Single-molecule sequencing reveals a large population of long cell-free DNA molecules in maternal plasma.

In the field of circulating cell-free DNA, most of the studies have focused on short DNA molecules (e.g., <500 bp). The existence of long cell-free DNA molecules has been poorly explored. In this study, we demonstrated that single-molecule real-time sequencing allowed us to detect and analyze a substantial proportion of long DNA molecules from both fetal and maternal sources in maternal plasma. Such molecules were beyond the size detection limits of short-read sequencing technologies. The proportions of long cell-free DNA molecules in maternal plasma over 500 bp were 15.5%, 19.8%, and 32.3% for the first, second, and third trimesters, respectively. The longest fetal-derived plasma DNA molecule observed was 23,635 bp. Long plasma DNA molecules demonstrated predominance of A or G 5' fragment ends. Pregnancies with preeclampsia demonstrated a reduction in long maternal plasma DNA molecules, reduced frequencies for selected 5' 4-mer end motifs ending with G or A, and increased frequencies for selected motifs ending with T or C. Finally, we have developed an approach that employs the analysis of methylation patterns of the series of CpG sites on a long DNA molecule for determining its tissue origin. This approach achieved an area under the curve of 0.88 in differentiating between fetal and maternal plasma DNA molecules, enabling the determination of maternal inheritance and recombination events in the fetal genome. This work opens up potential clinical utilities of long cell-free DNA analysis in maternal plasma including noninvasive prenatal testing of monogenic diseases and detection/monitoring of pregnancy-associated disorders such as preeclampsia.

Health behaviour practices and expectations for a local cancer survivorship programme: a cross-sectional study of survivors of childhood cancer in Hong Kong.

INTRODUCTION: Lifestyle choices may influence health outcomes in cancer survivors. This study of childhood cancer survivors in Hong Kong investigated factors associated with health-protective and health-damaging behaviours; it also examined expectations of a survivorship programme. METHODS: This cross-sectional study recruited survivors of childhood cancer ≥2 years after treatment. Survivors completed a structured questionnaire to report their health practices and the perceived values of survivorship programme components. Multivariable logistic regression analysis was conducted to identify factors associated with health behaviours. RESULTS: Two hundred survivors were recruited (mean age=23.4 ± 8.8 years; mean duration since treatment, 13.4 ± 7.6 years). Comparatively few survivors exercised ≥4 days/week (16.0%), used sun protection (18.0%), and had a balanced diet (38.5%). Furthermore, comparatively few survivors reported that they had not undergone any immunisation (24.5%) or were unsure (18.5%) about their immunisation history. Most adult survivors were never-drinkers (71.0%) and never-smokers (93.0%). Brain tumour survivors were more likely to have unhealthy eating habits, compared with haematological malignancy survivors (odds ratio [OR]=2.45; 95% confidence interval [CI]=1.29-4.68). Lower socioeconomic status was associated with inadequate sun protection (OR=0.20; 95% CI=0.05-0.83), smoking (OR=5.13; 95% CI=1.48-17.75), and exposure to second-hand smoke (OR=3.52; 95% CI=1.42-8.69). Late-effects screening (78.5%) and psychosocial services to address psychological distress (77%) were considered essential components of a survivorship programme. CONCLUSIONS: Despite the low prevalences of health-damaging behaviours, local survivors of childhood cancer are not engaging in health-protective behaviours. A multidisciplinary programme addressing late effects and psychosocial aspects may address the multifaceted needs of this special population.

Association of proinflammatory cytokines and chemotherapy-associated cognitive impairment in breast cancer patients: a multi-centered, prospective, cohort study.

