Patients' perceived quality of care and their satisfaction with care given for MDR-TB at referral hospitals in Ethiopia.

BACKGROUND: There is presently dearth of evidence in Ethiopia on patients' perception on quality of care given for multi-drug resistant tuberculosis (MDR-TB) and their satisfaction with the care and services they receive for the disease. Moreover, there is no evidence on the experiences and practices of caregivers for MDR-TB regarding the functionality of the programmatic management of MDR-TB at referral hospitals in Ethiopia. Thus, this study was conducted to address these gaps. Evidence in these areas would help to institute interventions that could enhance patient satisfaction and their adherence to the treatment given for MDR-TB. DESIGN AND METHODS: This study employed an inductive phenomenological approach to investigate patients' perception of the quality of care given for MDR-TB, level of their satisfaction with the care they received for MDR-TB and the experiences and practices of caregivers for MDR-TB on the functionality of the programmatic management of MDR-TB at referral hospitals in Ethiopia. The data were analysed manually, and that helped to get more control over the data. RESULTS: The majority of the patients were satisfied with the compassionate communication and clinical care they received at hospitals. However, as no doctor was dedicated exclusively for the MDR-TB centre of the hospitals, patients could not get timely medical attention during emergent medical conditions. Patients were dissatisfied with the poor communication and uncaring practice of caregivers found at treatment follow-up centres (TFCs). Patients perceived that socio-economic difficulties are both the cause of MDR-TB and it has also challenged their ability to cope-up with the disease and its treatment. Patients were dissatisfied with the poor quality and inadequate quantity of the socio-economic support they got from the programme. Despite the high MDR-TB and HIV/AIDS co-infection, services for both diseases were not available under one roof. CONCLUSIONS: Socio-economic challenges, inadequate socio-economic support, absence of integrated care for MDR-TB and HIV/AIDS, and the uncaring practice of caregivers at treatment follow-up centres are found to negatively affect patients' perceived quality of care and their satisfaction with the care given for MDR-TB. Addressing these challenges is recommended to assist patients' coping ability with MDR-TB and its treatment.

GNE-064: A Potent, Selective, and Orally Bioavailable Chemical Probe for the Bromodomains of SMARCA2 and SMARCA4 and the Fifth Bromodomain of PBRM1.

Bromodomains are acetyllysine recognition domains present in a variety of human proteins. Bromodomains also bind small molecules that compete with acetyllysine, and therefore bromodomains have been targets for drug discovery efforts. Highly potent and selective ligands with good cellular permeability have been proposed as chemical probes for use in exploring the functions of many of the bromodomain proteins. We report here the discovery of a class of such inhibitors targeting the family VIII bromodomains of SMARCA2 (BRM) and SMARCA4 (BRG1), and PBRM1 (polybromo-1) bromodomain 5. We propose one example from this series, GNE-064, as a chemical probe for the bromodomains SMARCA2, SMARCA4, and PBRM1(5) with the potential for in vivo use.

Treatment outcomes of patients with MDR-TB and its determinants at referral hospitals in Ethiopia.

BACKGROUND: There is limited empirical evidence in Ethiopia on the determinants of treatment outcomes of patients with multidrug-resistant tuberculosis (MDR-TB) who were enrolled to second-line anti-tuberculosis drugs. Thus, this study investigated the determinants of treatment outcomes in patients with MDR-TB at referral hospitals in Ethiopia. DESIGN AND METHODS: This study was underpinned by a cross-sectional quantitative research design that guided both data collection and analysis. Data is collected using structured questionnaire and data analyses was performed using the Statistical Package for Social Sciences. Multi-variable logistic regression was used to control for confounders in determining the association between treatment outcomes of patients with MDR-TB and selected predictor variables, such as co-morbidity with MDR-TB and body mass index. RESULTS: From the total of 136 patients with MDR-TB included in this study, 31% had some co-morbidity with MDR-TB at baseline, and 64% of the patients had a body mass index of less than 18.5 kg/m2. At 24 months after commencing treatment, 76 (69%), n = 110), of the patients had successfully completed treatment, while 30 (27%) died of the disease. The odds of death was significantly higher among patients with low body mass index (AOR = 2.734, 95% CI: 1.01-7.395; P<0.048) and those with some co-morbidity at baseline (AOR = 4.260, 95%CI: 1.607-11.29; p<0.004). CONCLUSION: The higher proportion of mortality among patients treated for MDR-TB at Adama and Nekemte Hospitals, central Ethiopia, is attributable to co-morbidities with MDR-TB, including HIV/AIDS and malnutrition. Improving socio-economic and nutritional support and provision of integrated care for MDR-TB and HIV/AIDS is recommended to mitigate the higher level of death among patients treated for MDR-TB.

