 infection. However, they are characterized by poor oral bioavailability and a need for boosting with a pharmacokinetic enhancer, which results in additional drug-drug interactions that are sometimes difficult to manage. We investigated a chemo-activated, acyl migration-based prodrug design approach to improve the pharmacokinetic profile of 1 but failed to obtain improved oral bioavailability over dosing the parent drug in rats. This strategy was refined by conjugating the amine with a promoiety designed to undergo bio-activation, as a means of modulating the subsequent chemo-activation. This culminated in a lead prodrug that (1) yielded substantially better oral drug delivery of 1 when compared to the parent itself, the simple acyl migration-based prodrug, and the corresponding simple l-Val prodrug, (2) acted as a depot which resulted in a sustained release of the parent drug in vivo, and (3) offered the benefit of mitigating the pH-dependent absorption associated with 1, thereby potentially reducing the risk of decreased bioavailability with concurrent use of stomach-acid-reducing drugs.

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., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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 EC 50 values in the HCV pseudotype particle (HCVpp) assay., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Survival for many individuals with paralysis is increasing, making this population a larger subset of the aging population (Molton, & Jensen, 2010). Yet little is known about the demographics and health of this population (Freedman, 2014)., Objective: This study is one of the first evaluations of the differences in etiology, sociodemographic and health characteristics (i.e., health status, chronic, and secondary and medical conditions) of adults aging with versus into disability., Methods: A cross sectional epidemiological study was performed using secondary data from a nationally representative sample of adults with paralysis. The National Paralysis Survey is a random digit-dial survey of over 70,000 households. Weighted descriptive and regression analyses were conducted., Results: Eighty percent of those aging with paralysis had disabilities for 40+ years. They showed significantly better self-reported health status, and a trend for more secondary and medical conditions. Those aging into paralysis had more chronic diseases., Conclusions: Differences are evident between those aging with vs. into paralysis. These findings suggest that differentiating subgroups of older adults with disabilities by onset of disability makes disability and health information more actionable for programs and policies. Additional studies to explore the intersection of aging and disability onset across adulthood could increase our understanding of the dynamics of aging in persons with early and later onset disabilities., (Published by Elsevier Inc.)

The phosphoinositide 3-kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or by the genetic mutation and amplification of key pathway components. A variety of PI3K isoforms play differential roles in cancers. As such, the development of PI3K inhibitors from novel compound classes should lead to differential pharmacological and pharmacokinetic profiles and allow exploration in various indications, combinations, and dosing regimens. A screening effort aimed at the identification of PI3Kγ inhibitors for the treatment of inflammatory diseases led to the discovery of the novel 2,3-dihydroimidazo[1,2-c]quinazoline class of PI3K inhibitors. A subsequent lead optimization program targeting cancer therapy focused on inhibition of PI3Kα and PI3Kβ. Herein, initial structure-activity relationship findings for this class and the optimization that led to the identification of copanlisib (BAY 80-6946) as a clinical candidate for the treatment of solid and hematological tumors are described., (© 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Purpose: The purpose of this descriptive study was to assess data pertinent to the Permit L local anesthesia license among practicing dental hygienists in Massachusetts, providing an overview of characteristics, practice behaviors, barriers for obtaining the permit and self-perceived competency., Methods: A convenience sample of dental hygienists (n=6,167) identified through a publically available data base were invited to participate in a web-based survey. The survey consisted of demographic and Permit L specific questions. Items regarding opinions were rated using a 5-point Likert scale while frequencies and percentiles were used to evaluate demographics and practice-based information. Spearman's Rank correlation was performed to determine association between variables., Results: A 10% (n=615) response rate was attained with (n=245) non-Permit L holders and (n=370) Permit L holders. Respondents reported significant differences in demographics and opinions between non-Permit L holders and Permit L holders (p<0.01) and between those certified through continuing education or curriculum based programs (p<0.01). Significant relationships were found in demographics (p<0.01) and practice (p<0.05) items in relation to the length of time the Permit L has been held. Themes from the data and comments indicate multiple factors influencing obtaining or not obtaining the Permit L., Conclusion: The results of this study provide an overview of Permit L local anesthesia administration that is generally comparable to previous studies and offers new insights into why some Massachusetts dental hygienists choose not to pursue certification. This study highlights the potential to increase the prevalence of the Permit L, address barriers to pursuing the Permit L, and further evaluate self-perceived barriers., (Copyright © 2016 The American Dental Hygienists’ Association.)