BACKGROUND: Existing evidence suggests that proinflammatory cytokines play an intermediary role in postchemotherapy cognitive impairment. This is one of the largest multicentered, cohort studies conducted in Singapore to evaluate the prevalence and proinflammatory biomarkers associated with cognitive impairment in breast cancer patients. PATIENTS AND METHODS: Chemotherapy-receiving breast cancer patients (stages I-III) were recruited. Proinflammatory plasma cytokines concentrations [interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, interferon-γ and tumor necrosis factor-α] were evaluated at 3 time points (before chemotherapy, 6 and 12 weeks after chemotherapy initiation). The FACT-Cog (version 3) was utilized to evaluate patients' self-perceived cognitive disturbances and a computerized neuropsychological assessment (Headminder) was administered to evaluate patients' memory, attention, response speed and processing speed. Changes of cognition throughout chemotherapy treatment were compared against the baseline. Linear mixed-effects models were applied to test the relationships of clinical variables and cytokine concentrations on self-perceived cognitive disturbances and each objective cognitive domain. RESULTS: Ninety-nine patients were included (age 50.5 ± 8.4 years; 81.8% Chinese; mean duration of education = 10.8 ± 3.3 years). Higher plasma IL-1ß was associated with poorer response speed performance (estimate: -0.78; 95% confidence interval (CI) -1.34 to -0.03; P = 0.023), and a higher concentration of IL-4 was associated with better response speed performance (P = 0.022). Higher concentrations of IL-1ß and IL-6 were associated with more severe self-perceived cognitive disturbances (P = 0.018 and 0.001, respectively). Patients with higher concentrations of IL-4 also reported less severe cognitive disturbances (P = 0.022). CONCLUSIONS: While elevated concentrations of IL-6 and IL-1ß were observed in patients with poorer response speed performance and perceived cognitive disturbances, IL-4 may be protective against chemotherapy-associated cognitive impairment. This study is important because cytokines would potentially be mechanistic mediators of chemotherapy-associated cognitive changes.

Circulating tumour DNA analysis for early detection of lung cancer: a systematic review.

Background: Circulating tumor DNA (ctDNA) analysis has been applied in cancer diagnostics including lung cancer. Specifically for the early detection purpose, various modalities of ctDNA analysis have demonstrated their potentials. Such analyses have showed diverse performance across different studies. Methods: We performed a systematic review of original studies published before 1 January 2023. Studies that evaluated ctDNA alone and in combination with other biomarkers for early detection of lung cancer were included. Results: The systematic review analysis included 56 original studies that were aimed for early detection of lung cancer. There were 39 studies for lung cancer only and 17 for pan-cancer early detection. Cancer and control cases included were heterogenous across studies. Different molecular features of ctDNA have been evaluated, including 7 studies on cell-free DNA concentration, 17 on mutation, 29 on methylation, 5 on hydroxymethylation and 8 on fragmentation patterns. Among these 56 studies, 17 have utilised different combinations of the above-mentioned ctDNA features and/or circulation protein markers. For all the modalities, lower sensitivities were reported for the detection of early-stage cancer. Conclusions: The systematic review suggested the clinical utility of ctDNA analysis for early detection of lung cancer, alone or in combination with other biomarkers. Future validation with standardised testing protocols would help integration into clinical care.

Cognitive changes in multiethnic Asian breast cancer patients: a focus group study.

BACKGROUND: This study aims to gather descriptions from multiethnic Asian breast cancer patients on their experiences and impact of chemotherapy-associated cognitive changes on their daily lives and their coping strategies. PATIENTS AND METHODS: Forty-three chemotherapy-receiving breast cancer patients participated in eight English or Chinese structured focus group discussions, conducted by trained psychosocial oncologists and medical social workers. RESULTS: Participants were unfamiliar and averse to both English and Chinese-translated equivalent of the term 'chemobrain'. Participants viewed this phenomenon holistically as a by-product of the physical (fatigue and aging) and psychosocial (anxiety and mood changes) adverse effects associated with chemotherapy. Most participants encountered memory loss, difficulty in decision making and speech problems after receiving chemotherapy. Married participants expressed frustration as cognitive deterioration limited their conservative roles as homemakers. Despite knowing the potential neurocognitive effects, participants valued the benefits of chemotherapy. Identified coping strategies included playing mahjong for mind stimulation and management of psychosocial factors, such as practicing qi gong, to regulate their moods and to take complementary alternative medicines to reduce the severity of their fatigue. CONCLUSIONS: The phenomenon 'chemobrain' is unfamiliar to most Asian cancer patients yet it has significantly impacted their daily lives. Our results suggested that a culturally relevant approach should be adopted to evaluate and manage cognitive changes in these patients.