Paramedic students' confidence and satisfaction with clinical simulations of an emergency medical care programme in South Africa: A cross-sectional study.

BACKGROUND: There has been an increase in the use of clinical simulations as instructional tools in healthcare education. This is because of their role in ensuring patients' safety and quality-care provision. AIM: This study investigated the paramedic students' satisfaction and self-confidence in the clinical simulation of an emergency medical care programme. SETTING: The study was conducted at the Durban University of Technology in the KwaZulu-Natal Province of South Africa. The paramedic students' satisfaction and self-confidence in the clinical simulation of an emergency medical care programme were the focus of the study. METHODS: The study used a cross-sectional research design. A convenience sampling method was used to select the 83-paramedic students who participated in the study. Data were collected between July and September 2017 using a structured questionnaire. Descriptive statistics (frequencies and percentages and Spearman's rank-order correlation coefficient) and an inferential test, ordinal logistic regression analysis, were used for data analysis. RESULTS: High levels of paramedic students' satisfaction and self-confidence in simulation activities were reported. Generally, the paramedic students' demographics were associated with the satisfaction and self-confidence variables with p-values ≤ 0.04. Emergency medical care training undertaken by the paramedic students was significantly associated with self-confidence (p = 0.00). CONCLUSION: Clinical simulation can bridge the theory-practice gap for paramedic students. It is a hands-on approach that promotes students learning of clinical skills through reflection.

Determinants of compassion in providing care to older people: Educational implications.

BACKGROUND: Care provision underpinned by compassion builds trust and ensures a deeper understanding of the health needs of older people. Yet nursing curricula in the United Kingdom focus on knowledge and skill acquisition rather than caring with compassion. This negatively impacts on the quality of care. Despite this, there is limited research on compassion in the care of older people. AIM: To explore the views of nurse educators (NE), pre-registration nursing students (PNS) and clinical mentors (CM) of the determinants of compassion in the care of older people. METHODS: A generic qualitative research design was used. Data were collected using semi-structured interviews with 39 participants (NE = 8; CM = 8; PNS = 23). These were digitally-recorded, fully transcribed and analysed thematically using NVivo software. FINDINGS: Three main themes emerged from the data analysis: the meaning of compassion, extrinsic determinants of compassion in care, and intrinsic determinants of compassion in care. DISCUSSION: The outcome of this study suggests that nurses and students think that compassion speeds up older people's recovery and enhances the quality of care. NEs consider its application in clinical practice a demonstration of competence. CONCLUSION: The inclusion of compassion in practical sessions of pre-registration nursing curricula and in the care of the older person may result in improved understanding of the latter and provision of holistic, safe and effective care.

Sexual behaviour among adolescents living with the human immunodeficiency virus in Zimbabwe: educational implications.

The incidence of HIV infection is increasing among adolescents in Zimbabwe. This rise in incidence is partly due to risky sexual behaviours yet there are no published research studies on sexual behaviours of HIV-positive adolescents in Zimbabwe. Hence, this study, which examined the sexual behaviours of HIV-positive adolescents. This study utilised a cross-sectional design with a conveniently selected sample of 341 HIV-positive adolescents. Data were collected through a questionnaire. Data were analysed using descriptive and analytical statistics. The study revealed that approximately 37 (11%) of the adolescents had engaged in sexual intercourse, and approximately 14 (60%) of these did not use condoms. Approximately 11 (30%) of the sexually active adolescents had multiple sexual partners, and only 9 (24.3%) of them had disclosed their HIV serostatus to their partners before sexual intercourse. A bivariate analysis revealed factors that were associated with being sexually activity. Examples of these include age (OR = 1.56, p < 0.001) and being treated by a psychiatrist (OR = 47.9, p < 0.001). A multivariate logistic regression analysis was carried out, revealing factors that were independently associated with being sexually active. Examples of these include age (AOR = 1.91, p < 0.01) and exposure to erotic television programmes (AOR = 3.9, p < 0.04). The results of the study indicate that the sexual risk behaviours of HIV-positive adolescents contributes to the increase in incidence and prevalence of HIV/AIDS in Zimbabwe. The development and rolling out of a health education programme will help health care workers to address this concern.

GNE-886: A Potent and Selective Inhibitor of the Cat Eye Syndrome Chromosome Region Candidate 2 Bromodomain (CECR2).

The biological function of bromodomains, epigenetic readers of acetylated lysine residues, remains largely unknown. Herein we report our efforts to discover a potent and selective inhibitor of the bromodomain of cat eye syndrome chromosome region candidate 2 (CECR2). Screening of our internal medicinal chemistry collection led to the identification of a pyrrolopyridone chemical lead, and subsequent structure-based drug design led to a potent and selective CECR2 bromodomain inhibitor (GNE-886) suitable for use as an in vitro tool compound.

