E4F1 and ZNF148 are transcriptional activators of the -57A > C and wild-type TERT promoter.

Point mutations within the TERT promoter are the most recurrent somatic noncoding mutations identified across different cancer types, including glioblastoma, melanoma, hepatocellular carcinoma, and bladder cancer. They are most abundant at -146C > T and -124C > T, and rarer at -57A > C, with the latter originally described as a familial case, but subsequently shown also to occur somatically. All three mutations create de novo E26-specific (ETS) binding sites and result in activation of the TERT gene, allowing cancer cells to achieve replicative immortality. Here, we used a systematic proteomics screen to identify transcription factors preferentially binding to the -146C > T, -124C > T, and -57A > C mutations. Although we confirmed binding of multiple ETS factors to the mutant -146C > T and -124C > T sequences, we identified E4F1 as a -57A > C-specific binder and ZNF148 as a TERT wild-type (WT) promoter binder that showed reduced interaction with the -124C > T allele. Both proteins are activating transcription factors that bind specifically to the -57A > C and WT (at position 124) TERT promoter sequence in corresponding cell lines, and up-regulate TERT transcription and telomerase activity. Our work describes new regulators of TERT gene expression with possible roles in cancer.

Postoperative radiotherapy omission in selected patients with early breast cancer following preoperative breast MRI (PROSPECT): primary results of a prospective two-arm study.

BACKGROUND: Adjuvant breast radiotherapy as a standard component of breast-conserving treatment for early cancer can overtreat many women. Breast MRI is the most sensitive modality to assess local tumour burden. The aim of this study was to determine whether a combination of MRI and pathology findings can identify women with truly localised breast cancer who can safely avoid radiotherapy. METHODS: PROSPECT is a prospective, multicentre, two-arm, non-randomised trial of radiotherapy omission in patients selected using preoperative MRI and postoperative tumour pathology. It is being conducted at four academic hospitals in Australia. Women aged 50 years or older with cT1N0 non-triple-negative breast cancer were eligible. Those with apparently unifocal cancer had breast-conserving surgery (BCS) and, if pT1N0 or N1mi, had radiotherapy omitted (group 1). Standard treatment including excision of MRI-detected additional cancers was offered to the others (group 2). All were recommended systemic therapy. The primary outcome was ipsilateral invasive recurrence rate (IIRR) at 5 years in group 1. Primary analysis occurred after the 100th group 1 patient reached 5 years follow-up. Quality-adjusted life-years (QALYs) and cost-effectiveness of the PROSPECT pathway were analysed. This study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12610000810011). FINDINGS: Between May 17, 2011, and May 6, 2019, 443 patients with breast cancer underwent MRI. Median age was 63·0 years. MRI detected 61 malignant occult lesions separate from the index cancer in 48 patients (11%). Of 201 group 1 patients who had BCS without radiotherapy, the IIRR at 5 years was 1·0% (upper 95% CI 5·4%). In group 1, one local recurrence occurred at 4·5 years and a second at 7·5 years. In group 2, nine patients had mastectomy (2% of total cohort), and the 5-year IIRR was 1·7% (upper 95% CI 6·1%). The only distant metastasis in the entire cohort was genetically distinct from the index cancer. The PROSPECT pathway increased QALYs by 0·019 (95% CI 0·008-0·029) and saved AU$1980 (95% CI 1396-2528) or £953 (672-1216) per patient. INTERPRETATION: PROSPECT suggests that women with unifocal breast cancer on MRI and favourable pathology can safely omit radiotherapy. FUNDING: Breast Cancer Trials, National Breast Cancer Foundation, Cancer Council Victoria, the Royal Melbourne Hospital Foundation, and the Breast Cancer Research Foundation.

Radiation doses and fractionation schedules in non-low-risk ductal carcinoma in situ in the breast (BIG 3-07/TROG 07.01): a randomised, factorial, multicentre, open-label, phase 3 study.

