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Bee Kim Tan,1 Ping Chong Bee,2 Siew Siang Chua,1 Li-Chia Chen3 1School of Pharmacy, Faculty of Health and Medical Sciences, Taylor’s University, Subang Jaya, Selangor, 47500, Malaysia; 2Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, 50603, Malaysia; 3Centre for Pharmacoepidemiology and Drug Safety, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UKCorrespondence: Bee Kim TanSchool of Pharmacy, Faculty of Health and Medical Sciences, Taylor’s University, Subang Jaya, Selangor, 47500, MalaysiaTel +6 03 5629 5000Email beekim.tan@taylors.edu.myPurpose: Suboptimal adherence to tyrosine kinase inhibitors (TKIs) is a widely recognized issue compromising the disease control and survival of patients with chronic myeloid leukemia (CML). A recently published review by Heiney et al reported inconclusive findings on the effects of a broad range of adherence enhancing interventions. The current systematic review aimed to identify studies that evaluated adherence-enhancing interventions implemented by healthcare professionals and determine their effect on CML patients’ medication adherence and clinical outcomes.Methods: A systematic literature search was performed in 5 databases for articles published between 2002 and 2021. Studies that compared adherence enhancing interventions implemented by healthcare professionals with a comparison group were included. Relevant data on study characteristics were extracted. Medication adherence and clinical outcomes between intervention and control arms were compared.Results: Nine studies were included in two randomised controlled trials, four cohort studies, and three before-and-after comparison studies. All the included studies incorporated complex interventions, including intensive education or consultation with pharmacists, nurses or multidisciplinary team, in combination with one or more other strategies such as structured follow-up, written materials or video, psychotherapy, medication reminder or treatment diary, with the overall goal of monitoring and improving TKI adherence. Most (7 out of 9) studies demonstrated significantly better adherence to TKIs in the intervention group than the comparison group. The relative proportion of participants who adhered to TKIs ranged from 1.22 to 2.42. The improvement in the rate of TKI doses taken/received ranged from 1.5% to 7.1%. Only one study showed a significant association between intervention and clinical outcomes, with a 22.6% higher major molecular response rate and improvement in 6 out of 20 subscales of health-related quality-of-life.Conclusion: Complex interventions delivered by healthcare professionals showed improvement in adherence to TKIs in CML patients. Further studies are required to clarify the cost-effectiveness of adherence-enhancing interventions.Keywords: medication adherence, tyrosine kinase inhibitors, chronic myeloid leukemia, systematic review, complex interventions

Bee Kim Tan,1,2 Seng Beng Tan,3 Li-Chia Chen,4 Kian Meng Chang,5 Siew Siang Chua,1,6 Sharmini Balashanker,7 Habiba Nazeera Begum Kamarul Jaman,5 Syed Carlo Edmund,8 Ping Chong Bee3 1Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 2Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia; 3Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 4Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, UK; 5Department of Hematology, Ampang Hospital, Ampang, Selangor, Malaysia; 6School of Pharmacy, Faculty of Health and Medical Sciences, Taylor’s University, Lakeside Campus, Subang, Selangor, Malaysia; 7School of Pharmacy, University of Nottingham Malaysia Campus, Semenyih, Selangor, Malaysia; 8Clinical Research Center, Ampang Hospital, Ampang, Selangor, Malaysia Purpose: Poor adherence to tyrosine kinase inhibitors (TKIs) could compromise the control of chronic myeloid leukemia (CML) and contributes to poorer survival. Little is known about how medication-related issues affect CML patients’ adherence to TKI therapy in Malaysia. This qualitative study aimed to explore these issues.Patients and methods: Individual face-to-face, semistructured interviews were conducted at the hematology outpatient clinics of two medical centers in Malaysia from August 2015 to January 2016. CML patients aged ≥18 years who were prescribed a TKI were invited to participate in the study. Interviews were audio-recorded, transcribed verbatim, and thematically analyzed.Results: Four themes were identified from 18 interviews: 1) concerns about adverse reactions to TKIs, 2) personal beliefs regarding the use of TKIs, 3) mismanagement of TKIs in daily lives, and 4) financial burden in accessing treatment. Participants skipped their TKIs due to ineffective emesis control measures and perceived wastage of medication from vomiting. Participants also modified their TKI therapy due to fear of potential harm from long-term use, and stopped taking their TKIs based on belief in curative claims of traditional medicines and misconception about therapeutic effects of TKIs. Difficulty in integrating the dosing requirements of TKIs into daily lives led to unintentional skipping of doses, as well as the risk of toxicities from inappropriate dosing intervals or food interactions. Furthermore, financial constraints also resulted in delayed initiation of TKIs, missed clinic appointments, and treatment interruptions.Conclusion: Malaysian CML patients encountered a range of medication-related issues leading to a complex pattern of nonadherence to TKI therapy. Further studies should investigate whether regular contact with patients to improve understanding of treatment rationale, to elicit and address patients’ concerns about adverse reactions, and to empower patients with skills to self-manage their medications might promote better adherence to TKIs and improve CML patients’ outcome. Keywords: medication-related issues, adherence, tyrosine kinase inhibitors, chronic myeloid leukemia, qualitative study, thematic analysis

