Knowledge, practices and expectations of preventive care: a qualitative study of patients attending government general outpatient clinics in Hong Kong.

BACKGROUND: Evidence-based preventive care recommendations have been well established, but studies have persistently reported gaps between these recommendations and general practitioners' practices in providing preventive care. Many studies have explored factors that affect the delivery of preventive care from the perspectives of the practitioners, but relatively few have evaluated the patients' point of view. The purpose of this study was to explore patients' understanding of preventive care, the actions they were taking in terms of preventive health and their expectations from family doctors in providing preventive care. METHODS: A qualitative study was conducted based on one-on-one in-depth interviews. Twenty-eight patients without chronic illnesses were purposively recruited from government general outpatient clinics in Hong Kong. The interviews took place between November 2013 and February 2014. RESULTS: The participants' knowledge of preventive care was limited, and their preventive practices were mostly restricted to healthy lifestyle practices. They rarely obtained individualised preventive care advice from doctors. Screening investigations were initiated after symptoms had already occurred, and the decision of what to check was arbitrary. Few of the participants knew what they wanted from their doctors in terms of preventive care. CONCLUSIONS: These findings show significant gaps between evidence-based preventive recommendations and patients' current knowledge and practice, and show the need for a wider spectrum of preventive care education and reliable sources to provide individualised and affordable preventive assessment and screening services. Most importantly, primary care providers must take a more proactive role to provide preventive services.

Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer.

We describe here the existence of a heregulin-HER3 autocrine loop, and the contribution of heregulin-dependent, HER2-mediated HER3 activation to gefitinib insensitivity in non-small cell lung cancer (NSCLC). ADAM17 protein, a major ErbB ligand sheddase, is upregulated in NSCLC and is required not only for heregulin-dependent HER3 signaling, but also for EGFR ligand-dependent signaling in NSCLC cell lines. A selective ADAM inhibitor, INCB3619, prevents the processing and activation of multiple ErbB ligands, including heregulin. In addition, INCB3619 inhibits gefitinib-resistant HER3 signaling and enhances gefitinib inhibition of EGFR signaling in NSCLC. These results show that ADAM inhibition affects multiple ErbB pathways in NSCLC and thus offers an excellent opportunity for pharmacological intervention, either alone or in combination with other drugs.

Detection and management of depression in adult primary care patients in Hong Kong: a cross-sectional survey conducted by a primary care practice-based research network.

BACKGROUND: This study aimed to examine the prevalence, risk factors, detection rates and management of primary care depression in Hong Kong. METHODS: A cross-sectional survey containing the PHQ-9 instrument was conducted on waiting room patients of 59 primary care doctors. Doctors blinded to the PHQ-9 scores reported whether they thought their patients had depression and their management. RESULTS: 10,179 patients completed the survey (response rate 81%). The prevalence of PHQ-9 positive screening was 10.7% (95% CI: 9.7%-11.7%). Using multivariate analysis, risk factors for being PHQ-9 positive included: being female; aged ≤34 years; being unmarried; unemployed, a student or a homemaker; having a monthly household income < HKD$30,000 (USD$3,800); being a current smoker; having no regular exercise; consulted a doctor or Chinese medical practitioner within the last month; having ≥ two co-morbidities; having a family history of mental illness; and having a past history of depression or other mental illness. Overall, 23.1% of patients who screened PHQ-9 positive received a diagnosis of depression by the doctor. Predictors for receiving a diagnosis of depression included: having higher PHQ-9 scores; a past history of depression or other mental health problem; being female; aged ≥35 years; being retired or a homemaker; being non-Chinese; having no regular exercise; consulted a doctor within the last month; having a family history of mental health problems; and consulted a doctor in private practice.In patients diagnosed with depression, 43% were prescribed antidepressants, 11% were prescribed benzodiazepines, 42% were provided with counseling and 9% were referred, most commonly to a counselor. CONCLUSION: About one in ten primary care patients screen positive for depression, of which doctors diagnose depression in approximately one in four. At greatest risk for depression are patients with a past history of depression, who are unemployed, or who have multiple illnesses. Patients most likely to receive a diagnosis of depression by a doctor are those with a past history of depression or who have severe symptoms of depression. Chinese patients are half as likely to be diagnosed with depression as non-Chinese patients. Over half of all patients diagnosed with depression are treated with medications.