BACKGROUND: Whole breast irradiation (WBI) after conservative surgery for ductal carcinoma in situ (DCIS) reduces local recurrence. We investigated whether a tumour bed boost after WBI improved outcomes, and examined radiation dose fractionation sensitivity for non-low-risk DCIS. METHODS: The study was an international, randomised, unmasked, phase 3 trial involving 136 participating centres of six clinical trials organisations in 11 countries (Australia, New Zealand, Singapore, Canada, the Netherlands, Belgium, France, Switzerland, Italy, Ireland, and the UK). Eligible patients were women aged 18 years or older with unilateral, histologically proven, non-low-risk DCIS treated by breast-conserving surgery with at least 1 mm of clear radial resection margins. They were assigned to one of four groups (1:1:1:1) of no tumour bed boost versus boost after conventional versus hypofractionated WBI, or randomly assigned to one of two groups (1:1) of no boost versus boost after each centre prespecified conventional or hypofractionated WBI. The conventional WBI used was 50 Gy in 25 fractions, and hypofractionated WBI was 42·5 Gy in 16 fractions. A boost dose of 16 Gy in eight fractions, if allocated, was delivered after WBI. Patients and clinicians were not masked to treatment allocation. The primary endpoint was time to local recurrence. This trial is registered with ClinicalTrials.gov (NCT00470236). FINDINGS: Between June 25, 2007, and June 30, 2014, 1608 patients were randomly assigned to have no boost (805 patients) or boost (803 patients). Conventional WBI was given to 831 patients, and hypofractionated WBI was given to 777 patients. Median follow-up was 6·6 years. The 5-year free-from-local-recurrence rates were 92·7% (95% CI 90·6-94·4%) in the no-boost group and 97·1% (95·6-98·1%) in the boost group (hazard ratio 0·47; 0·31-0·72; p<0·001). The boost group had higher rates of grade 2 or higher breast pain (10% [8-12%] vs 14% [12-17%], p=0·003) and induration (6% [5-8%] vs 14% [11-16%], p<0·001). INTERPRETATION: In patients with resected non-low-risk DCIS, a tumour bed boost after WBI reduced local recurrence with an increase in grade 2 or greater toxicity. The results provide the first randomised trial data to support the use of boost radiation after postoperative WBI in these patients to improve local control. The international scale of the study supports the generalisability of the results. FUNDING: National Health and Medical Research Council of Australia, Susan G Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society, Canadian Cancer Trials Group.

pH-Responsive Polymeric Micelle Dynamic Complexes for Selective Killing of Helicobacter pylori.

Helicobacter pylori, the world's most common chronic infection-causing pathogen, is responsible for causing gastric ulcers, the fourth-leading cause of cancer-related death globally in 2020. In recent years, the effectiveness of the current treatment regimen (two antibiotics and one proton pump inhibitor) has often been plagued with problems such as resistance and the undesired elimination of commensal bacteria. Herein, we report the synthesis of block and random copolycarbonates, functionalized with cationic guanidinium and anionic acetate functional groups, aimed at selectively killing H. pylori in the acidic environment of the stomach, while remaining nontoxic to the commensal bacteria in the gut. The compositions of the polymers were fine-tuned so that the polymers were readily dispersed in water without any difficulty at both pH 3.0 and 7.4. The self-assembly behavior of the polymers at different pH values by dynamic light scattering showed that the random and block copolymers formed stable micelles in a simulated gastric environment (pH 3.0) while aggregated at pH 7.4. Both polymers demonstrated stronger antibacterial activity against H. pylori than the guanidinium-functionalized homopolymer without any acetate functional group at pH 3.0. The block copolymer was significantly more bactericidal at pH 3.0 across the concentrations tested, as compared to the random copolymer, while it did not show significant toxicity toward rat red blood cells (rRBCs) and HK-2 cells or bactericidal effect toward E. coli (a common gut bacterium) and nor caused aggregation of rRBCs at its effective concentration and at physiological pH of 7.4. Additionally, both the block and random copolymers were much more stable against hydrolysis at pH 3.0 than at pH 7.4. This study provides insight into the influence of both polymer architecture and dynamic assembly on the bioactivities of antimicrobial polymers, where the disassembly of coacervates into narrowly dispersed micelles at pH 3 make them potent antimicrobials aided by the protonated carboxylic acid block.

CIDE family proteins control lipid homeostasis and the development of metabolic diseases.

Dysregulation of lipid homeostasis leads to the development of metabolic disorders including obesity, diabetes, cardiovascular disease and cancer. Lipid droplets (LDs) are subcellular organelles vital in the maintenance of lipid homeostasis by coordinating lipid synthesis, lipid storage, lipid secretion and lipolysis. Under fed condition, free fatty acids (FFAs) are remodeled and esterified into neutral lipids by lipogenesis and stored in the LDs. The lipid storage capacity of LDs is controlled by its growth via local lipid synthesis or by LD fusion. During fasting, neutral lipids are hydrolyzed by lipolysis, released as FFAs and secreted to meet energy demand. Cell death-inducing DNA fragmentation factor alpha (DFFA)-like effector (CIDE) family proteins composed of Cidea, Cideb and Cidec/Fsp27 are ER- and LD-associated proteins and have emerged as important regulators of lipid homeostasis. Notably, when localized on the LDs, CIDE proteins enrich at the LD-LD contact sites (LDCSs) and control LD fusion and growth. Here, we summarize these recent advances made on the role of CIDE proteins in the regulation of lipid metabolism with a particular focus on the molecular mechanisms underlying CIDE-mediated LD fusion and growth.