Neuroprotective effects of minocycline on double-stranded RNA-induced neurotoxicity in cultured cortical neurons.

1. Minocycline, memantine,and glycoconjugate were assessed for their ability to protect cultured primary cortical neurons against double-stranded RNA-induced neurotoxicity. 2. Minocycline but not memantine or glycoconjugate protected cultured cells and warrants further investigation.

An empirical study of characteristics and types of homicide-suicides in Hong Kong, 1989-2005.

BACKGROUND: Clinical classification of types of homicide-suicide (HS) was proposed, but no information on empirical-based classification and prevalence of different types of HS was available. This paper aimed to empirically classify HS events into different clusters and to discuss specific evidence-based prevention initiatives. METHOD: Data of HS offenders from Coroner's Court were analyzed through a two-step cluster analysis. Number of clusters and appropriate allocations of cases were obtained. External background variables were tested through post hoc tests to explore the differences among clusters. RESULTS: Two hundred and thirty-one people died in 98 episodes in the study period (1989-2005). The majority of HS offenders were male (n=68, 68.7%) and aged 30-49 (n=62, 62.6%). Domestic killing was the major type of HS in which over 60% of the homicide motivation was related to spousal conflicts or altruistic reasons. Spouses (n=46, 46.5%) and children (n=47, 47.5%) were predominantly the victims. The common killing methods included chopping with weapons (n=33, 33.3%) and charcoal burning (n=22, 22.2%). Six clusters of HS were derived from the cluster analysis and were further reduced to four major classes. Four major classes were dispute, conflicts in a relationship, altruistic, and mental illness. These classes could be differentiated by methods of homicide and suicide, gender of perpetrator, relationship with victim, and indebtedness. CONCLUSIONS: Financial problem, dispute and domestic violence are significant precipitants of HS in Hong Kong. Those people associated with the precipitating factors should be the targets for intervention and prevention.

A revisit on older adults suicides and Severe Acute Respiratory Syndrome (SARS) epidemic in Hong Kong.

BACKGROUND: The Severe Acute Respiratory Syndrome (SARS) outbreak in 2003 had an enormous impact on Hong Kong society and the suicide rate was also at its historical high, 18.6 per 100,000. The most significant increase was found among the older adults aged 65 or above. METHODS: Poisson Regression Models were used to examine impact of the SARS epidemic on older adults suicides in Hong Kong. A complete set of the suicide statistics for the period 1993-2004 from the Coroners' Court were made available for the analysis. Chi-square test was used to compare the profile of the older adult suicide cases in the pre-SARS, peri-SARS and post-SARS periods. RESULTS: It showed an excess of older adults suicides in April 2003, when compared to the month of April of the other years. A trough, instead of the usual summer peak, was observed in June, suggesting some of the older adults suicides might have been brought forward. On a year basis, the annual older adult's suicide rates in 2003 and 2004 were significantly higher than that in 2002, suggesting the suicide rate did not return to the level before the SARS epidemic. Based on the Coroners' suicide death records, overall severity of illness, level of dependency and worrying of having sickness among the older adult suicides were found to be significantly different in the pre-SARS, peri-SARS and post-SARS periods. CONCLUSION: The SARS epidemic was associated with an increase in older adults' suicide rate in April 2003 and some suicide deaths in June 2003 might have been brought forward. Moreover, an increase in the annual older adults' suicide rate in 2003 was observed and the rate in 2004 did not return to the level of 2002. Loneliness and disconnectedness among the older adults in the community were likely to be associated with the excess older adults' suicides in 2003. Maintaining and enhancing mental well being of the public over the period of epidemic is as important as curbing the spread of the epidemic. Attention and effort should also be made to enhance the community's ability to manage fear and anxiety, especially in vulnerable groups over the period of epidemic to prevent tragic and unnecessary suicide deaths.

The Impact of Persistent Leukoencephalopathy on Brain White Matter Microstructure in Long-Term Survivors of Acute Lymphoblastic Leukemia Treated with Chemotherapy Only.