Discovery of (4-Pyrazolyl)-2-aminopyrimidines as Potent and Selective Inhibitors of Cyclin-Dependent Kinase 2.

CDK2 is a critical regulator of the cell cycle. For a variety of human cancers, the dysregulation of CDK2/cyclin E1 can lead to tumor growth and proliferation. Historically, early efforts to develop CDK2 inhibitors with clinical applications proved unsuccessful due to challenges in achieving selectivity over off-target CDK isoforms with associated toxicity. In this report, we describe the discovery of (4-pyrazolyl)-2-aminopyrimidines as a potent class of CDK2 inhibitors that display selectivity over CDKs 1, 4, 6, 7, and 9. SAR studies led to the identification of compound 17, a kinase selective and highly potent CDK2 inhibitor (IC50 = 0.29 nM). The evaluation of 17 in CCNE1-amplified mouse models shows the pharmacodynamic inhibition of CDK2, measured by reduced Rb phosphorylation, and antitumor activity.

The associations of body mass index with physical and mental aspects of health-related quality of life in Chinese patients with type 2 diabetes mellitus: results from a cross-sectional survey.

BACKGROUND: This study aimed to determine the associations of various clinical factors with generic health-related quality of life (HRQOL) scores among Hong Kong Chinese patients with type 2 diabetes mellitus (T2DM) in the outpatient primary care setting using the short-form 12 (SF-12). METHODS: A cross-sectional survey of 488 Chinese adults with T2DM recruited from a primary care outpatient clinic was conducted from May to August 2008. Data on the standard Chinese (HK) SF-12 Health Survey and patients' socio-demographics were collected from face-to-face interviews. Glycaemic control, body mass index (BMI), chronic co-morbidities, diabetic complications and treatment modalities were determined for each patient through medical records. Associations of socio-demographic and clinical factors with physical component summary (PCS-12) and mental component summary scores (MCS-12) were evaluated using multiple linear regression. RESULTS: The socio-demographic correlates of PCS-12 and MCS-12 were age, gender and BMI. After adjustment for socio-demographic variables, the BMI was negatively associated with PCS-12 but positively associated with MCS-12. The presence of diabetic complications was associated with lower PCS-12 (regression coefficient:-3.0 points, p < 0.05) while being on insulin treatment was associated with lower MCS-12 (regression coefficient:-5.8 points, p < 0.05). In contrast, glycaemic control, duration of T2DM and treatment with oral hypoglycaemic drugs were not significantly associated with PCS-12 or MCS-12. CONCLUSIONS: Among T2DM subjects in the primary care setting, impairments in the physical aspect of HRQOL were evident in subjects who were obese or had diabetic complications whereas defects in the mental aspect of HRQOL were observed in patients with lower BMI or receiving insulin injections.

Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms.

