Inverted triplications formed by iterative template switches generate structural variant diversity at genomic disorder loci.

The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a complex genomic rearrangement (CGR). Although it has been identified as an important pathogenic DNA mutation signature in genomic disorders and cancer genomes, its architecture remains unresolved. Here, we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the DNA of 24 patients identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted structural variant (SV) haplotypes. Using a combination of short-read genome sequencing (GS), long-read GS, optical genome mapping, and single-cell DNA template strand sequencing (strand-seq), the haplotype structure was resolved in 18 samples. The point of template switching in 4 samples was shown to be a segment of ∼2.2-5.5 kb of 100% nucleotide similarity within inverted repeat pairs. These data provide experimental evidence that inverted low-copy repeats act as recombinant substrates. This type of CGR can result in multiple conformers generating diverse SV haplotypes in susceptible dosage-sensitive loci.

Comparison of networks of loneliness, depressive symptoms, and anxiety symptoms in at-risk community-dwelling older adults before and during COVID-19.

Network analysis provides an innovative approach to examining symptom-to-symptom interactions in mental health, and adverse external conditions may change the network structures. This study compared the networks of common risk factors and mental health problems (loneliness, depressive symptoms, and anxiety symptoms) in community-dwelling older people before and during COVID-19. Older adults (aged ≥ 60) at risk for depression were recruited through non-governmental organizations. Loneliness, depressive symptoms and anxiety symptoms were measured using the three-item Loneliness Scale (UCLA-3), nine-item Patient Health Questionnaire (PHQ-9), and seven-item Generalized Anxiety Disorder Scale (GAD-7), respectively. Data from 2549 (before) and 3506 (during COVID-19) respondents were included using propensity score matching. Being restless (GAD-7-item5) was most central, indicated by Expected Influence, in both pre and during COVID-19 networks despite low severity (mean score). The network during COVID-19 had higher global strength and edge variability than the pre-pandemic network, suggesting easier symptom spread and potentially more complex symptom presentation. In addition, feeling isolated from others (UCLA-3-item3) had stronger connections with feeling worthless/guilty (PHQ-9-item6) and anticipatory anxiety (GAD-7-item7) during COVID-19 than before. These findings may enhance our knowledge of the symptom structure of common mental health problems and the impacts of the pandemic. Targeting central symptoms may offer novel preventive strategies for older people.

Mind the gap: the relevance of the genome reference to resolve rare and pathogenic inversions.

Both long-read genome sequencing (lrGS) and the recently published Telomere to Telomere (T2T) reference genome provide increased coverage and resolution across repetitive regions promising heightened structural variant detection and improved mapping. Inversions (INV), intrachromosomal segments which are rotated 180° and inserted back into the same chromosome, are a class of structural variants particularly challenging to detect due to their copy-number neutral state and association with repetitive regions. Inversions represent about 1/20 of all balanced structural chromosome aberrations and can lead to disease by gene disruption or altering regulatory regions of dosage sensitive genes in cis . Here we remapped the genome data from six individuals carrying unsolved cytogenetically detected inversions. An INV6 and INV10 were resolved using GRCh38 and T2T-CHM13. Finally, an INV9 required optical genome mapping, de novo assembly of lrGS data and T2T-CHM13. This inversion disrupted intron 25 of EHMT1, confirming a diagnosis of Kleefstra syndrome 1 (MIM#610253). These three inversions, only mappable in specific references, prompted us to investigate the presence and population frequencies of differential reference regions (DRRs) between T2T-CHM13, GRCh37, GRCh38, the chimpanzee and bonobo, and hundreds of megabases of DRRs were identified. Our results emphasize the significance of the chosen reference genome and the added benefits of lrGS and optical genome mapping in solving rearrangements in challenging regions of the genome. This is particularly important for inversions and may impact clinical diagnostics.

Robotic versus laparoscopic pelvic lateral lymph node dissection in locally advanced rectal cancer: a systemic review and meta-analysis.

