Search

Objective: This study tested the mediation effect of maladaptive cognition of internet gaming and moderation effect of internet gaming history in the relationship between internet gaming engagement and internet gaming disorder in adolescents., Method: A total of 2,902 secondary school students were surveyed in Hong Kong from February 2021 to December 2021. The proposed moderated mediation model was tested by PROCESS., Results: Internet gaming engagement, internet gaming history and maladaptive cognition were positively associated with internet gaming disorder symptoms. Maladaptive cognition significantly mediated the association between internet gaming engagement and internet gaming disorder symptoms in both males and females. In addition, a significant interaction between internet gaming engagement and internet gaming history was detected among females but not for males, namely, the positive relationships of internet gaming engagement with maladaptive cognition and internet gaming disorder symptoms were weaker with the increased years of internet gaming., Conclusions: Our study provides a better understanding of the underlying mechanism and boundary condition in the association between internet gaming engagement and internet gaming disorder among adolescents. Preventing interventions should aim to reduce maladaptive cognition and internet gaming engagement. Interventions targeting internet gaming engagement maybe more effective among female gamers who are beginners and all male gamers., Competing Interests: The authors have declared that no competing interests exist, (Copyright: © 2023 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Acute respiratory infections (ARIs) are one of the leading causes of childhood morbidity and mortality worldwide. However, there is limited surveillance data on the epidemiological burden of respiratory pathogens in tropical countries like Malaysia. This study aims to estimate the prevalence of respiratory pathogens causing ARIs among children aged <18 years old in Malaysia and their epidemiological characteristics., Methods: Nasopharyngeal swab specimens received at 12 laboratories located in different states of Malaysia from 2015-2019 were studied. Detection of 18 respiratory pathogens were performed using multiplex PCR., Results: Data from a total of 23,306 paediatric patients who presented with ARI over a five-year period was studied. Of these, 18538 (79.5%) were tested positive. The most prevalent respiratory pathogens detected in this study were enterovirus/ rhinovirus (6837/ 23000; 29.7%), influenza virus (5176/ 23000; 22.5%) and respiratory syncytial virus (RSV) (3652/ 23000; 15.9%). Throughout the study period, RSV demonstrated the most pronounce seasonality; peak infection occurred during July to September. Whereas the influenza virus was detected year-round in Malaysia. No seasonal variation was noted in other respiratory pathogens. The risk of RSV hospitalisation was found to be significantly higher in children aged less than two years old, whereas hospitalisation rates for the influenza virus peaked at children aged between 3-6 years old., Conclusion: This study provides insight into the epidemiology and the seasonality of the causative pathogens of ARI among the paediatric population in Malaysia. Knowledge of seasonal respiratory pathogens epidemiological dynamics will facilitate the identification of a target window for vaccination., Competing Interests: The authors have declared that no competing interests exist.

Objectives: This study aims to investigate the potential factors associated with mental health outcomes among Chinese adults during the Coronavirus disease 2019 (COVID-19) epidemic., Methods: This is an online cross-sectional survey conducted among Chinese adults in February 2020. Outcome measurements included the three-item UCLA Loneliness Scale (UCLA-3), two-item Patient Health Questionnaire (PHQ-2), two-item Generalized Anxiety Disorder Questionnaire (GAD-2), and two items from the Clinician-Administered Post-traumatic Stress Disorder (PTSD) Scale. COVID-19 related factors, physical health, lifestyle, and self-efficacy were also measured. Univariable and multivariable logistic regressions were performed., Results: This study included 1456 participants (age: 33.8±10.5 years; female: 59.1%). The prevalence of depressive symptoms, anxiety symptoms, loneliness, and PTSD symptoms were 11.3%, 7.6%, 38.7%, and 33.9%, respectively. In multivariable analysis, loneliness was associated with being single, separated/divorced/widowed, low level of education, current location, medication, more somatic symptoms, lower self-efficacy, and going out frequently. Depression was associated with fear of infection, binge drinking, more somatic symptoms, lower self-efficacy, and longer screen time. Anxiety was associated with more somatic symptoms and lower self-efficacy. PTSD symptoms were associated with more somatic symptoms, lower self-efficacy, higher perceived risk of infection, fear of infection, and self-rated more negative influence due to the epidemic (p<0.05)., Conclusions: Mental health problems during the COVID-19 epidemic were associated with various biopsychosocial and COVID-19 related factors. Psychological interventions should be aware of these influencing factors and prioritize support for those people at higher risk., Competing Interests: The authors have declared that no competing interests exist.