Dataset for pathology reporting of ductal carcinoma in situ, variants of lobular carcinoma in situ and low-grade lesions: recommendations from the International Collaboration on Cancer Reporting (ICCR).

AIMS: To describe a new international dataset for pathology reporting of ductal carcinoma in situ (DCIS), variants of lobular carcinoma in situ (LCIS) and low-grade lesions (encapsulated papillary carcinoma, solid papillary carcinoma in situ, Paget's disease) produced by the International Collaboration on Cancer Reporting (ICCR). METHODS AND RESULTS: The ICCR, a global alliance of pathology bodies, uses a rigorous and efficient process for the development of evidence-based, structured datasets for pathology reporting of common cancers. Their aim is to support quality pathology reporting and engender understanding between the breast surgeon, pathologist, and oncologist for optimal and uniform patient management globally. Here we describe the dataset for DCIS, some variants of LCIS (namely the pleomorphic and the florid variants), and low-grade lesions by a multidisciplinary panel of internationally recognized experts. The agreed dataset comprises 12 core (required) and five noncore (recommended) elements suitable for both developed and low-income jurisdictions, derived from a review of current evidence. Areas of contention were addressed using a pragmatic approach in the absence of evidence. Use of all core elements is the minimum reporting standard for any individual case. Commentary is provided, explaining each element's clinical relevance, definitions to be applied where appropriate for the agreed list of value options and the rationale for considering the element as core or noncore. CONCLUSION: This first internationally agreed dataset for DCIS, variants of LCIS, and low-grade lesions reporting will enable their standardization of pathology reporting and enhance clinicopathological communication leading to improved patient outcomes. Widespread adoption will also facilitate international comparisons, multinational clinical trials, and help to improve the management of breast disease globally.

A prospective observational study exploring the association of comorbid chronic health conditions with total healthcare expenditure in people with mental health conditions in an Asian setting.

BACKGROUND: It is pertinent to focus on chronic medical condition (CMC) comorbidity with mental health conditions (MHC) as their co-occurrence has significant cost and health implications. However, current evidence on co-occurrence of MHC with CMC is mixed and mostly from Western settings. Therefore, our study aimed to (i) describe the association between MHC and total healthcare expenditure, (ii) examine the association between CMC and total healthcare expenditure and (iii) examine determinants of total and different types of healthcare expenditure in respondents with and without MHC in an Asian setting. METHODS: The data from Singapore Mental Health Study (SMHS) 2016, a nationwide epidemiological survey, were linked with the National claims record (from 2017 to 2019). Multivariable Generalized Linear Models (GLM) were used to examine the association between MHC and total and different types of healthcare expenditure. RESULTS: A total of 3077 survey respondents were included in current analysis. Respondents with MHC had a lower mean age of 38.6 years as compared to those without MHC (47.1 years). MHC was associated with increased total healthcare expenditure after adjusting for covariates (b = 0.508, p < 0.05). In respondents with MHC, presence of CMC increased the total healthcare expenditure by 35% as compared to 40% increase in those without MHC. Interestingly, 35-49 years age group with MHC had almost 3 times higher total healthcare expenditure and 7.5 times higher inpatient expenditure as compared to the 18-34 years age group. CONCLUSION: Our study highlights variations in association of CMC and age with total healthcare expenditure in those with versus without MHC in an Asian setting. Practical recommendations include appropriate planning and resource allocation for early diagnosis and management of MHC, proactive screening for CMC in those with MHC and addressing the dual issues of treatment gap and stigma to facilitate early help seeking and prevent episodic, costly healthcare utilization.

Prevalence and impact of peer victimisation among youth seeking treatment at a tertiary psychiatric institution in Singapore: a cross-sectional study.

BACKGROUND: Peer victimization is common among adolescents and leads to negative consequences. However, few studies have examined the extent of peer-victimization and its correlates among adolescent patients in a psychiatric setting. The current study aimed to examine the prevalence and correlates of peer victimisation among youth with mental illness and to examine its association with depressive symptoms and health-related quality of life (HRQOL). METHODS: A sample of 239 youths aged 15-24 years were recruited from the outpatient clinics of a tertiary psychiatric hospital in Singapore using convenience sampling. All participants were administered the Multidimensional Peer Victimisation Scale (MPVS), Short Form 12 (SF-12) questionnaire and the Patient Health Questionnaire-8 (PHQ-8). The effect of MPVS  total and subscores on depression scores, quality of life subscores and quality of life total scores were examined using multiple linear regression analyses. RESULTS: The majority of the patients reported that they had experienced at least one form of peer victimisation (95.8%, n = 229) during their school years. Higher levels of 'verbal victimisation', 'attacks on property' and higher total MPVS scores were significantly associated with lower social functioning; additionally, higher levels of 'verbal victimisation' were significantly associated with lower mental component summary scores in the quality of life assessment. Higher scores on all four subscales as well as higher total scores on the MPVS were significantly associated with more severe depressive symptoms. CONCLUSIONS: Given the high prevalence of peer victimisation in our sample and its associations with more severe depressive symptoms and lower quality of life, it is vital to implement interventions that prevent peer victimisation in educational and other social settings and to provide youth with strategies to more effectively manage instances of peer victimisation.