Inhibition of bromodomain-containing protein 9 for the prevention of epigenetically-defined drug resistance.

Bromodomain-containing protein 9 (BRD9), an epigenetic "reader" of acetylated lysines on post-translationally modified histone proteins, is upregulated in multiple cancer cell lines. To assess the functional role of BRD9 in cancer cell lines, we identified a small-molecule inhibitor of the BRD9 bromodomain. Starting from a pyrrolopyridone lead, we used structure-based drug design to identify a potent and highly selective in vitro tool compound 11, (GNE-375). While this compound showed minimal effects in cell viability or gene expression assays, it showed remarkable potency in preventing the emergence of a drug tolerant population in EGFR mutant PC9 cells treated with EGFR inhibitors. Such tolerance has been linked to an altered epigenetic state, and 11 decreased BRD9 binding to chromatin, and this was associated with decreased expression of ALDH1A1, a gene previously shown to be important in drug tolerance. BRD9 inhibitors may therefore show utility in preventing epigenetically-defined drug resistance.

Identification of potent, selective KDM5 inhibitors.

This communication describes the identification and optimization of a series of pan-KDM5 inhibitors derived from compound 1, a hit initially identified against KDM4C. Compound 1 was optimized to afford compound 20, a 10nM inhibitor of KDM5A. Compound 20 is highly selective for the KDM5 enzymes versus other histone lysine demethylases and demonstrates activity in a cellular assay measuring the increase in global histone 3 lysine 4 tri-methylation (H3K4me3). In addition compound 20 has good ADME properties, excellent mouse PK, and is a suitable starting point for further optimization.

Regulatory T Cell Modulation by CBP/EP300 Bromodomain Inhibition.

Covalent modification of histones is a fundamental mechanism of regulated gene expression in eukaryotes, and interpretation of histone modifications is an essential feature of epigenetic control. Bromodomains are specialized binding modules that interact with acetylated histones, linking chromatin recognition to gene transcription. Because of their ability to function in a domain-specific fashion, selective disruption of bromodomain:acetylated histone interactions with chemical probes serves as a powerful means for understanding biological processes regulated by these chromatin adaptors. Here we describe the discovery and characterization of potent and selective small molecule inhibitors for the bromodomains of CREBBP/EP300 that engage their target in cellular assays. We use these tools to demonstrate a critical role for CREBBP/EP300 bromodomains in regulatory T cell biology. Because regulatory T cell recruitment to tumors is a major mechanism of immune evasion by cancer cells, our data highlight the importance of CREBBP/EP300 bromodomain inhibition as a novel, small molecule-based approach for cancer immunotherapy.

Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains.

Inhibition of the bromodomains of the BET family, of which BRD4 is a member, has been shown to decrease myc and interleukin (IL) 6 in vivo, markers that are of therapeutic relevance to cancer and inflammatory disease, respectively. Herein we report substituted benzo[b]isoxazolo[4,5-d]azepines and benzotriazolo[4,3-d][1,4]diazepines as fragment-derived novel inhibitors of the bromodomain of BRD4. Compounds from these series were potent and selective in cells, and subsequent optimization of microsomal stability yielded representatives that demonstrated dose- and time-dependent reduction of plasma IL-6 in mice.

Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials.

In recent years, inhibition of the interaction between the bromodomain and extra-terminal domain (BET) family of chromatin adaptors and acetyl-lysine residues on chromatin has emerged as a promising approach to regulate the expression of important disease-relevant genes, including MYC, BCL-2, and NF-κB. Here we describe the identification and characterization of a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor that attenuates BET-dependent gene expression in vivo, demonstrates antitumor efficacy in an MV-4-11 mouse xenograft model, and is currently undergoing human clinical trials for hematological malignancies (CPI-0610).

Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma.

Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Selective targeting of multiple myeloma cell lines through CBP/EP300 bromodomain inhibition is the result of direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4, which is essential for the viability of myeloma cells, and the concomitant repression of the IRF4 target gene c-MYC. Ectopic expression of either IRF4 or MYC antagonizes the phenotypic and transcriptional effects of CBP/EP300 bromodomain inhibition, highlighting the IRF4/MYC axis as a key component of its mechanism of action. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network.

Development of methyl isoxazoleazepines as inhibitors of BET.

In this report we detail the evolution of our previously reported thiophene isoxazole BET inhibitor chemotype exemplified by CPI-3 to a novel bromodomain selective chemotype (the methyl isoxazoleazepine chemotype) exemplified by carboxamide 23. The methyl isoxazoleazepine chemotype provides potent inhibition of the bromodomains of the BET family, excellent in vivo PK across species, low unbound clearance, and target engagement in a MYC PK-PD model.