The novel coronavirus (COVID-19) infection has spread worldwide since late 2019. People who have social contacts with COVID-19 patients might be at higher risk of physical or mental health problems. This study investigated whether people who had social contacts with COVID-19 patients would have poorer physical or mental outcomes, and different attitudes and behaviors. Chinese adults were recruited to fill in an online survey using snowball sampling during 21st-26nd February 2020. Physical symptoms, psychological outcomes, quality of life, COVID-19 related attitudes, and behaviors were measured. The differences in the outcomes between participants who had COVID-19 social contacts and those who had not were analyzed. The survey included 1,447 non-infected eligible participants. Among those, 173 (12.0%) reported at least one confirmed/suspected case in their social contacts. In the multiple regression adjusted for demographic data, the presence of confirmed/suspected infection cases in one's social contacts was significantly associated with poorer physical and mental outcomes, lower health-related quality of life, and different COVID-19 related attitudes and behaviors (p<0.05). In conclusion, people who had social contacts with COVID-19 patients were at risk of adverse health outcomes. Future studies are needed to understand the long-term impacts. Similarly, strategies to improve health outcomes for these people are needed., Competing Interests: The authors have declared that no competing interests exist.

The primary components of human hair shaft-keratin and keratin-associated proteins (KAPs), together with their cross-linked networks-are the underlying reason for its rigid structure. It is therefore requisite to overcome the obstacle of hair insolubility and establish a reliable protocol for the proteome analysis of this accessible specimen. The present study employed an alkaline-based method for the efficient isolation of hair proteins and subsequently examined them using gel-based proteomics. The introduction of two proteomic protocols, namely the conventional and modified protocol, have resulted in the detection of more than 400 protein spots on the two-dimensional gel electrophoresis (2DE). When compared, the modified protocol is deemed to improve overall reproducibility, whilst offering a quick overview of the total protein distribution of hair. The development of this high-performance protocol is hoped to provide a new approach for hair analysis, which could possibly lead to the discovery of biomarkers for hair in health and diseases in the future., Competing Interests: The authors have declared that no competing interests exist.

Although Hong Kong is one of the richest cities in the world and has some of the best health outcomes such as long life expectancy, little is known about the people who are unable to access healthcare due to lack of financial means. Cross-sectional data from a sample of 2,233 participants aged 18 or above was collected from the first wave of the "Trends and Implications of Poverty and Social Disadvantages in Hong Kong" survey. Socio-demographic factors, lifestyle factors, and physical and mental health conditions associated with people who were unable to seek medical services due to lack of financial means in the past year were examined using forward stepwise logistic regression analyses. Of the 2,233 participants surveyed, 8.4% did not seek medical care due to lack of financial means during the past year. They were more likely to be income-poor. With respect to physical and mental health, despite having less likelihood to have multimorbidity, they tended to have higher levels of both anxiety and stress, poorer physical and mental health-related quality of life, and suffer from more severe disability and pain symptoms affecting their daily activities, when compared to the rest of the Hong Kong population. People who were denied of medical care due to financial barriers are generally sicker than people in the general Hong Kong population, implying that those with greater healthcare needs may have financial difficulties in receiving timely and appropriate medical care. Our findings suggest that inequity in healthcare utilization remains a critical issue in Hong Kong., Competing Interests: The authors have declared that no competing interests exist.

Competing Interests: The authors have declared that no competing interests exist.

Proteome analysis of the human hair remains challenging due to the poor solubility of hair proteins and the difficulty in their extraction. In the present study, we have developed a rapid extraction protocol for hair shaft protein using alkaline-based buffer. The new protocol accelerated the procedure by reducing the extraction time from at least a day to less than two hours and showed a protein recovery of 47.3 ± 3.72%. Further analyses of the extracted protein sample through sodium dodecyl sulfate polyacrylamide gel electrophoresis and Quadrupole-time-of-flight mass spectrometry analysis unveiled a total of 60 proteins, including 25 that were not previously reported. Identification of these proteins is anticipated to be crucial in helping to understand the molecular basis of hair for potential applications in the future., Competing Interests: The authors have declared that no competing interests exist.