Postmastectomy radiotherapy: a review.

PURPOSE OF REVIEW: We review the role of postmastectomy radiotherapy (PMRT) in the management of patients with early breast cancer. RECENT FINDINGS: PMRT in patients with 4 or more involved axillary lymph nodes is the current standard of care but the indications for PMRT in patients with 1-3 involved nodes remain controversial. The Early Breast Cancer Trialists' Collaborative Group meta-analysis of randomised trials of PMRT provides the most comprehensive level 1 evidence base. However, its applicability in contemporary practice in the context of recent multidisciplinary advances in surgery, radiation therapy and systemic therapy remains challenging. SUMMARY: The lack of consensus on the indications for PMRT in patients with 1-3 positive nodes underpins the variations in the national and international guidelines on PMRT. We emphasise the need for contemporary randomised trial data, and the potential to refine patient selection for PMRT using novel biomarkers of recurrence and radiosensitivity.

Early age of onset of mood, anxiety and alcohol use disorders is associated with sociodemographic characteristics and health outcomes in adults: results from a cross-sectional national survey.

PURPOSE: This cross-sectional study investigated distribution, sociodemographic correlates, and health outcomes in early versus late age of onset (AOO) of mood, anxiety, and alcohol use disorders in Singapore. METHODS: The Composite International Diagnostic Interview established lifetime diagnoses of major depressive, bipolar, generalized anxiety, obsessive compulsive and alcohol use disorders in a representative sample of residents aged 18 years and over (n = 6126). The AOO of the individual and any mental disorders were classified into early and late onset using median values as cut-offs. Data included socio-demographic and health background, health utility score, and productivity losses. Multivariable logistic regression analysis was conducted to assess sociodemographic correlates of early versus late AOO of any mental disorder while linear regression analysis investigated the associations between AOO of individual disorders with health utility score and productivity loss. RESULTS: Respondents' mean (SD) age was 45.6 (16.5) years, comprising 50.5% women and majority of Chinese ethnicity (75.8%). The median AOO for any of the five studied disorders was 21 years (IQR: 15-29). Lowest AOO was observed for obsessive compulsive disorder (Median: 14, IQR: 11-26). Those aged 35 years and over (versus 18-34) were less likely to have earlier AOO [35-49 years (OR: 0.287; 95% CI: 0.154-0.534); 50-64 years (OR:0.156; 95% CI: 0.068-0.361) and 65 and over (OR:0.112; 95% CI:0.027-0.461)], while Malay ethnicity (versus Chinese) (OR: 2.319; 95% CI: 1.384-3.885) and being never married (versus married) (OR: 2.731; 95% CI: 1.493-4.993) were more likely to have early AOO for any mental disorder. Sample with early (versus late) AOO had a lower health utility score (ß = - 0.06,95% CI: - 0.08 to - 0.03) and higher number of days cut down on the type of work (ß = 1.61,95% CI: 0.12-3.10) in those with any mental disorders. CONCLUSION: This study showed that half of the adults with mood, anxiety or alcohol use disorders in Singapore experienced their illness onset by 21 years of age. Early AOO is associated with sociodemographic background and poor health outcomes. Prevention, early detection, and interventions to improve health outcomes in mental disorders should consider the sociodemographic profile and age at first onset of symptoms in the population.

Asthma Prevalence and its Risk Factors Among a Multi-Ethnic Adult Population.