Constitutive JAK2 activation in hematopoietic cells by the JAK2V617F mutation recapitulates myeloproliferative neoplasm (MPN) phenotypes in mice, establishing JAK2 inhibition as a potential therapeutic strategy. Although most polycythemia vera patients carry the JAK2V617F mutation, half of those with essential thrombocythemia or primary myelofibrosis do not, suggesting alternative mechanisms for constitutive JAK-STAT signaling in MPNs. Most patients with primary myelofibrosis have elevated levels of JAK-dependent proinflammatory cytokines (eg, interleukin-6) consistent with our observation of JAK1 hyperactivation. Accordingly, we evaluated the effectiveness of selective JAK1/2 inhibition in experimental models relevant to MPNs and report on the effects of INCB018424, the first potent, selective, oral JAK1/JAK2 inhibitor to enter the clinic. INCB018424 inhibited interleukin-6 signaling (50% inhibitory concentration [IC(50)] = 281nM), and proliferation of JAK2V617F(+) Ba/F3 cells (IC(50) = 127nM). In primary cultures, INCB018424 preferentially suppressed erythroid progenitor colony formation from JAK2V617F(+) polycythemia vera patients (IC(50) = 67nM) versus healthy donors (IC(50) > 400nM). In a mouse model of JAK2V617F(+) MPN, oral INCB018424 markedly reduced splenomegaly and circulating levels of inflammatory cytokines, and preferentially eliminated neoplastic cells, resulting in significantly prolonged survival without myelosuppressive or immunosuppressive effects. Preliminary clinical results support these preclinical data and establish INCB018424 as a promising oral agent for the treatment of MPNs.

Discovery of an orally-bioavailable CC Chemokine Receptor 2 antagonist derived from an acyclic diaminoalcohol backbone.

We describe an isostere-driven approach to improve upon a previously-described series of capped dipeptide antagonists of CC Chemokine Receptor 2 (CCR2). Modification of the substitution around the isostere was combined with additional changes in a distal aromatic substituent to provide single-digit nanomolar antagonists of CCR2. These studies led to the identification of 18, a compound that was suitable for studies in murine models of CCR2 activity.

Benzimidazoles as benzamide replacements within cyclohexane-based CC chemokine receptor 2 (CCR2) antagonists.

We describe the design, synthesis, and evaluation of benzimidazoles as benzamide replacements within a series of trisubstituted cyclohexane CCR2 antagonists. 7-Trifluoromethylbenzimidazoles displayed potent binding and functional antagonism of CCR2 while being selective over CCR3. These benzimidazoles were also incorporated into lactam-containing antagonists, thus completely eliminating the customary bis-amide.

The importance of transcultural nursing in cancer care.

All patients around the time of cancer diagnosis are emotionally vulnerable. This sense of anxiety is further heightened for patients who are not fully integrated into the society in which they are receiving care because of the cultural shock and language barriers they may face. This article explores the author's experience of caring for a patient from China who was studying in the UK and was admitted with acute promyelocytic leukaemia. The patient had a limited grasp of English and was used to very different cultural norms. Bridging the cultural gap as outlined by Narayanasamy in the ACCESS model (2002) enabled the author to provide the important holistic nursing care that could be easily overlooked in these situations. There is a need for nurses to actively seek to understand cultural differences and take the opportunity to experience transcultural nursing.

Discovery of 5,7-Dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-ones as Highly Selective CDK2 Inhibitors.

A series of exceptionally selective CDK2 inhibitors are described. Starting from an HTS hit, we successfully scaffold hopped to a 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one core structure, which imparted a promising initial selectivity within the CDK family. Extensive further SAR identified additional factors that drove selectivity to above 200× for CDKs 1/4/6/7/9. General kinome selectivity was also greatly improved. Finally, use of in vivo metabolite identification allowed us to pinpoint sulfonamide dealkylation as the primary metabolite, which was ameliorated through the deuterium effect.

Does vocational training in family medicine have an impact on antibiotic prescribing pattern?