Objective: To investigate the effects of obesity on superfertility.Design: Retrospective observational study.Setting: A tertiary referral implantation clinic.Population: Four hundred and fourteen women attending a tertiary implantation clinic with a history of recurrent miscarriage (RMC), over a 4-year period.Methods: Pattern of pregnancy loss and time to pregnancy intervals for each pregnancy were collected by medical staff from women with RMC. The women were categorised into normal, overweight and obese according to their body mass index (BMI). Kaplan-Meier curves were constructed estimating the cumulative probability of a spontaneous pregnancy over time. The pregnancy loss patterns were correlated with BMI and data were compared between the categories using the Kruskal-Wallis test.Main Outcome Measures: Pregnancy loss pattern and time to pregnancy intervals.Results: Overall, 23.2, 51.4 and 64.2% of women conceived within first 1, 3 and 6 months, respectively. Obese women had cumulative pregnancy rates of 65.2 and 80% by three and 6 months, respectively, which was more than the cumulative pregnancy rates for women with normal BMI (49.2 and 65.8%). Comparison of survival curves indicated a significant difference in time to conceive for obese when compared with normal and overweight women (*P = 0.01), suggesting a higher prevalence of superfertility in obese women with RMC.Conclusions: Our findings suggest that obese women may have a greater efficacy to achieve pregnancy, but with an increased risk of miscarriage, which may suggest the possible metabolic effects of obesity on endometrium. [ABSTRACT FROM AUTHOR]

Objective: Reports of increased circulating fibroblast growth factor 21 (FGF21) levels in obesity indicate that FGF21 may be implicated in body weight homeostasis. We sought to investigate the existence of FGF21 in human cerebrospinal fluid (CSF) and, if present, the relationship between CSF FGF21 with body adiposity and metabolic parameters.Research Design and Methods: CSF and corresponding plasma FGF21 were measured by an enzyme-linked immunosorbent assay (18 men and 20 women, aged 19-80 years, and BMI 16.2-38.1 kg/m(2)) and correlated to body adiposity and metabolic parameters.Results: CSF and plasma FGF21 increased in particular with rising BMI and fat mass. In CSF, FGF21 was detectable at concentrations ~40% that of plasma levels. CSF and plasma FGF21 levels were significantly positively correlated with BMI and fat mass, body weight, plasma insulin, and homeostasis model assessment of insulin resistance. Plasma FGF21 levels were significantly negatively correlated with plasma adiponectin. When subjected to multiple regression analysis, only fat mass was predictive of plasma FGF21 (β = 0.758; P = 0.004) and CSF FGF21 (β = 0.767; P = 0.007). The CSF-to-plasma FGF21 ratio was significantly negatively correlated with BMI, fat mass, and plasma FGF21. Subjects in the highest plasma FGF21 quintile had a lower CSF-to-plasma FGF21 ratio (12.7% [9.7-14.9%]) compared with those in the lowest plasma FGF21 quintile (94.7% [37.3-99.8%]) (P < 0.01).Conclusions: Our observations have important implications with respect to the potential central actions of FGF21. Future research should seek to clarify whether FGF21 would be beneficial in the management of obesity and its metabolic complications. [ABSTRACT FROM AUTHOR]