Asthma is a substantial global health problem characterized by chronic airway inflammation, leading to intermittent symptoms. This study aims to establish the prevalence and risk factors of asthma in a multi-ethnic adult population. Data for the study were extracted from the Singapore Mental Health Study 2016, a population-based, cross-sectional, epidemiological study of Singapore residents aged 18 years and above. The data relating to asthma prevalence was captured using the modified World Mental Health Composite International Diagnostic Interview (CIDI) version 3.0 chronic conditions checklist. The prevalence of lifetime asthma in this population was 11.9% (95% CI, 10.83-13.12). Those of Malay and Indian ethnicity (versus Chinese), ex-smokers (versus never smoked) and those who were overweight and obese (versus normal weight) were more likely to be associated with asthma. Participants belonging to the age group of 35 years and above (versus 18-34 years of age), male gender (versus female) were less likely to be associated with lifetime asthma. Asthma was also more likely to be associated with bipolar disorder. Those with current asthma (ie, those who had received treatment during the past 12 months) were significantly associated with lower health-related quality of life in the physical component score (PCS) than those without asthma. The high prevalence and association with lowered health-related quality of life makes asthma a significant public health concern. Our study's findings can help create awareness and encourage integrated approaches for managing asthma in the health sector.

Breast Irradiation in Ductal Carcinoma In Situ.

There is strong and consistent evidence that whole breast irradiation after breast conserving surgery significantly decreases the risk of ipsilateral breast events, in situ or invasive, underpinning its established role in patients with ductal carcinoma in situ (DCIS). Pending publication of the full results of BIG 3-07/TROG 07.01 randomised trial, addition of tumour bed boost to whole breast irradiation is recommended in the presence of adverse clinical-pathologic features, and the use of moderately hypofractionated whole breast dose-fractionation schedules is supported. As published data supporting the use of adjuvant partial breast irradiation in patients with low-risk DCIS are limited, its off-study application should be limited to low-risk patients defined by international and national guidelines. Finally, low-risk patients may not derive clinically meaningful benefits from radiation therapy and research on molecular profiling is ongoing to improve prognostic precision and guide safe omission of radiation therapy after breast conserving surgery.

Quality of life after breast-conserving therapy and adjuvant radiotherapy for non-low-risk ductal carcinoma in situ (BIG 3-07/TROG 07.01): 2-year results of a randomised, controlled, phase 3 trial.

BACKGROUND: BIG 3-07/TROG 07.01 is an international, multicentre, randomised, controlled, phase 3 trial evaluating tumour bed boost and hypofractionation in patients with non-low-risk ductal carcinoma in situ following breast-conserving surgery and whole breast radiotherapy. Here, we report the effects of diagnosis and treatment on health-related quality of life (HRQOL) at 2 years. METHODS: The BIG 3-07/TROG 07.01 trial is ongoing at 118 hospitals in 11 countries. Women aged 18 years or older with completely excised non-low-risk ductal carcinoma in situ were randomly assigned, by use of a minimisation algorithm, to tumour bed boost or no tumour bed boost, following conventional whole breast radiotherapy or hypofractionated whole breast radiotherapy using one of three randomisation categories. Category A was a 4-arm randomisation of tumour bed boost versus no boost following conventional whole breast radiotherapy (50 Gy in 25 fractions over 5 weeks) versus hypofractionated whole breast radiotherapy (42·5 Gy in 16 fractions over 3·5 weeks). Category B was a 2-arm randomisation between tumour bed boost versus no boost following conventional whole breast radiotherapy, and category C was a 2-arm randomisation between tumour bed boost versus no boost following hypofractionated whole breast radiotherapy. Stratification factors were age at diagnosis, planned endocrine therapy, and treating centre. The primary endpoint, time to local recurrence, will be reported when participants have completed 5 years of follow-up. The HRQOL statistical analysis plan prespecified eight aspects of HRQOL, assessed by four questionnaires at baseline, end of treatment, and at 6, 12, and 24 months after radiotherapy: fatigue and physical functioning (EORTC QLQ-C30); cosmetic status, breast-specific symptoms, arm and shoulder functional status (Breast Cancer Treatment Outcome Scale); body image and sexuality (Body Image Scale); and perceived risk of invasive breast cancer (Cancer Worry Scale and a study-specific question). For each of these measures, tumour bed boost was compared with no boost, and conventional whole breast radiotherapy compared with hypofractionated whole breast radiotherapy, by use of generalised estimating equation models. Analyses were by intention to treat, with Hochberg adjustment for multiple testing. This trial is registered with ClinicalTrials.gov, NCT00470236. FINDINGS: Between June 1, 2007, and Aug 14, 2013, 1208 women were enrolled and randomly assigned to receive no tumour bed boost (n=605) or tumour bed boost (n=603). 396 of 1208 women were assigned to category A: conventional whole breast radiotherapy with tumour bed boost (n=100) or no boost (n=98), or to hypofractionated whole breast radiotherapy with tumour bed boost (n=98) or no boost (n=100). 447 were assigned to category B: conventional whole breast radiotherapy with tumour bed boost (n=223) or no boost (n=224). 365 were assigned to category C: hypofractionated whole breast radiotherapy with tumour bed boost (n=182) or no boost (n=183). All patients were followed up at 2 years for the HRQOL analysis. 1098 (91%) of 1208 patients received their allocated treatment, and most completed their scheduled HRQOL assessments (1147 [95%] of 1208 at baseline; 988 [87%] of 1141 at 2 years). Cosmetic status was worse with tumour bed boost than with no boost across all timepoints (difference 0·10 [95% CI 0·05-0·15], global p=0·00014, Hochberg-adjusted p=0·0016); at the end of treatment, the estimated difference between tumour bed boost and no boost was 0·13 (95% CI 0·06-0·20; p=0·00021), persisting at 24 months (0·13 [0·06-0·20]; p=0·00021). Arm and shoulder function was also adversely affected by tumour bed boost across all timepoints (0·08 [95% CI 0·03-0·13], global p=0·0033, Hochberg adjusted p=0·045); the difference between tumour bed boost and no boost at the end of treatment was 0·08 (0·01 to 0·15, p=0·021), and did not persist at 24 months (0·04 [-0·03 to 0·11], p=0·29). None of the other six prespecified aspects of HRQOL differed significantly after adjustment for multiple testing. Conventional whole breast radiotherapy was associated with worse body image than hypofractionated whole breast radiotherapy at the end of treatment (difference -1·10 [95% CI -1·79 to -0·42], p=0·0016). No significant differences were reported in the other PROs between conventional whole breast radiotherapy compared with hypofractionated whole breast radiotherapy. INTERPRETATION: Tumour bed boost was associated with persistent adverse effects on cosmetic status and arm and shoulder functional status, which might inform shared decision making while local recurrence analysis is pending. FUNDING: National Health and Medical Research Council, Susan G Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society.