BACKGROUND AND PURPOSE: Survivors of acute lymphoblastic leukemia are at risk for neurocognitive deficits and leukoencephalopathy. We performed a longitudinal assessment of leukoencephalopathy and its associations with long-term brain microstructural white matter integrity and neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia treated on a modern chemotherapy-only protocol. MATERIALS AND METHODS: One hundred seventy-three survivors of acute lymphoblastic leukemia (49% female), treated on a chemotherapy-only protocol, underwent brain MR imaging during active therapy and repeat imaging and neurocognitive testing at follow-up (median, 13.5 years of age; interquartile range, 10.7-17.6 years; median time since diagnosis, 7.5 years; interquartile range, 6.3-9.1 years). Persistence of leukoencephalopathy was examined in relation to demographic and treatment data and to brain DTI in major fiber tracts and neurocognitive testing at follow-up. RESULTS: Leukoencephalopathy was found in 52 of 173 long-term survivors (30.0%) and persisted in 41 of 52 (78.8%) who developed it during therapy. DTI parameters were associated with leukoencephalopathy in multiple brain regions, including the corona radiata (fractional anisotropy, P = .001; mean diffusivity, P < .001), superior longitudinal fasciculi (fractional anisotropy, P = .02; mean diffusivity, P < .001), and superior fronto-occipital fasciculi (fractional anisotropy, P = .006; mean diffusivity, P < .001). Mean diffusivity was associated with neurocognitive impairment including in the genu of the corpus callosum (P = .04), corona radiata (P = .02), and superior fronto-occipital fasciculi (P = .02). CONCLUSIONS: Leukoencephalopathy during active therapy and neurocognitive impairment at long-term follow-up are associated with microstructural white matter integrity. DTI may be more sensitive than standard MR imaging for detection of clinically consequential white matter abnormalities in childhood acute lymphoblastic leukemia survivors treated with chemotherapy and in children undergoing treatment.

The impact of epidemic outbreak: the case of severe acute respiratory syndrome (SARS) and suicide among older adults in Hong Kong.

BACKGROUND: Previous studies revealed that there was a significant increase in suicide deaths among those aged 65 and over in 2003. The peak coincided with the majority of SARS cases being reported in April 2003. AIMS: In this paper we examine the mechanism of how the SARS outbreak resulted in a higher completed suicide rate especially among older adults in Hong Kong. METHODS: We used Qualitative data analysis to uncover the association between the occurrence of SARS and older adult suicide. Furthermore, we used a qualitative study based on the Coroner Court reports to provide empirical evidence about the relationship between SARS and the excessive number of suicide deaths among the elderly. RESULTS: SARS-related older adult suicide victims were more likely to be afraid of contracting the disease and had fears of disconnection. The suicide motives among SARS-related suicide deaths were more closely associated with stress over fears of being a burden to their families during the negative impact of the epidemic. Social disengagement, mental stress, and anxiety at the time of the SARS epidemic among a certain group of older adults resulted in an exceptionally high rate of suicide deaths. CONCLUSIONS: We recommend that the mental and psychological well-being of the community, in particular older adults, be taken into careful account when developing epidemic control measures to combat the future outbreak of diseases in the community. In addition, it is important to alert family members to vulnerable individuals who are at potential risk because of their illnesses or anxieties.

Filtering of ineffective siRNAs and improved siRNA design tool.

MOTIVATION: Short interfering RNAs (siRNAs) can be used to suppress gene expression and possess many potential applications in therapy, but how to design an effective siRNA is still not clear. Based on the MPI (Max-Planck-Institute) basic principles, a number of siRNA design tools have been developed recently. The set of candidates reported by these tools is usually large and often contains ineffective siRNAs. In view of this, we initiate the study of filtering ineffective siRNAs. RESULTS: The contribution of this paper is 2-fold. First, we propose a fair scheme to compare existing design tools based on real data in the literature. Second, we attempt to improve the MPI principles and existing tools by an algorithm that can filter ineffective siRNAs. The algorithm is based on some new observations on the secondary structure, which we have verified by AI techniques (decision trees and support vector machines). We have tested our algorithm together with the MPI principles and the existing tools. The results show that our filtering algorithm is effective. AVAILABILITY: The siRNA design software tool can be found in the website http://www.cs.hku.hk/~sirna/ CONTACT: smyiu@cs.hku.hk