Study Design: Observational cross-sectional study.Objective: To perform a psychometric evaluation of Simplified Chinese versions of back pain beliefs questionnaires for use in health care professionals living in mainland China.Summary Of Background Data: Back pain beliefs are of importance in the development of chronic low back pain (LBP) and disability. Different types of beliefs exist with regard to LBP and these include inevitable consequences of LBP and fear-avoidance beliefs. LBP beliefs held by health care providers are also known to influence their patients' pain beliefs and can contribute to the development of chronic LBP and disability. At present, validated questionnaires such as the Back Beliefs Questionnaire, Health Care Providers' Pain and Impairment Relationship Scale, and Fear-Avoidance Beliefs Questionnaire are commonly used to investigate back pain beliefs held by health care professionals working in western countries. There are no published nor validated Simplified Chinese versions to allow investigation of back pain beliefs in health care professionals living in mainland China.Methods: The English versions of the earlier mentioned questionnaires were translated and culturally adapted into Simplified Chinese using the double-back-translation method. A psychometric evaluation of the translated questionnaires was conducted on 65 health care professionals (rehabilitation medicine specialists, osteopaths, and nurses), with and without LBP, practicing in Shanghai, China. The questionnaires were completed twice within 7- to 10-day period.Results: The Back Beliefs Questionnaire, Health Care Providers' Pain and Impairment Relationship Scale, and Fear-Avoidance Beliefs Questionnaire (work and physical subscales) had acceptable internal consistency (Cronbach α range: 0.70-0.87) and construct validity (r = 0.40-0.49, P < 0.05), good reproducibility (Intraclass correlation coefficients, ICC(2,1) range: 0.85-0.93) and an absence of any floor or ceiling effects.Conclusion: This study showed that the Simplified Chinese versions of back pain beliefs questionnaires are valid and reliable. Therefore, these questionnaires can be used in research involving Chinese health care professionals living in mainland China. [ABSTRACT FROM AUTHOR]

This study investigated the effects of Rehmannia glutinosa individually as well as in combination with the oral hypoglycemic agent, metformin in streptozotocin (STZ)-induced diabetic Wistar rats. R. glutinosa ethanolic extract was prepared and the constituents were characterized using fractionation by column chromatography, followed by high performance liquid chromatography-mass spectrometry. STZ (65 mg/kg) was injected intraperitoneally to induce diabetes in Wistar rats. The diabetic rats were divided into the following groups (each n = 6) and received the respective treatments for 30 days: (1) metformin (500 mg/kg), (2) R. glutinosa (200 mg/kg), (3) metformin (500 mg/kg) and R. glutinosa (200 mg/kg) and (4) diabetic control (DC). A reduction in plasma glucose levels caused by the herb was not as significant as metformin compared to the diabetic control (p < 0.05). However, R. glutinosa-treated group showed reductions in plasma C-reactive protein (CRP) levels compared to the diabetic controls (p < 0.05) as well as metformin-treated group (p < 0.05). An enhanced reduction in CRP concentration was observed in the group receiving both herb and metformin compared to metformin-treated group (p < 0.05). Reduction in CRP levels suggests an anti-inflammatory activity of the herb. [ABSTRACT FROM AUTHOR]