BACKGROUND: Antibiotics overuse is common and is the major cause of antibiotic resistance. Rational use of antibiotics by GPs is essential as most health problems are exclusively dealt within primary care. Postgraduate family medicine (FM) training has become established in various countries over the last few decades but little is known about the effect of FM training on antibiotic prescribing. OBJECTIVE: To determine whether GPs with FM training prescribe less antibiotics than those without training. METHODS: GPs working in a pluralistic primary health care system took part in the 2007-08 primary care morbidity and management survey in Hong Kong and collected information of all consecutive patient encounters during predetermined weeks of data collection. Characteristics of GPs, training status, patient morbidity and antibiotic prescribing pattern were compared using multivariate regression analyses. RESULTS: One hundred and nine GPs, of whom 67 had FM training, participated in the study and recorded 69 973 health problems. The overall antibiotic prescribing rate was 8.5% and that of GPs with FM training was 5.4% compared with the 13.3% among those without. Multivariate logistic regression showed that GPs with FM training were less likely to prescribe antibiotics (odds ratio 0.68, P < 0.05). They had lower antibiotic prescribing rates when managing upper respiratory tract infections, acute bronchitis and cough but higher in treating infective conjunctivitis and acute laryngitis. CONCLUSIONS: Postgraduate FM training in Hong Kong is associated with significantly lower antibiotic prescribing rates. This supports the importance of FM training in rationalizing the use of antibiotics in Hong Kong.

The epidemiology and natural history of depressive disorders in Hong Kong's primary care.

BACKGROUND: Depressive disorders are commonly managed in primary care and family physicians are ideally placed to serve as central providers to these patients. Around the world, the prevalence of depressive disorders in patients presenting to primary care is between 10-20%, of which around 50% remain undiagnosed. In Hong Kong, many barriers exist preventing the optimal treatment and management of patients with depressive disorders. The pathways of care, the long term outcomes and the factors affecting prognosis of these patients requires closer examination. METHODS/DESIGN: The aim of this study is to examine the prevalence, incidence and natural history of depressive disorders in primary care and the factors influencing diagnosis, management and outcomes using a cross-sectional study followed by a longitudinal cohort study.Doctors working in primary care settings across Hong Kong have been invited to participate in this study. On one day each month over twelve months, patients in the doctor's waiting room are invited to complete a questionnaire containing items on socio-demography, co-morbidity, family history, previous doctor-diagnosed mental illness, recent mental and other health care utilization, symptoms of depression and health-related quality of life. Following the consultation, the doctors provide information regarding presenting problem, whether they think the patient has depression, and if so, whether the diagnosis is new or old, and the duration of the depressive illness if not a new diagnosis. If the doctor detects a depressive disorder, they are asked to provide information regarding patient management. Patients who consent are followed up by telephone at 2, 12, 26 and 52 weeks. DISCUSSION: The study will provide information regarding cross-sectional prevalence, 12 month incidence, remission rate, outcomes and factors affecting outcomes of patients with depressive disorders in primary care. The epidemiology, outcomes, pathways of care, predictors for prognosis and service needs for primary care patients with depressive disorders will be described and recommendations made for policy and service planning.

gamma-Lactams as glycinamide replacements in cyclohexane-based CC chemokine receptor 2 (CCR2) antagonists.

We describe the design, synthesis, and evaluation, of gamma-lactams as glycinamide replacements within a series of di- and trisubstituted cyclohexane CCR2 antagonists. The lactam-containing trisubstituted cyclohexanes proved to be more potent than the disubstituted analogs, as trisubstituted analog, lactam 13, displayed excellent activity (CCR2 binding IC(50)=1.0 nM and chemotaxis IC(50) = 0.5 nM) and improved metabolic stability over its parent glycinamide.

Brief problem-solving treatment in primary care (PST-PC) was not more effective than placebo for elderly patients screened positive of psychological problems.