Religion-related stigma and discrimination experienced by lesbian, gay, bisexual and transgender students at a South African rural-based university.

This paper reports on the stigma and discrimination experienced by lesbian, gay, bisexual and transgender students at a rural university in South Africa. Twenty lesbian, gay, bisexual and transgender students recruited through snowball sampling participated in this study. Interpretative Phenomenological Analysis was used as a framework for data analysis. Findings indicate that religion-related stigma and discrimination are common at a rural-based university in South Africa. Lesbian, gay, bisexual and transgender students are typically ascribed a range of labels, including 'sinners', 'devils' and 'demon possessed'. They are also exposed to a number of discriminatory acts, such as the denial of financial and healthcare services and threats of and/or actual rape. Study participants reported attempts to convert lesbian, gay, bisexual and transgender students' sexual orientation which involved the use of intervention in the form of prayers. Derogatory labelling and associated discriminatory acts, for example the threat of rape, led many students to conceal their sexual identity, not attend specific classes, terminate their studies and even attempt suicide. Universities should develop policies to promote greater social inclusion and the acceptance of lesbian, gay, bisexual and transgender students. Policies should also specify the steps or approaches to be taken in addressing discriminatory practices.

Blockade of oncogenic IκB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors.

In the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), NF-κB activity is essential for viability of the malignant cells and is sustained by constitutive activity of IκB kinase (IKK) in the cytoplasm. Here, we report an unexpected role for the bromodomain and extraterminal domain (BET) proteins BRD2 and BRD4 in maintaining oncogenic IKK activity in ABC DLBCL. IKK activity was reduced by small molecules targeting BET proteins as well as by genetic knockdown of BRD2 and BRD4 expression, thereby inhibiting downstream NF-κB-driven transcriptional programs and killing ABC DLBCL cells. Using a high-throughput platform to screen for drug-drug synergy, we observed that the BET inhibitor JQ1 combined favorably with multiple drugs targeting B-cell receptor signaling, one pathway that activates IKK in ABC DLBCL. The BTK kinase inhibitor ibrutinib, which is in clinical development for the treatment of ABC DLBCL, synergized strongly with BET inhibitors in killing ABC DLBCL cells in vitro and in a xenograft mouse model. These findings provide a mechanistic basis for the clinical development of BET protein inhibitors in ABC DLBCL, particularly in combination with other modulators of oncogenic IKK signaling.

Identification of EZH2 and EZH1 small molecule inhibitors with selective impact on diffuse large B cell lymphoma cell growth.

The histone methyltransferase enhancer of Zeste homolog 2 (EZH2) is a candidate oncogene due to its prevalent overexpression in malignant diseases, including late stage prostate and breast cancers. The dependency of cancer cells on EZH2 activity is also predicated by recurrent missense mutations residing in the catalytic domain of EZH2 that have been identified in subtypes of diffuse large B cell lymphoma, follicular lymphoma and melanoma. Herein, we report the identification of a highly selective small molecule inhibitor series of EZH2 and EZH1. These compounds inhibit wild-type and mutant versions of EZH2 with nanomolar potency, suppress global histone H3-lysine 27 methylation, affect gene expression, and cause selective proliferation defects. These compounds represent a structurally distinct EZH2 inhibitor chemotype for the exploration of the role of Polycomb Repressive Complex 2-mediated H3K27 methylation in various biological contexts.

The ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability.

Sequencing efforts led to the identification of somatic mutations that could affect the self-renewal and differentiation of cancer-initiating cells. One such recurrent mutation targets the binding pocket of the ubiquitin ligase Fbxw7. Missense FBXW7 mutations are prevalent in various tumors, including T cell acute lymphoblastic leukemia (T-ALL). To study the effects of such lesions, we generated animals carrying regulatable Fbxw7 mutant alleles. Here, we show that these mutations specifically bolster cancer-initiating cell activity in collaboration with Notch1 oncogenes but spare normal hematopoietic stem cell function. We were also able to show that FBXW7 mutations specifically affect the ubiquitylation and half-life of c-Myc protein, a key T-ALL oncogene. Using animals carrying c-Myc fusion alleles, we connected Fbxw7 function to c-Myc abundance and correlated c-Myc expression to leukemia-initiating activity. Finally, we demonstrated that small-molecule-mediated suppression of MYC activity leads to T-ALL remission, suggesting an effective therapeutic strategy.

Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors.

The identification of a novel series of small molecule BET inhibitors is described. Using crystallographic binding modes of an amino-isoxazole fragment and known BET inhibitors, a structure-based drug design effort lead to a novel isoxazole azepine scaffold. This scaffold showed good potency in biochemical and cellular assays and oral activity in an in vivo model of BET inhibition.