Oxidative stress is the root cause of diabetic macro- and microvascular complications. Biochemical and epidemiological studies indicate that current treatments for diabetes do not reduce risks of developing complications, suggesting their inability to alleviate the levels of oxidative stress. This study in streptozotocin (STZ)-induced diabetic rats was carried out to investigate the effect of combining the antidiabetic drug, metformin, with an ethanolic extract of Scutellaria baicalensis, a plant whose root is known for its radical scavenging activity. Three groups of STZ-induced diabetic rats were given the following treatments for 30 days: (1) metformin 500 mg/kg, (2) S. baicalensis 400 mg/kg, (3) metformin 500 mg/kg + S. baicalensis extract 400 mg/kg. In addition, vehicle-treated diabetic and nondiabetic controls were used in the experiment. The rats treated with S. baicalensis and metformin + S. baicalensis had elevated hepatic activities of the antioxidant enzymes - superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) compared to the vehicle- and metformin-treated diabetic groups (p < 0.05). Plasma and hepatic lipid peroxide concentrations in the herb-treated and herb + metformin-treated groups were also significantly reduced (p < 0.05). In addition, the combined treatment caused significant elevations of plasma and pancreatic insulin levels and reductions of plasma and hepatic triglycerides (TG) and cholesterol levels. The study thus showed that S. baicalensis enhanced the antidiabetic effect of metformin in STZ-induced diabetic rats by improving the antioxidant status. It also increased pancreatic insulin content as well as improved the lipid profile in these rats. [ABSTRACT FROM AUTHOR]

Questions: Are there any differences in the displacement and endurance of an elevating voluntary pelvic floor muscle contraction in standing and in crook-lying? Are there any differences in these variables between males and females in either test position? Design: An experimental study. Participants: Forty-five nulliparous female and 20 male participants aged 23 years (SD 3) with no symptoms of urinary incontinence or low back pain. Intervention: Voluntary pelvic floor muscle contraction was measured in both standing and crook-lying. Outcome measures: Transabdominal ultrasound was used to measure the displacement (mm) and endurance (s) of pelvic floor elevation. Results: Displacement was greater in standing than in crook-lying (mean difference 2.6 mm, 95% CI 1.5 to 3.7). There was no difference between males and females (mean difference 1.3 mm, 95% CI 0.5 to 3.2). Similarly, endurance of pelvic floor elevation was longer in standing than in crook-lying (mean difference 17.3 s, 95% CI 12.2 to 22.4). Again there was no difference between males and females (mean difference 0.5 s, 95% CI 9.3 to 8.3). Conclusion: Standing was found to be a more effective position for achieving and sustaining an elevation of the pelvic floor compared to crook-lying, regardless of sex, and this should be taken into account when assessing and training pelvic floor muscle contraction. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Visfatin is elevated in obesity and type 2 diabetes and is thought to be an inflammatory mediator within atherosclerotic lesions and to induce gelatinase activity. We investigated the activation of nuclear factor-kappaB (NF-kappaB), a well-known proinflammatory transcription factor, by visfatin in endothelial cells. RESEARCH DESIGN AND METHODS: Human endothelial cells were transfected with pNF-kappaB-Luc plasmid. Using quantitative PCR, Western blot analysis, and gelatin zymography, we studied NF-kappaB signaling in gelatinase-mediated vascular inflammation by visfatin using the NF-kappaB inhibitor BAY 11-7085. RESULTS: Visfatin significantly increased NF-kappaB transcriptional activity (P < 0.001). We also found a significant inhibition of tumor necrosis factor-alpha (TNF-alpha)-induced NF-kappaB activity by visfatin (P < 0.001). Furthermore, the NF-kappaB inhibitor significantly negated visfatin-induced matrix metalloproteinase (MMP)-2/9 mRNA expression, protein levels, and gelatinolytic activity (P < 0.001). CONCLUSIONS: Visfatin-induced NF-kappaB signaling in human endothelial cells affects the activation of gelatinases MMP-2 and -9, suggesting an important role of visfatin in the pathogenesis of vascular inflammation in obesity and type 2 diabetes. [ABSTRACT FROM AUTHOR]