The Sonic hedgehog (Shh) signaling pathway regulates developmental, homeostatic, and repair processes throughout the body. In the skin, touch domes develop in tandem with primary hair follicles and contain sensory Merkel cells. The developmental signaling requirements for touch dome specification are largely unknown. We found dermal Wnt signaling and subsequent epidermal Eda/Edar signaling promoted Merkel cell morphogenesis by inducing Shh expression in early follicles. Lineage-specific gene deletions revealed intraepithelial Shh signaling was necessary for Merkel cell specification. Additionally, a Shh signaling agonist was sufficient to rescue Merkel cell differentiation in Edar-deficient skin. Moreover, Merkel cells formed in Fgf20 mutant skin where primary hair formation was defective but Shh production was preserved. Although developmentally associated with hair follicles, fate mapping demonstrated Merkel cells primarily originated outside the hair follicle lineage. These findings suggest that touch dome development requires Wnt-dependent mesenchymal signals to establish reciprocal signaling within the developing ectoderm, including Eda signaling to primary hair placodes and ultimately Shh signaling from primary follicles to extrafollicular Merkel cell progenitors. Shh signaling often demonstrates pleiotropic effects within a structure over time. In postnatal skin, Shh is known to regulate the self-renewal, but not the differentiation, of touch dome stem cells. Our findings relate the varied effects of Shh in the touch dome to the ligand source, with locally produced Shh acting as a morphogen essential for lineage specification during development and neural Shh regulating postnatal touch dome stem cell maintenance.

Background: The increase in non-communicable disease (NCD) is becoming a global health problem and there is an increasing need for primary care doctors to look after these patients although whether family doctors are adequately trained and prepared is unknown., Objective: This study aimed to determine if doctors with family medicine (FM) training are associated with enhanced empathy in consultation and enablement for patients with chronic illness as compared to doctors with internal medicine training or without any postgraduate training in different clinic settings., Methods: This was a cross-sectional questionnaire survey using the validated Chinese version of the Consultation and Relational Empathy (CARE) Measure as well as Patient Enablement Instrument (PEI) for evaluation of quality and outcome of care. 14 doctors from hospital specialist clinics (7 with family medicine training, and 7 with internal medicine training) and 13 doctors from primary care clinics (7 with family medicine training, and 6 without specialist training) were recruited. In total, they consulted 823 patients with chronic illness. The CARE Measure and PEI scores were compared amongst doctors in these clinics with different training background: family medicine training, internal medicine training and those without specialist training. Generalized estimation equation (GEE) was used to account for cluster effects of patients nested with doctors., Results: Within similar clinic settings, FM trained doctors had higher CARE score than doctors with no FM training. In hospital clinics, the difference of the mean CARE score for doctors who had family medicine training (39.2, SD = 7.04) and internal medicine training (35.5, SD = 8.92) was statistically significant after adjusting for consultation time and gender of the patient. In the community care clinics, the mean CARE score for doctors with family medicine training and those without specialist training were 32.1 (SD = 7.95) and 29.2 (SD = 7.43) respectively, but the difference was not found to be significant. For PEI, patients receiving care from doctors in the hospital clinics scored significantly higher than those in the community clinics, but there was no significant difference in PEI between patients receiving care from doctors with different training backgrounds within similar clinic setting., Conclusion: Family medicine training was associated with higher patient perceived empathy for chronic illness patients in the hospital clinics. Patient enablement appeared to be associated with clinic settings but not doctors' training background. Training in family medicine and a clinic environment that enables more patient doctor time might help in enhancing doctors' empathy and enablement for chronic illness patients.