BACKGROUND: There are few available studies that compare the feasibility, efficacy, and safety of robotic pelvic lateral lymph node dissection compared to laparoscopic pelvic lateral lymph node dissection (LPLND) in advanced rectal cancer. This meta-analysis aims to compare perioperative outcomes between robotic and LPLND. METHODS: We performed a systemic literature review of PubMed, Embase, and Web of Science databases. Perioperative parameters were extracted and pooled for analysis. This meta-analysis provided an analysis of heterogeneity and prediction intervals. RESULTS: Five studies were included: 567 patients divided between 266 robotic and 301 LPLND. Overall operation time was longer in the robotic group than laparoscopic group (difference in means = 67.11, 95% CI [30.80, 103.42], p < 0.001) but the difference in the pelvic lateral lymph dissection time was not statistically significant (difference in means = - 1.212, 95% CI [ - 11.594, 9.171], p = 0.819). There were fewer overall complications in the robotic than in the laparoscopic group (OR = 1.589, 95% CI [1.009, 2.503], p = 0.046), especially with respect to urinary retention (OR = 2.23, 95% CI [1.277, 3.894], p = 0.005). More pelvic lateral lymph nodes were harvested by robotic surgery than by laparoscopy (differences in means = - 1.992, 95% CI [ - 2.421, 1.563], p < 0.001). CONCLUSIONS: In this meta-analysis, robotic pelvic lateral lymph node dissection was associated with more pelvic lateral lymph nodes harvested and lower overall complications, especially urinary retention when compared to LPLND. Further studies are needed to reinforce these findings.

Throat microbiota drives alterations in pulmonary alveolar microbiota in patients with septic ARDS.

OBJECTIVES: The translocation of intestinal flora has been linked to the colonization of diverse and heavy lower respiratory flora in patients with septic ARDS, and is considered a critical prognostic factor for patients. METHODS: On the first and third days of ICU admission, BALF, throat swab, and anal swab were collected, resulting in a total of 288 samples. These samples were analyzed using 16S rRNA analysis and the traceability analysis of new generation technology. RESULTS: On the first day, among the top five microbiota species in abundance, four species were found to be identical in BALF and throat samples. Similarly, on the third day, three microbiota species were found to be identical in abundance in both BALF and throat samples. On the first day, 85.16% of microorganisms originated from the throat, 5.79% from the intestines, and 9.05% were unknown. On the third day, 83.52% of microorganisms came from the throat, 4.67% from the intestines, and 11.81% were unknown. Additionally, when regrouping the 46 patients, the results revealed a significant predominance of throat microorganisms in BALF on both the first and third day. Furthermore, as the disease progressed, the proportion of intestinal flora in BALF increased in patients with enterogenic ARDS. CONCLUSIONS: In patients with septic ARDS, the main source of lung microbiota is primarily from the throat. Furthermore, the dynamic trend of the microbiota on the first and third day is essentially consistent.It is important to note that the origin of the intestinal flora does not exclude the possibility of its origin from the throat.

Complementary use of visual and olfactory cues to assess capture of Bactrocera dorsalis (Hendel): Implementation and field verification via an IoT-based automatic monitoring system.

This study examined the effect of combining visual and olfactory cues to attract oriental fruit flies (OFFs). Six different colored light-emitting diodes (LEDs) served as a visual attractant and methyl eugenol served as olfactory bait to lure male flies. An internet of things (IoT)-based pest monitoring system, consisting of sensor nodes, a gateway, and automatic counting traps, was deployed in the field to automatically collect environmental data and pest counts. The results of the calibrated experiments indicated that green, yellow, or red LEDs exhibited better performance in attracting flies than white, purple, or blue LEDs or no LEDs. With an accurate combination of visual and olfactory cues, the proposed IoT-based pest monitoring system may be an effective tool in agricultural pest management, given its advantages for efficiently capturing OFFs in a labor and time saving manner, providing accurate information regarding increases in pest populations, and enabling long-term, real-time data collection.

Comorbidity of autism spectrum and attention deficit/hyperactivity disorder symptoms and their associations with 1-year mental health outcomes in adolescents and young adults.