External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial.

BACKGROUND: Whole breast irradiation delivered once per day over 3-5 weeks after breast conserving surgery reduces local recurrence with good cosmetic results. Accelerated partial breast irradiation (APBI) delivered over 1 week to the tumour bed was developed to provide a more convenient treatment. In this trial, we investigated if external beam APBI was non-inferior to whole breast irradiation. METHODS: We did this multicentre, randomised, non-inferiority trial in 33 cancer centres in Canada, Australia and New Zealand. Women aged 40 years or older with ductal carcinoma in situ or node-negative breast cancer treated by breast conserving surgery were randomly assigned (1:1) to receive either external beam APBI (38·5 Gy in ten fractions delivered twice per day over 5-8 days) or whole breast irradiation (42·5 Gy in 16 fractions once per day over 21 days, or 50 Gy in 25 fractions once per day over 35 days). Patients and clinicans were not masked to treatment assignment. The primary outcome was ipsilateral breast tumour recurrence (IBTR), analysed by intention to treat. The trial was designed on the basis of an expected 5 year IBTR rate of 1·5% in the whole breast irradiation group with 85% power to exclude a 1·5% increase in the APBI group; non-inferiority was shown if the upper limit of the two-sided 90% CI for the IBTR hazard ratio (HR) was less than 2·02. This trial is registered with ClinicalTrials.gov, NCT00282035. FINDINGS: Between Feb 7, 2006, and July 15, 2011, we enrolled 2135 women. 1070 were randomly assigned to receive APBI and 1065 were assigned to receive whole breast irradiation. Six patients in the APBI group withdrew before treatment, four more did not receive radiotherapy, and 16 patients received whole breast irradiation. In the whole breast irradiation group, 16 patients withdrew, and two more did not receive radiotherapy. In the APBI group, a further 14 patients were lost to follow-up and nine patients withdrew during the follow-up period. In the whole breast irradiation group, 20 patients were lost to follow-up and 35 withdrew during follow-up. Median follow-up was 8·6 years (IQR 7·3-9·9). The 8-year cumulative rates of IBTR were 3·0% (95% CI 1·9-4·0) in the APBI group and 2·8% (1·8-3·9) in the whole breast irradiation group. The HR for APBI versus whole breast radiation was 1·27 (90% CI 0·84-1·91). Acute radiation toxicity (grade ≥2, within 3 months of radiotherapy start) occurred less frequently in patients treated with APBI (300 [28%] of 1070 patients) than whole breast irradiation (484 [45%] of 1065 patients, p<0·0001). Late radiation toxicity (grade ≥2, later than 3 months) was more common in patients treated with APBI (346 [32%] of 1070 patients) than whole breast irradiation (142 [13%] of 1065 patients; p<0·0001). Adverse cosmesis (defined as fair or poor) was more common in patients treated with APBI than in those treated by whole breast irradiation at 3 years (absolute difference, 11·3%, 95% CI 7·5-15·0), 5 years (16·5%, 12·5-20·4), and 7 years (17·7%, 12·9-22·3). INTERPRETATION: External beam APBI was non-inferior to whole breast irradiation in preventing IBTR. Although less acute toxicity was observed, the regimen used was associated with an increase in moderate late toxicity and adverse cosmesis, which might be related to the twice per day treatment. Other approaches, such as treatment once per day, might not adversely affect cosmesis and should be studied. FUNDING: Canadian Institutes for Health Research and Canadian Breast Cancer Research Alliance.