Introduction: Multimorbidity has been well researched in terms of consequences and healthcare implications. Nevertheless, its risk factors and determinants, especially in the Asian context, remain understudied. We tested the hypothesis of a negative relationship between socioeconomic status and multimorbidity, with contextually different patterns from those observed in the West., Methods: We conducted our study in the general Hong Kong (HK) population. Data on current health conditions, health behaviours, socio-demographic and socioeconomic characteristics was obtained from HK Government's Thematic Household Survey. 25,780 individuals aged 15 or above were sampled. Binary logistic and negative binomial regression analyses were conducted to identify risk factors for presence of multimorbidity and number of chronic conditions, respectively. Sub-analysis of possible mediation effect through financial burden borne by private housing residents on multimorbidity was also conducted., Results: Unadjusted and adjusted models showed that being female, being 25 years or above, having an education level of primary schooling or below, having less than HK$15,000 monthly household income, being jobless or retired, and being past daily smoker were significant risk factors for the presence of multimorbidity and increased number of chronic diseases. Living in private housing was significantly associated with higher chance of multimorbidity and increased number of chronic diseases only after adjustments., Conclusions: Less advantaged people tend to have higher risks of multimorbidity and utilize healthcare from the public sector with poorer primary healthcare experience. Moreover, middle-class people who are not eligible for government subsidized public housing may be of higher risk of multimorbidity due to psychosocial stress from paying for the severely unaffordable private housing.

Objectives: Primary care is the key element of health reform in China. The objective of this study was to compare patient assessed quality of public primary care between Hong Kong, a city with established primary care environment influenced by its colonial history, and Shanghai, a city leading primary care reform in Mainland China; and to measure the equity of care in the two cities., Methods: Cross sectional stratified random sampling surveys were conducted in 2011. Data were collected from 1,994 respondents in Hong Kong and 811 respondents in Shanghai. A validated Chinese version of the primary care assessment tool was employed to assess perceived quality of primary care with respect to socioeconomic characteristics and health status., Results: We analyzed 391 and 725 respondents in Hong Kong and Shanghai, respectively, who were regular public primary care users. Respondents in Hong Kong reported significant lower scores in first contact accessibility (1.59 vs. 2.15), continuity of care (2.33 vs. 3.10), coordination of information (2.84 vs. 3.64), comprehensiveness service availability (2.43 vs. 3.31), comprehensiveness service provided (2.11 vs. 2.40), and the total score (23.40 vs. 27.40), but higher scores in first contact utilization (3.15 vs. 2.54) and coordination of services (2.67 vs. 2.40) when compared with those in Shanghai. Respondents with higher income reported a significantly higher total primary care score in Hong Kong, but not in Shanghai., Conclusions: Respondents in Shanghai reported better quality of public primary care than those in Hong Kong, while quality of public primary care tended to be more equitable in Shanghai.

Objective: To examine the diagnostic performance of shorter versions of Alcohol Use Disorder Identification Test (AUDIT), including Alcohol Consumption (AUDIT-C), in identifying risky drinkers in primary care settings using conventional performance measures, supplemented by decision curve analysis and reclassification table., Study Design and Setting: A cross-sectional study of adult males in general outpatient clinics in Hong Kong. The study included only patients who reported at least sometimes drinking alcoholic beverages. Timeline follow back alcohol consumption assessment method was used as the reference standard. A Chinese translated and validated 10-item AUDIT (Ch-AUDIT) was used as a screening tool of risky drinking., Results: Of the participants, 21.7% were classified as risky drinkers. AUDIT-C has the best overall performance among the shorter versions of Ch-AUDIT. The AUC of AUDIT-C was comparable to Ch-AUDIT (0.898 vs 0.901, p-value = 0.959). Decision curve analysis revealed that when the threshold probability ranged from 15-30%, the AUDIT-C had a higher net-benefit than all other screens. AUDIT-C improved the reclassification of risky drinking when compared to Ch-AUDIT (net reclassification improvement = 0.167). The optimal cut-off of AUDIT-C was at ≥5., Conclusion: Given the rising levels of alcohol consumption in the Chinese regions, this Chinese translated 3-item instrument provides convenient and time-efficient risky drinking screening and may become an increasingly useful tool.

Background: Chronic low back pain is a serious global health problem. There is substantial evidence that physicians' attitudes towards and beliefs about chronic low back pain can influence their subsequent management of the condition., Objectives: (1) to evaluate the attitudes and beliefs towards chronic low back pain among primary care physicians in Asia; (2) to study the cultural differences and other factors that are associated with these attitudes and beliefs., Method: A cross sectional online survey was sent to primary care physicians who are members of the Hong Kong College of Family Physician (HKCFP). The Pain Attitudes and Beliefs Scale for Physiotherapist (PABS-PT) was used as the questionnaire to determine the biomedical and biopsychosocial orientation of the participants., Results: The mean Biomedical (BM) score was 34.8+/-6.1; the mean biopsychosocial (BPS) score was 35.6 (+/- 4.8). Both scores were higher than those of European doctors. Family medicine specialists had a lower biomedical score than General practitioners. Physicians working in the public sector tended to have low BM and low BPS scores; whereas physicians working in private practice tended to have high BM and high BPS scores., Conclusion: The lack of concordance in the pain explanatory models used by private and public sector may have a detrimental effect on patients who are under the care of both parties. The uncertain treatment orientation may have a negative influence on patients' attitudes and beliefs, thus contributing to the tension and, perhaps, even ailing mental state of a person with chronic LBP.