HIV-1 maturation inhibition (MI) has been clinically validated as an approach to the control of HIV-1 infection. However, identifying an MI with both broad polymorphic spectrum coverage and good oral exposure has been challenging. Herein, we describe the design, synthesis, and preclinical characterization of a potent, orally active, second generation HIV-1 MI, BMS-955176 (2), which is currently in Phase IIb clinical trials as part of a combination antiretroviral regimen.

We have recently reported on the discovery of a C-3 benzoic acid (1) as a suitable replacement for the dimethyl succinate side chain of bevirimat (2), an HIV-1 maturation inhibitor that reached Phase II clinical trials before being discontinued. Recent SAR studies aimed at improving the antiviral properties of 2 have shown that the benzoic acid moiety conferred topographical constraint to the pharmacophore and was associated with a lower shift in potency in the presence of human serum albumin. In this manuscript, we describe efforts to improve the polymorphic coverage of the C-3 benzoic acid chemotype through modifications at the C-28 position of the triterpenoid core. The dimethylaminoethyl amides 17 and 23 delivered improved potency toward bevirimat-resistant viruses while increasing C24 in rat oral PK studies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A series of C-3 phenyl- and heterocycle-substituted derivatives of C-3 deoxybetulinic acid and C-3 deoxybetulin was designed and synthesized as HIV-1 maturation inhibitors (MIs) and evaluated for their antiviral activity and cytotoxicity in cell culture. A 4-subsituted benzoic acid moiety was identified as an advantageous replacement for the 3'3'-dimethylsuccinate moiety present in previously disclosed MIs that illuminates new aspects of the topography of the pharmacophore. The new analogs exhibit excellent in vitro antiviral activity against wild-type (wt) virus and a lower serum shift when compared with the prototypical HIV-1 MI bevirimat (1, BVM), the first MI to be evaluated in clinical studies. Compound 9a exhibits comparable cell culture potency toward wt virus as 1 (WT EC50=16 nM for 9a compared to 10nM for 1). However, the potency of 9a is less affected by the presence of human serum, while the compound displays a similar pharmacokinetic profile in rats to 1. Hence 9a, the 4-benzoic acid derivative of deoxybetulinic acid, represents a new starting point from which to explore the design of a 2nd generation MI., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The incidence of early childhood caries (ECC) is a global public health concern. The oral health knowledge of a caregiver can affect a child's risk for developing ECC. An exploratory study of the oral health knowledge and behaviors among caregivers of children 6 years of age and younger was conducted with a convenience sample of adults (n = 114) enrolled in English language or high school equivalency examination courses. The majority of study participants were born in Asia (47 %). Other birth regions included South America (16 %), Caribbean (16 %), Africa (10 %), and Central America (6 %). Study findings showed caregivers with low oral health knowledge were more likely to engage in behaviors that increase a child's risk for developing ECC. A statistically significant relationship was found between participants' rating of their child's dental health as poor and the belief that children should not be weaned from the nursing bottle by 12 months of age (P = 0.002), brushing should not begin upon tooth eruption (P = 0.01), and fluoride does not strengthen teeth and prevent dental caries (P = 0.005). Subjects who pre-chewed their child's food also exhibited behaviors including sharing eating utensils or a toothbrush with their child (P < 0.001). Additional caregiver behaviors included providing their child with a bottle containing cariogenic liquids in a crib (P < 0.001). As a result of this research, it is pertinent that culturally sensitive oral health promotion programs are developed and implemented to raise awareness and reduce the risk of dental disease among immigrant populations.