Understanding the relationships between mental disorders, self-reported health outcomes and positive mental health: findings from a national survey.

BACKGROUND: The link between mental illness and mental health is gaining focus in research and practice. This study aimed to investigate the association of mental disorders with positive mental health (PMH), overall health and quality of life. In addition, the role of PMH in mediating the relationships between mental disorders and health outcomes was assessed. METHODS: The study sample comprised 2270 residents aged 18 years and above who participated in a nationally representative, cross-sectional survey estimating the lifetime prevalence of mood, anxiety and alcohol use disorders, and health outcomes (self-reported overall health, quality of life and PMH) in Singapore. The Positive Mental Health Instrument was used to estimate the level of Total PMH among the respondents with and without mental disorders. Associations between mental disorders and health outcomes were assessed through regression models. Path analyses were conducted to investigate mediating role of PMH. RESULTS: Total PMH (Mean ± SD) was significantly lower among individuals having any of the studied lifetime mental disorders (4.23 ± 0.64 versus 4.50 ± 0.67 among those without these disorders). Although having a mood or anxiety disorder was associated with significantly lower Total PMH even after controlling for socio-demographic characteristics, similar relationship was not observed for alcohol use disorders. History of any mental disorders was also associated with lower overall health and quality of life. Total PMH mediated the relationships between mental disorders and overall health and quality of life by reducing the effect sizes for the associations between mental disorders and these health outcomes. CONCLUSIONS: Mental disorders were associated with poor health outcomes in affected individuals. This study showed that PMH can mediate the relationships between mental disorders and health outcomes, and act as an underlying mechanism to improve overall health and quality of life in individuals with mental disorders. Findings thus highlight the significance of incorporating mental health promotion and interventions in clinical populations.

Development and validation of the Rapid Positive Mental Health Instrument (R-PMHI) for measuring mental health outcomes in the population.

BACKGROUND: The multidimensional Positive Mental Health Instrument (PMHI) has 47 items and six subscales. This study aimed to develop and validate a short unidimensional version of the PMHI among Singapore's adult resident population. METHODS: Using pooled data from three earlier studies (n = 1050), PMHI items were reduced by Partial Credit Rasch Model (PCRM) runs in a random split-half sample, while psychometric properties of the resulting measure were tested through confirmatory factor analysis (CFA), item response theory-graded response model and internal consistency reliability in the other half. Its reliability, construct and concurrent validity, agreement with the original scale, floor and ceiling effect, and scale estimates were further investigated in an external representative general population sample (n = 1925). RESULTS: The average age of the participants was around 41 years. Four PCRM re-runs for item selection resulted in a 6-item unidimensional Rapid PMHI (R-PMHI). CFA confirmed the unidimensional structure of the R-PMHI in the internal (RMSEA = 0.075, CFI = 0.985, TLI = 0.974) and external (RMSEA = 0.051, CFI = 0.992, TLI = 0.987) validation samples. In the external validation sample, the R-PMHI met concurrent validity criteria, showing high agreement with the 47-item version with intra-class correlation coefficient of 0.872 (95% CI: 0.861 to 0.882) and low floor and ceiling effects. Weight-adjusted mean (SE, 95% CI) R-PMHI score in the population was 4.86 (0.2, 4.82-4.90). CONCLUSION: The unidimensional 6-item R-PMHI offers brevity over the original multidimensional measure while appropriately representing the positive mental health construct. Prospective studies are needed to assess its responsiveness and test-retest reliability.

Prevalence and comorbidity of migraine headache: results from the Singapore Mental Health Study 2016.