Objective: Depression is common in women with much research focusing on hormonal changes and menopausal symptoms but with little exploration of psychosocial problems in midlife. This study investigates the prevalence of clinically relevant depressive symptoms in midlife Chinese women and its association with psychosocial factors., Methods: A cross-sectional, community-based household survey of women aged 45 to 64 years of age was conducted in Hong Kong from September 2010 to March 2011. The structured questionnaire included demographic data, educational status, marital status and household income, as well as perceived current stressful events and significant life events in the past 12 months. Information on clinically relevant depressive symptoms was measured by the validated chinese Patient Health Questionnaire (PHQ-9)., Results: A total of 402 participants were recruited in the study period. Of the 393 women who completed the questionnaire, the prevalence of clinically relevant depressive symptoms (PHQ-9 score≧10) was 11.0%. In multiple regression analysis, being single/divorced/separated/widowed, having an educational level of primary school level or below, having multiple chronic diseases, loss of hobby or loss of close social support in the past 12 months in midlife were associated with clinically relevant depressive symptoms., Conclusions: Correlates of clinically relevant depressive symptoms in midlife Chinese women can be used to identify those at increased risk and potentiate further studies to explore early psychosocial and community interventions.

To delineate the temporal dynamics between alcohol tax policy changes and related health outcomes, this study examined the age, period and cohort effects on alcohol-related mortality in relation to changes in government alcohol policies. We used the age-period-cohort modeling to analyze retrospective mortality data over 30 years from 1981 to 2010 in a rapidly developed Chinese population, Hong Kong. Alcohol-related mortality from 1) chronic causes, 2) acute causes, 3) all (chronic+acute) causes and 4) causes 100% attributable to alcohol, as defined according to the Alcohol-Related Disease Impact (ARDI) criteria developed by the US Centers for Disease Control and Prevention, were examined. The findings illustrated the possible effects of alcohol policy changes on adult alcohol-related mortality. The age-standardized mortality trends were generally in decline, with fluctuations that coincided with the timing of the alcohol policy changes. The age-period-cohort analyses demonstrated possible temporal dynamics between alcohol policy changes and alcohol-related mortality through the period effects, and also generational impact of alcohol policy changes through the cohort effects. Based on the illustrated association between the dramatic increase of alcohol imports in the mid-1980s and the increased alcohol-related mortality risk of the generations coming of age of majority at that time, attention should be paid to generations coming of drinking age during the 2007-2008 duty reduction.

Background: Isoniazid (INH) is a highly effective antibiotic central for the treatment of Mycobacterium tuberculosis (MTB). INH-resistant MTB clinical isolates are frequently mutated in the katG gene and the inhA promoter region, but 10 to 37% of INH-resistant clinical isolates have no detectable alterations in currently known gene targets associated with INH-resistance. We aimed to identify novel genes associated with INH-resistance in these latter isolates., Methodology/principal Findings: INH-resistant clinical isolates of MTB were pre-screened for mutations in the katG, inhA, kasA and ndh genes and the regulatory regions of inhA and ahpC. Twelve INH-resistant isolates with no mutations, and 17 INH-susceptible MTB isolates were subjected to whole genome sequencing. Phylogenetically related variants and synonymous mutations were excluded and further analysis revealed mutations in 60 genes and 4 intergenic regions associated with INH-resistance. Sanger sequencing verification of 45 genes confirmed that mutations in 40 genes were observed only in INH-resistant isolates and not in INH-susceptible isolates. The ratios of non-synonymous to synonymous mutations (dN/dS ratio) for the INH-resistance associated mutations identified in this study were 1.234 for INH-resistant and 0.654 for INH-susceptible isolates, strongly suggesting that these mutations are indeed associated with INH-resistance., Conclusion: The discovery of novel targets associated with INH-resistance described in this study may potentially be important for the development of improved molecular detection strategies.