Autism spectrum (ASD) and attention deficit/hyperactivity disorders (ADHD) share genetic, neurological, and behavioural features. However, related research in Asia is limited. We collected self-reported ASD and ADHD symptoms from 2186 Hong Kong adolescents and young adults aged 15-24 years, among whom, 1200 provided 1-year data on mental health-related outcomes. Comparative and network analyses were performed. Rating scale cutoff scores were used to divide participants into ASD, ADHD, comorbid, and control groups. The prevalence rates of ASD, ADHD, and comorbidities in Hong Kong were 13.3 %, 10.6 %, and 2.7 %, respectively. Compared with the control group, the comorbid group experienced more psychotic-like experiences (PLEs), the ASD group had poorer functioning, and the ADHD group had higher depression and anxiety symptoms and a lower quality of life after 1 year. The ability to switch attention, preference for routines and difficulty with change, and problems with organisation and planning were positively associated with depressive symptoms, forgetfulness and working memory issues with anxiety symptoms, and heightened sensory input and difficulties in sustaining attention and task completion with PLEs after 1 year. Our findings provide insight into support strategies to address the needs of young Asians to improving their well-being and long-term outcomes.

Lung metastasis-Harnessed in-Situ adherent porous organic nanosponge-mediated antigen capture for A self-cascaded detained dendritic cells and T cell infiltration.

The infiltration of cytotoxic T lymphocytes promises to suppress the most irresistible metastatic tumor for immunotherapy, yet immune privilege and low immunogenic responses in these aggressive clusters often restrict lymphocyte recruitment. Here, an in situ adherent porous organic nanosponge (APON) doubles as organ selection agent and antigen captor to overcome immune privilege is developed. With selective organ targeting, the geometric effect of APON composed of disc catechol-functionalized covalent organic framework (COF) boosts the drug delivery to lung metastases. Along with a self-cascaded immune therapy, the therapeutic agents promote tumor release of damage-associated molecular patterns (DAMPs), and then, in situ deposition of gels to capture these antigens. Furthermore, APON with catechol analogs functions as a reservoir of antigens and delivers autologous DAMPs to detain dendritic cells, resulting in a sustained enhancement of immunity. This disc sponges (APON) at lung metastasis as antigen reservoirs and immune modulators effectively suppress the tumor in 60 days and enhanced the survival rate.

Break-induced replication underlies formation of inverted triplications and generates unexpected diversity in haplotype structures.

Background: The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a type of complex genomic rearrangement (CGR) hypothesized to result from replicative repair of DNA due to replication fork collapse. It is often mediated by a pair of inverted low-copy repeats (LCR) followed by iterative template switches resulting in at least two breakpoint junctions in cis . Although it has been identified as an important mutation signature of pathogenicity for genomic disorders and cancer genomes, its architecture remains unresolved and is predicted to display at least four structural variation (SV) haplotypes. Results: Here we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the genomic DNA of 24 patients with neurodevelopmental disorders identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted SV haplotypes. Using a combination of short-read genome sequencing (GS), long- read GS, optical genome mapping and StrandSeq the haplotype structure was resolved in 18 samples. This approach refined the point of template switching between inverted LCRs in 4 samples revealing a DNA segment of ∼2.2-5.5 kb of 100% nucleotide similarity. A prediction model was developed to infer the LCR used to mediate the non-allelic homology repair. Conclusions: These data provide experimental evidence supporting the hypothesis that inverted LCRs act as a recombinant substrate in replication-based repair mechanisms. Such inverted repeats are particularly relevant for formation of copy-number associated inversions, including the DUP-TRP/INV-DUP structures. Moreover, this type of CGR can result in multiple conformers which contributes to generate diverse SV haplotypes in susceptible loci .

Resilient, undercontrolled, and overcontrolled personality types in Hong Kong youths and the association with mental health outcomes.