OBJECTIVES: To evaluate whether screening followed by brief problem-solving treatment by primary care doctors (PST-PC) could improve health-related quality of life (HRQOL) and reduce consultation rates in the elderly. DESIGN: A single-blind randomized placebo controlled trial (RCT). SETTING: Two government funded primary care clinics in Hong Kong. PARTICIPANTS: Two hundred and ninety nine Chinese patients aged 60 years or over, with positive screening scores for psychological problems by the Hospital Anxiety and Depression Scale (HADS). INTERVENTIONS: One hundred and forty nine subjects were randomized to receive brief PST-PC from primary care doctors (treatment) and 150 to group video-viewing (placebo). All subjects were followed up by telephone at 6, 12, 26 and 52 weeks. MAIN OUTCOME MEASURES: Changes in SF-36 HRQOL scores, HADS scores and monthly consultation rates were compared within and between groups. RESULTS: Study completion rates were 69-71%. There was significant improvement in the SF-36 role-emotional (RE) and mental component summary (MCS) scores at week 6 in the PST-PC group but not in the placebo group. Several SF-36 scores improved significantly in the placebo (video) group at week 6-52. Mixed effects analysis adjusting for baseline values and cofounders did not show any difference in any of the outcomes between the PST-PC and placebo (video) groups. CONCLUSIONS: Screening followed by brief PST-PC was associated with a short-term improvement in HRQOL in Chinese elderly patients screened positive of psychological problems, but the HRQOL benefit was not greater than those found in the placebo group who participated in group-viewings of health education videos.

A qualitative study of the views of patients with long-term conditions on family doctors in Hong Kong.

BACKGROUND: Primary care based management of long-term conditions (LTCs) is high on the international healthcare agenda, including the Asia-Pacific region. Hong Kong has a 'mixed economy' healthcare system with both public and private sectors with a range of types of primary care doctors. Recent Hong Kong Government policy aims to enhance the management of LTCs in primary care possibly based on a 'family doctor' model. Patients' views on this are not well documented and the aim of the present study was to explore the views of patients with LTCs on family doctors in Hong Kong. METHODS: The views of patients (with a variety of LTCs) on family doctors in Hong Kong were explored. Two groups of participants were interviewed; a) those who considered themselves as having a family doctor, b) those who considered themselves as not having a family doctor (either with a regular primary care doctor but not a family doctor or with no regular primary care doctor). In-depth individual semi-structured interviews were carried out with 28 participants (10 with a family doctor, 10 with a regular doctor, and 8 with no regular doctor) and analysed using the constant comparative method. RESULTS: Participants who did not have a family doctor were familiar with the concept but regarded it as a 'luxury item' for the rich within the private healthcare system. Those with a regular family doctor (all private) regarded having one as important to their and their family's health. Participants in both groups felt that as well as the more usual family medicine specialist or general practitioner, traditional Chinese medicine practitioners also had the potential to be family doctors. However most participants attended the public healthcare system for management of their LTCs whether they had a family doctor or not. Cost, perceived need, quality, trust, and choice were all barriers to the use of family doctors for the management of their LTCs. CONCLUSIONS: Important barriers to the adoption of a 'family doctor' model of management of LTCs exist in Hong Kong. Effective policy implementation seems unlikely unless these complex barriers are addressed.

Identification of pAKT as a pharmacodynamic marker for MER kinase in human melanoma G361 cells.

BACKGROUND: The MER signaling pathway represents an attractive therapeutic target for human cancers. Growth arrest-specific protein 6 (GAS6)-induced MER phosphorylation is often unstable and difficult to detect without pervanadate pretreatment in human cancer cells, posing a challenge for the development of selective MER kinase inhibitors. Here, we identified phosphorylated AKT (pAKT) as a specific pharmacodynamic marker for MER kinase inhibitors in human melanoma G361 cells. METHODS: The expression of MER, TYRO3, and AXL were profiled among multiple human cancer cells. To determine whether they play a role in the activation of pAKT, MER and TYRO3 were selectively depleted by small, interfering RNA knockdown. In addition, using AKT phosphorylation as a readout, a high-throughput cell-based assay was established in G361 cells for evaluation of the potency of potential inhibitors of MER pathway activation. RESULTS: We demonstrated that high levels of MER and TYRO3, but not AXL, were expressed in G361 cells. In these cells, pAKT was induced by GAS6 treatment, which could be reversed by AXL/MER inhibitors. We showed that GAS6-induced pAKT is only dependent on MER kinase, but not TYRO3, in G361 cells. Furthermore, we observed a correlation in potency between inhibition of pAKT in G361 cells and pMER in MER-overexpressing Ba/F3 cells by these inhibitors. CONCLUSIONS: In summary, we have demonstrated that GAS6-induced pAKT is a possible pharmacodynamic marker for the inhibition of MER kinase, and we have successfully developed a cell-based functional assay for screening small-molecule inhibitors of MER kinase for potential therapeutic utility in treating GAS6/MER-deregulated human cancers.