Background and Objectives: Many studies have shown the adverse effects of air pollution on respiratory health, but few have examined the effects of air pollution on service utilisation in the primary care setting. The aim of this study was to examine the association between air pollution and the daily number of consultations due to upper respiratory tract infections (URTIs) in general outpatient clinics (GOPCs) in Hong Kong., Methods: Daily data on the numbers of consultations due to URTIs in GOPCs, the concentrations of major air pollutants, and the mean values of metrological variables were retrospectively collected over a 3-year period (2008-2010, inclusive). Generalised additive models were constructed to examine the association between air pollution and the daily number of consultations, and to derive the relative risks and 95% confidence intervals (95% CI) of GOPC consultations for a unit increase in the concentrations of air pollutants., Results: The mean daily consultations due to URTIs in GOPCs ranged from 68.4 to 253.0 over the study period. The summary relative risks (and 95% CI) of daily consultations in all GOPCs for the air pollutants PM10, NO2, O3, and SO2 were 1.005 (1.002, 1.009), 1.010 (1.006, 1.013), 1.009 (1.006, 1.012), and 1.004 (1.000, 1.008) respectively, per 10 µg/m(3) increase in the concentration of each pollutant., Conclusion: Significant associations were found between the daily number of consultations due to URTIs in GOPCs and the concentrations of air pollutants, implying that air pollution incurs a substantial morbidity and increases the burden of primary health care services.

A cross-sectional relationship between lower urinary tract symptoms (LUTS) and depressive symptoms was previously reported among Southern Chinese men; however, the temporal relationship was unclear. Our objective is to evaluate the temporal relationship between moderate to severe lower urinary tract symptoms and clinically significant depressive symptoms in elderly Chinese men aged 65 in a prospective manner. In a prospective cohort of 2,000 Chinese men aged 65 to 92 years in Hong Kong, we studied the association of having moderate to severe LUTS at baseline and having clinically relevant depressive symptoms at year 2 follow-up. After excluding men with prostate or bladder cancer or surgery (n = 20) and lost to follow-up (n = 254), data on 1,726 subjects were analyzed. LUTS were measured by the International Prostate Symptom score; and clinically relevant depressive symptoms were measured by the Geriatric Depression Scale. The multiple logistic regressions showed that the presence of moderate-to-severe LUTS at baseline were significantly associated with increased risk for being depressed at two-year follow-up, with adjustments for demographic, lifestyle, medical factors, weight status and stressful life events (OR = 2.97; CI: 1.70-5.20). Association remained significant with additional adjustments for baseline GDS score (OR = 1.88; CI: 1.03-3.41). LUTS are important risk factors in predicting the presence of clinically relevant depressive symptoms. In elderly men, increased awareness and possible screening are needed to detect the increased risk of clinically relevant depressive symptoms.

Background: The healthcare system of mainland China is undergoing drastic reform and the optimal models for healthcare financing for provision of primary care will need to be identified. This study compared the performance indicators of the community health centres (CHCs) under different healthcare financing systems in the six cities of the Pearl River Delta region., Methods: Approximately 300 hypertensive patients were randomly recruited from the computerized chronic disease management records provided by one CHC in each of the six cities in 2011 using a multi-stage cluster random sampling method. The major outcome measures included the treatment rate of hypertension, defined as prescription of ≥ one antihypertensive agent; and the control rate of hypertension, defined as systolic blood pressure levels <140 mmHg and diastolic blood pressure levels <90 mmHg in patients without diabetes mellitus, or <130/80 mmHg among patients with concomitant diabetes. Binary logistic regression analyses were conducted with these two measures as outcome variables, respectively, controlling for patients' socio-demographic variables. The financing system (Hospital- vs. Government- vs. private-funded) was the independent variable tested for association with the outcomes., Results: From 1,830 patients with an average age of 65.9 years (SD 12.8), the overall treatment and control rates were 75.4% and 20.2%, respectively. When compared with hospital-funded CHCs, patients seen in the Government-funded (adjusted odds ratio [AOR] 0.462, 95% C.I. 0.325-0.656) and private-funded CHCs (AOR 0.031, 95% C.I. 0.019-0.052) were significantly less likely to be prescribed antihypertensive medication. However, the Government-funded CHC was more likely to have optimal BP control (AOR 1.628, 95% C.I. 1.157-2.291) whilst the privately-funded CHC was less likely to achieve BP control (AOR 0.146, 95% C.I. 0.069-0.310), irrespective of whether antihypertensive drugs were prescribed., Conclusions: Privately-funded CHCs had the lowest rates of BP treatment and control due to a variety of potential factors as discussed.