OBJECTIVE: This study aimed to investigate the relationship between RUO types and mental health in a youth sample in Hong Kong. BACKGROUND: Previous research has found that Resilient, Undercontrolled, and Overcontrolled (RUO) personality types derived from Big Five personality traits are associated with mental health outcomes. Most studies, however, have predominantly been conducted in Western societies. METHOD: Clinical diagnostic interviews and self-rated measures of psychological constructs, covering resilience, rumination, self-esteem and more, were administered to 860 youths aged 15 to 24 recruited from an ongoing epidemiological youth mental health study in Hong Kong. RESULTS: Three personality clusters were identified. The first (mean age = 19.6, 63.3% female) and second (mean age = 19.5, 60.7% female) cluster both have characteristics of the under- and overcontrolled personalities. The third personality type resembled the resilient profile in RUO typology (mean age = 19.6, 50.5% female) and showed the lowest prevalence of poor mental health. CONCLUSIONS: The results suggest that the replicability of the RUO profiles was only partial in a Hong Kong sample predominantly Chinese. The resilient profile was replicated but not the undercontrolled and overcontrolled profiles proposed by previous studies. The findings of the current study implicated that culturally contextual considerations are necessary when relating mental health to personality.

Effects of a culturally adapted counselling service for low-income ethnic minorities experiencing mental distress: a pragmatic randomised clinical trial.

BACKGROUND: Culturally competent early mental health interventions for ethnic minorities (EMs) with no formal diagnoses are needed. OBJECTIVES: To determine whether 8-12 weeks culturally adapted counselling (CAC) is better than waiting (waitlist (WL) group) to reduce depressive and anxiety symptoms and stress levels among EMs with elevated mental distress. METHODS: Hong Kong EMs with mild and above-mild mental distress were randomly assigned to CAC or WL in this pragmatic, randomised, WL-controlled trial. The CAC group received the intervention after randomisation and the WL group received the intervention after 8-12 weeks (T1). The prespecified primary outcomes were depressive and anxiety symptoms and stress levels measured by the Depression, Anxiety and Stress subscales of the Depression, Anxiety and Stress Scale (DASS-D, DASS-A and DASS-S, respectively) at postintervention (T1, 8-12 weeks). FINDINGS: A total of 120 participants were randomly assigned to either CAC (n=60) or WL (n=60), of whom 110 provided primary outcome data. At T1, CAC led to significantly lower depressive and anxiety symptom severity and stress levels compared with waiting, with unstandardised regression coefficients of -8.91 DASS-D points (95% CI -12.57 to -5.25; d=-0.90),-6.33 DASS-A points (95% CI -9.81 to -2.86; d=-0.68) and -8.60 DASS-S points (95% CI -12.14 to -5.06; d=-0.90). CONCLUSIONS: CAC clinically outperformed WL for mild and above-mild levels of mental distress in EMs. CLINICAL IMPLICATIONS: Making CAC routinely available for EMs in community settings can reduce healthcare burden. TRIAL REGISTRATION NUMBER: NCT04811170.

Evaluation of the Prognostic Value of Low-Frequency KRAS Mutation Detection in Circulating Tumor DNA of Patients with Metastatic Colorectal Cancer.

KRAS mutation in tumor tissue is a well-known predictor of resistance to the treatment of anti-EGFR antibodies in metastatic colorectal cancers (mCRC). However, the prognostic value of low-frequency plasma circulating tumor DNA (ctDNA) KRAS mutation in predicting treatment resistance in pretreated mCRC patients remains controversial. This study retrospectively reviewed the clinical course, including response to anti-EGFR and anti-VEGF therapies, and changes in serum tumor marker levels along with image studies in mCRC patients with <1.5% KRAS mutations detected in plasma ctDNA by next-generation sequencing (NGS) at a single center in Taiwan. We identified six pretreated mCRC patients with low-frequency KRAS G12V/G12D/G12S/G13D mutations (variant allele frequency 0.26~1.23%) in plasma ctDNA. Co-occurring low-frequency ctDNA mutations in APC, TP53, MAP2K1, KEAP1, or CTNNB1 were also detected. Although all six patients had treatment adjustments within one month after the ctDNA genetic test, image-evident tumor progression was noted in all patients within a median of 4 months afterwards. Re-challenge therapy with a combination of anti-EGFR, anti-VEGF, and FOLFIRI chemotherapy was found to be ineffective in a patient with 0.38% KRAS G12D mutation in baseline ctDNA. Our study suggests that the detection of low-frequency KRAS mutations in ctDNA could be used as a predictor of treatment response in mCRC patients.