BACKGROUND AND AIM: Migraine is a highly prevalent and disabling neurological disorder associated with a wide range of psychiatric comorbidities. Studies have revealed that those with migraine headache and coexisting psychiatric disorders have poorer treatment outcomes and increased disability. The study aims to establish the prevalence, correlates, and comorbidities of migraine headache among the multi-ethnic Asian population in Singapore. METHOD: Data were extracted from the Singapore Mental Health Study 2016 (SMHS 2016), a cross-sectional epidemiological survey of a nationally representative sample. Face-to-face interviews were completed with 6126 participants between 2016 and 2017. The data relating to chronic medical conditions, psychiatric conditions, and 30-day functioning and disability were captured using the World Mental Health Composite International Diagnostic Interview (CIDI) version 3.0. RESULTS: The lifetime prevalence for migraine headache in the Singapore general population was 8.2%. Malay ethnicity (versus Chinese), female gender (versus male), and diploma holders (versus university) were significantly more likely to experience migraine headache. Participants belonging to the older age group (65 years and above versus 18-34 years of age), and those who were economically inactive (versus employed) were less likely to experience migraine headache. The mean age of onset for migraine was 26.4 years (SD = 11.1). Poisson regression analyses showed that migraine headache was also significantly associated with psychiatric conditions such as major depressive disorder (MDD) (prevalence ratio (PR), 1.80; 95% CI, 1.25-2.58), bipolar disorder (BD) (PR, 3.55; 95% CI, 2.29-5.51), generalized anxiety disorder (GAD) (PR, 2.04; 95% CI, 1.12-3.69), obsessive compulsive disorder (OCD) (PR, 2.20; 95% CI, 1.49-3.26), and alcohol use disorder (AUD) (PR, 1.93; 95% CI, 1.20-3.08). Those with migraine headache were significantly associated with poor functioning and disability compared to those without migraine headache. CONCLUSIONS AND DISCUSSION: Our study showed significant associations between migraine headache and psychiatric disorders, as well as with role functioning and disability. The findings of our study emphasise the need for screening for psychiatric comorbidity among those with migraine and the development of appropriate interventions for this group.

Polybasic RKKR motif in the linker region of lipid droplet (LD)-associated protein CIDEC inhibits LD fusion activity by interacting with acidic phospholipids.

Lipid droplets (LDs) are intracellular organelles and a central site for lipid synthesis, storage, and mobilization. The size of LDs reflects the dynamic regulation of lipid metabolism in cells. Previously, we found that cell death-inducing DFFA-like effector C (CIDEC) mediates LD fusion and growth by lipid transfer through LD-LD contact sites in adipocytes and hepatocytes. The CIDE-N domains of CIDEC molecules form homodimers, whereas the CIDE-C domain plays an important role in LD targeting and enrichment. Here, using targeted protein deletions and GFP expression coupled with fluorescence microscopy, we identified a polybasic RKKR motif in the linker region that connects the CIDE-N and CIDE-C domains of CIDEC and functions as a regulatory motif for LD fusion. We found that deletion of the linker region or mutation of the RKKR motif increases the formation of supersized LDs compared with LD formation in cells with WT CIDEC. This enhanced LD fusion activity required the interaction between CIDE-N domains. Mechanistically, we found that the RKKR motif interacts with acidic phospholipids via electrostatic attraction. Loss of this motif disrupted the protein-lipid interaction, resulting in enhanced lipid droplet fusion activity and thus formation of larger LDs. In summary, we have uncovered a CIDEC domain that regulates LD fusion activity, a finding that provides insights into the inhibitory regulation of LD fusion through CIDEC-lipid interactions.

Primary angle closure glaucoma (PACG) susceptibility gene PLEKHA7 encodes a novel Rac1/Cdc42 GAP that modulates cell migration and blood-aqueous barrier function.

PLEKHA7, a gene recently associated with primary angle closure glaucoma (PACG), encodes an apical junctional protein expressed in components of the blood aqueous barrier (BAB). We found that PLEKHA7 is down-regulated in lens epithelial cells and in iris tissue of PACG patients. PLEKHA7 expression also correlated with the C risk allele of the sentinel SNP rs11024102 with the risk allele carrier groups having significantly reduced PLEKHA7 levels compared to non-risk allele carriers. Silencing of PLEKHA7 in human immortalized non-pigmented ciliary epithelium (h-iNPCE) and primary trabecular meshwork cells, which are intimately linked to BAB and aqueous humor outflow respectively, affected actin cytoskeleton organization. PLEKHA7 specifically interacts with GTP-bound Rac1 and Cdc42, but not RhoA, and the activation status of the two small GTPases is linked to PLEKHA7 expression levels. PLEKHA7 stimulates Rac1 and Cdc42 GTP hydrolysis, without affecting nucleotide exchange, identifying PLEKHA7 as a novel Rac1/Cdc42 GAP. Consistent with the regulatory role of Rac1 and Cdc42 in maintaining the tight junction permeability, silencing of PLEKHA7 compromises the paracellular barrier between h-iNPCE cells. Thus, downregulation of PLEKHA7 in PACG may affect BAB integrity and aqueous humor outflow via its Rac1/Cdc42 GAP activity, thereby contributing to disease etiology.