Nonhomologous end-joining (NHEJ) is the primary DNA repair pathway thought to underlie chromosomal translocations and other genomic rearrangements in somatic cells. The canonical NHEJ pathway, including DNA ligase IV (Lig4), suppresses genomic instability and chromosomal translocations, leading to the notion that a poorly defined, alternative NHEJ (alt-NHEJ) pathway generates these rearrangements. Here, we investigate the DNA ligase requirement of chromosomal translocation formation in mouse cells. Mammals have two other DNA ligases, Lig1 and Lig3, in addition to Lig4. As deletion of Lig3 results in cellular lethality due to its requirement in mitochondria, we used recently developed cell lines deficient in nuclear Lig3 but rescued for mitochondrial DNA ligase activity. Further, zinc finger endonucleases were used to generate DNA breaks at endogenous loci to induce translocations. Unlike with Lig4 deficiency, which causes an increase in translocation frequency, translocations are reduced in frequency in the absence of Lig3. Residual translocations in Lig3-deficient cells do not show a bias toward use of pre-existing microhomology at the breakpoint junctions, unlike either wild-type or Lig4-deficient cells, consistent with the notion that alt-NHEJ is impaired with Lig3 loss. By contrast, Lig1 depletion in otherwise wild-type cells does not reduce translocations or affect microhomology use. However, translocations are further reduced in Lig3-deficient cells upon Lig1 knockdown, suggesting the existence of two alt-NHEJ pathways, one that is biased toward microhomology use and requires Lig3 and a back-up pathway which does not depend on microhomology and utilizes Lig1., Competing Interests: SY-W Wong, J Lou, L Zhang, J Li, EJ Rebar, PD Gregory, and MC Holmes are full-time employees of Sangamo BioSciences.

Background: The PI3K-Akt signal pathway plays a key role in tumorigenesis and the development of drug-resistance. Cytotoxic chemotherapy resistance is linked to limited therapeutic options and poor prognosis., Methodology/principal Findings: Examination of FOXO3a and phosphorylated-Akt (P-Akt) expression in breast cancer tissue microarrays showed nuclear FOXO3a was associated with lymph node positivity (p = 0.052), poor prognosis (p = 0.014), and P-Akt expression in invasive ductal carcinoma. Using tamoxifen and doxorubicin-sensitive and -resistant breast cancer cell lines as models, we found that doxorubicin- but not tamoxifen-resistance is associated with nuclear accumulation of FOXO3a, consistent with the finding that sustained nuclear FOXO3a is associated with poor prognosis. We also established that doxorubicin treatment induces proliferation arrest and FOXO3a nuclear relocation in sensitive breast cancer cells. Induction of FOXO3a activity in doxorubicin-sensitive MCF-7 cells was sufficient to promote Akt phosphorylation and arrest cell proliferation. Conversely, knockdown of endogenous FOXO3a expression reduced PI3K/Akt activity. Using MDA-MB-231 cells, in which FOXO3a activity can be induced by 4-hydroxytamoxifen, we showed that FOXO3a induction up-regulates PI3K-Akt activity and enhanced doxorubicin resistance. However FOXO3a induction has little effect on cell proliferation, indicating that FOXO3a or its downstream activity is deregulated in the cytotoxic drug resistant breast cancer cells. Thus, our results suggest that sustained FOXO3a activation can enhance hyperactivation of the PI3K/Akt pathway., Conclusions/significance: Together these data suggest that lymph node metastasis and poor survival in invasive ductal breast carcinoma are linked to an uncoupling of the Akt-FOXO3a signaling axis. In these breast cancers activated Akt fails to inactivate and re-localize FOXO3a to the cytoplasm, and nuclear-targeted FOXO3a does not induce cell death or cell cycle arrest. As such, sustained nuclear FOXO3a expression in breast cancer may culminate in cancer progression and the development of an aggressive phenotype similar to that observed in cytotoxic chemotherapy resistant breast cancer cell models.