The emergence of primary negative symptoms: relevance of timing?

Negative symptoms are an important symptom dimension in schizophrenia that are often least responsive to antipsychotic medications. We revisit the current practice of identifying 'primary' negative symptoms and suggest that its concept would benefit from a further elaboration of their timing of emergence in relation to the dynamic neurobiological changes to enhance their utility in clinical decision-making and research.

Unpacking the mediating role of resilience in the relationship between ideal-actual self-discrepancy, stressful life events, depression and anxiety: Results from 1,144 young people in an epidemiological study in Hong Kong.

BACKGROUND: Self-discrepancy is associated with poorer mental health, yet its mechanism is understudied. A recent study found that resilience plays a moderating role in the relationship between self-discrepancy and depressive symptoms in adults. The current study investigated whether there were any similar relationships among young people aged 15 to 24 years. METHODS: As part of the ongoing Hong Kong Epidemiological Study of Mental Health (HK-YES) project, the current study analysed data from 1,144 participants who provided complete data on ideal-actual selfdiscrepancy, psychiatric conditions, resilience level and recent stressful life events (SLEs). RESULTS: Ideal-actual self-discrepancies were associated with increased depressive and anxiety symptoms, as well as odds of 12-month major depressive episodes (MDEs) and generalised anxiety disorder (GAD). All these associations became nonsignificant after adjusting for resilience. Separate models found resilience mediating rather than moderating the relationship. According to four-way decomposition, the pure indirect effect explained most of the total effects of self-discrepancy on mental health conditions. The mediation effects on symptom severity were recently revealed to be more prominent among individuals with substantial exposure to SLE. CONCLUSIONS: Resilience functions mainly as a mediator in the relationship between self-discrepancy and mental health conditions, and its effect is weakened by the exposure of SLEs. Important implications are discussed regarding the use of resilience-focused interventions and the consideration of recent adversity.

Experience of a demand-side subsidy scheme for residential long-term care: perspectives of elderly and their carers.

BACKGROUND: Vouchers, which are demand-side subsidies to targeted groups, are a type of consumer-led near-cash social transfer for specified benefits that have been used in education, health and other sectors. To provide better access to residential care services and an additional choice for elderly people in need, a novel means-tested residential care service voucher has been introduced in Hong Kong for elderly people to purchase places in the private sector to enable consumer-directed care. The objectives of this paper are to analyze the perspectives of voucher users and their carers toward the voucher scheme and to identify key elements in the design that will contribute to meeting the scheme's objectives. METHODS: An exploratory sequential mixed method design was adopted with initial explorative qualitative data collection of the perspectives of elderly people and their carers (Phase 1), which informed the design of the subsequent questionnaire survey (Phase 2). Thirty carers in 5 focus groups and 20 individual interviews with elderly people were conducted between April and May 2018. A total of 401 respondents (373 carers and 28 elderly people) completed the survey questionnaire. Findings from both phases were integrated both narratively and via a joint display. RESULTS: Five key themes summarized the features in two main elements of the design and implementation of the voucher scheme: awareness, meaning that inadequate knowledge and understanding of voucher schemes hinder participation; service needs and types, indicating that the urgent need for residential care services is the key reason for participation; shared responsibility, meaning that a high copayment level discourages participation; choice and flexibility, reflecting appreciation of the additional choices provided by voucher schemes although the availability of residential care beds limits choices; and service quality, indicating mixed perceptions of service quality and the impact of the voucher scheme. Voucher users believe that the voucher scheme is more helpful for relieving the financial burden (98.7%), reducing carers' stress (97.0%) and reducing the waiting time for subsidized homes for elderly people (89.0%) than for increasing choice and flexibility (78.1%) and improving service quality (62.1%). CONCLUSIONS: This study demonstrates how the design of a voucher scheme affects its take-up by targeted beneficiaries. When a voucher scheme is implemented in a long-term care system, it must consider the congruence with existing policies in long-term care provision and financing. The voucher scheme in Hong Kong has been able to generate the utilization of nonsubsidized places in homes for elderly people that were underutilized, but its effectiveness is limited by inadequate knowledge and understanding of the voucher scheme and the availability of residential care places. Giving the purchasing power and choice of providers to beneficiaries has the potential to enhance the quality of services, which will contribute to meeting the objectives. The study findings carry significant implications for long-term care policies and provide insights into the key features of the voucher scheme for residential care services and how to best design and implement a voucher scheme for elderly people in the context of policy objectives and a long-term care policy.