A Potent and Selective Dual Inhibitor of AXL and MERTK Possesses Both Immunomodulatory and Tumor-Targeted Activity.

TYRO3, AXL, and MERTK constitute the TAM family of receptor tyrosine kinases, which play important roles in tumor growth, survival, cell adhesion, as well as innate immunity, phagocytosis, and immune-suppressive activity. Therefore, targeting both AXL and MERTK kinases may directly impact tumor growth and relieve immunosuppression. We describe here the discovery of INCB081776, a potent and selective dual inhibitor of AXL and MERTK that is currently in phase 1 clinical trials. In cellular assays, INCB081776 effectively blocked autophosphorylation of AXL or MERTK with low nanomolar half maximal inhibitory concentration values in tumor cells and Ba/F3 cells transfected with constitutively active AXL or MERTK. INCB081776 inhibited activation of MERTK in primary human macrophages and partially reversed M2 macrophage-mediated suppression of T-cell proliferation, which was associated with increased interferon-γ production. In vivo, the antitumor activity of INCB081776 was enhanced in combination with checkpoint blockade in syngeneic models, and resulted in increased proliferation of intratumoral CD4+ and CD8+ T cells. Finally, antitumor activity of INCB081776 was observed in a subset of sarcoma patient-derived xenograft models, which was linked with inhibition of phospho-AKT. These data support the potential therapeutic utility of INCB081776 as an immunotherapeutic agent capable of both enhancing tumor immune surveillance and blocking tumor cell survival mechanisms.

Pharmacological characterization of INCB3344, a small molecule antagonist of human CCR2.

The chemokine receptor 2 (CCR2) directs migration of monocytes and has been proposed to be a drug target for chronic inflammatory diseases. INCB3344 was first published as a small molecule nanomolar inhibitor of rodent CCR2. Here, we show that INCB3344 can also bind human CCR2 (hCCR2) with high affinity, having a dissociation constant (K(d)) of approximately 5nM. The binding of the compound to the receptor is rapid and reversible. INCB3344 potently inhibits hCCR2 binding of monocyte chemoattractant protein-1 (MCP-1) and MCP-1-induced signaling and function in hCCR2-expressing cells, including ERK phosphorylation and chemotaxis, and is competitive against MCP-1 in vitro. INCB3344 also blocks MCP-1 binding to monocytes in human whole blood, with potency consistent with in vitro studies. The whole blood binding assay described here can be used for monitoring pharmacodynamic activity of CCR2 antagonists in both preclinical models and in the clinic.

Discovery of trisubstituted cyclohexanes as potent CC chemokine receptor 2 (CCR2) antagonists.

A series of trisubstituted cyclohexanes was designed, synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the identification of two distinct substitution patterns about the cyclohexane ring as potent and selective CCR2 antagonists. Compound 36 exhibited excellent binding (CCR2 IC(50)=2.4 nM) and functional antagonism (calcium flux IC(50)=2.0 nM and chemotaxis IC(50)=5.1 nM).

Novel sulfone-containing di- and trisubstituted cyclohexanes as potent CC chemokine receptor 2 (CCR2) antagonists.

Potent sulfone-containing di- and trisubstituted cyclohexanes were synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the trisubstituted derivative 54, which exhibited excellent binding (CCR2 IC(50)=1.3nM) and functional antagonism (calcium flux IC(50)=0.5nM and chemotaxis IC(50)=0.2nM). The superiority of the trisubstituted scaffold was rationalized to be the result of a conformational rigidification, which provided insight into the bioactive conformation of this chemotype.