The Hong Kong youth epidemiological study of mental health (HK-YES)-A population-based psychiatric epidemiology study of youth mental health in Hong Kong: A study protocol.

AIM: Young people in Hong Kong have been facing numerous population-level events over the past year, including social unrest and the COVID-19 pandemic. Representative data concerning the mental health of youths, however, is limited. The Hong Kong Youth Epidemiological Study of Mental Health (HK-YES) is commissioned to provide the first representative prevalence estimates and correlates of mental disorders among young people in Hong Kong. It will also examine the help-seeking behaviours, treatment rates, quality of life, and functional outcomes of the young people. More importantly, the direct and indirect economic costs of mental disorders in youths will be estimated. METHODS: A total of 4500 community-dwelling participants aged 15-24 years from Hong Kong will be surveyed. Participants will be selected using a multistage stratified sampling design to provide representative estimates of the youth population in Hong Kong. All interviews will be conducted using computer-assisted personal interviewing methods for assessments covering areas of psychiatric diagnoses, symptomatology, functioning, quality of life, disability, service utilization, health economic costs of mental disorders, and sociodemographic and lifestyle characteristics. A population-weighted prevalence will be estimated using survey weights. Methods such as multivariate logistic and linear regression analyses will be used to calculate the risks and odds of factors that might be associated with different mental disorders. CONCLUSION: As the first population-based youth study in Hong Kong, HK-YES collects extensive and representative data on different mental conditions and their associated factors among young people. The information gathered will be important for future planning on youth mental health services in Hong Kong and will offer the opportunity for a more meaningful comparison of data with other youth populations.

Prognostic significance of FIGO 2018 staging of loco-regionally advanced cervical cancer (LRACC) with the use of MRI and PET and implications for treatment selection.

INTRODUCTION: The FIGO 2018 staging of cervix cancer recognizes a total of 11 categories of loco-regionally advanced cervix cancer (LRACC). Whilst incorporating imaging is an improvement over clinical staging (FIGO 2009), this had led to more categories of disease which are not prognostically discrete groups. We aimed to analyze survival according to 2018 FIGO stages of cervix cancer and identify isoprognostic groups of patients based on primary tumor volume and nodal status. METHODS: Patients referred for radiotherapy with curative intent between 1996 and 2014 were eligible. Baseline clinico-pathological and follow up information was retrieved from an ethics-approved institutional prospective database. Patients were classified according to FIGO 2018 staging based on histo-pathology, MRI (tumor volume and local compartmental spread assessment) and PET results (nodal spread). Kaplan-Meier method was used to estimate survival at five years. Following survival analysis using recognized prognostic factors, isoprognostic categories were identified and merged to form 5 isoprognostic groups. RESULTS: Seven hundred and forty-four LRACC patients were included. The median (IQR) follow-up was 5.1 (2.6-8.4) yrs. Stage migration occurred in most patients, showing heterogeneous 5 years survival according to 2018 FIGO stages. In contrast progressively worsening prognosis could be demonstrated in the 5 observed isoprognostic clusters (p < 0.002). CONCLUSION/IMPLICATIONS: Prognosis in LRACC depends on the interplay between primary tumor characteristics, type of local spread and nodal disease. A prospective study of survival and patterns of failure according to isoprognostic clusters would be useful to determine the most appropriate treatment modality and estimate survival as well as better patient selection for clinical trials.