Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin-paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial.

BACKGROUND: Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer (EC). At the first interim analysis, the trial met one of its dual primary endpoints with statistically significant progression-free survival benefits in the mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis. PATIENTS AND METHODS: RUBY is a phase III, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent EC who were randomly assigned (1 : 1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual primary endpoint. RESULTS: A total of 494 patients were randomized (245 in the dostarlimab arm; 249 in the placebo arm). In the overall population, with 51% maturity, RUBY met the dual primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death [hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.54-0.89, P = 0.0020] in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32, 95% CI 0.17-0.63, nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair-proficient/microsatellite stable population (HR = 0.79, 95% CI 0.60-1.04, nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis. CONCLUSIONS: Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful OS benefit in the overall population of patients with primary advanced or recurrent EC while demonstrating an acceptable safety profile.

The global prevalence of premature ovarian insufficiency: a systematic review and meta-analysis.

OBJECTIVE: The objective of this review was to answer the global prevalence of premature ovarian insufficiency (POI), and explore the associated factors including etiopathology and regions with POI. METHODS: The search was conducted on reports from a total of eight databases that comprised Chinese National Knowledge Infrastructure (CNKI), Wanfang, China BioMedical Literature Database (CBM), PubMed, the Cochrane Library, Embase, Web of Science and Ovid MEDLINE® between 1946 and 2021. To analyze the source of heterogeneity, we performed subgroup analysis based on different etiologies and regions. Meta-analysis was carried out by Stata14.0 software. RESULTS: The results showed that the global overall prevalence of POI among women was 3.5%. By subgroup analysis, the prevalence of POI among women with iatrogenic etiology was 11.2%, followed by autoimmunity (10.5%); the prevalence of POI by region was 11.3% at the highest in North America followed by South America (5.4%); and the prevalence of POI was 5.3% in a developing country, higher than 3.1% in a developed country. The trend of prevalence of POI over the past 20 years was on the rise (although p > 0.05). CONCLUSION: We recommend that health and medical institutions strengthen public health awareness, achieve health-education goals related to POI and increase women's awareness of and attention to POI.

Trends in the prevalence of intellectual disability among children in Taiwan.

BACKGROUND: Intellectual disability (ID) is a major developmental disability. However, data on changes in the prevalence over time at the national level are limited. METHOD: Using data from the national disability registry, we conducted an ecological study to evaluate the time trends of ID among children in Taiwan. We calculated the prevalence of ID by age, sex and severity, from 2000 to 2011, and assessed the time trends. RESULTS: During the study period, the overall prevalence of ID in children aged 3-17 years increased from 3.60 to 5.91 per 1000 (ß = 0.22, P < 0.001, r2  = 0.97). The prevalence of mild ID (MID, intelligence quotient: 50-69) increased from 1.30 to 3.60 per 1000 (ß = 0.21, P < 0.001, r2  = 0.98). However, the prevalence of severe ID (SID, intelligence quotient: <50) was relatively constant, between 2.22 and 2.38 per 1000 (ß = 0.01, P = 0.076, r2  = 0.96). Boys had a higher prevalence than girls, and the average boy-to-girl prevalence ratio was 1.42 for MID and 1.31 for SID. The boy-to-girl prevalence ratios of MID and SID decreased over time (ß = -0.01, P < 0.001, r2  = 0.99 for MID; ß = -0.01, P < 0.001, r2  = 1.00 for SID). CONCLUSION: The prevalence of ID in Taiwanese children increased from 2000 to 2011 and was largely attributable to increases in MID. Boys had a higher prevalence of ID and were more likely to have MID.

An endophenotype approach to the genetics of alcohol dependence: a genome wide association study of fast beta EEG in families of African ancestry.

Fast beta (20-28 Hz) electroencephalogram (EEG) oscillatory activity may be a useful endophenotype for studying the genetics of disorders characterized by neural hyperexcitability, including substance use disorders (SUDs). However, the genetic underpinnings of fast beta EEG have not previously been studied in a population of African-American ancestry (AA). In a sample of 2382 AA individuals from 482 families drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a genome-wide association study (GWAS) on resting-state fast beta EEG power. To further characterize our genetic findings, we examined the functional and clinical/behavioral significance of GWAS variants. Ten correlated single-nucleotide polymorphisms (SNPs) (r2>0.9) located in an intergenic region on chromosome 3q26 were associated with fast beta EEG power at P<5 × 10-8. The most significantly associated SNP, rs11720469 (ß: -0.124; P<4.5 × 10-9), is also an expression quantitative trait locus for BCHE (butyrylcholinesterase), expressed in thalamus tissue. Four of the genome-wide SNPs were also associated with Diagnostic and Statistical Manual of Mental Disorders Alcohol Dependence in COGA AA families, and two (rs13093097, rs7428372) were replicated in an independent AA sample (Gelernter et al.). Analyses in the AA adolescent/young adult (offspring from COGA families) subsample indicated association of rs11720469 with heavy episodic drinking (frequency of consuming 5+ drinks within 24 h). Converging findings presented in this study provide support for the role of genetic variants within 3q26 in neural and behavioral disinhibition. These novel genetic findings highlight the importance of including AA populations in genetics research on SUDs and the utility of the endophenotype approach in enhancing our understanding of mechanisms underlying addiction susceptibility.

rs9939609 FTO genotype associations with FTO methylation level influences body mass and telomere length in an Australian rural population.

BACKGROUND: The fat mass- and obesity-associated (FTO) gene influences energy homeostasis in humans. Although the obesity-related variant, rs9939609 has been replicated across a number of cohort studies, there remains significant variance and a low to modest association. Telomere length is another commonly reported obesity risk factor. We hypothesize understanding the associations between FTO rs9939609 with FTO methylation and telomere length will provide a more accurate assessment of obesity risk. METHODS: Overall, 942 participants free of diabetes or pre-diabetes were included in the retrospective study. Leukocyte genomic DNA was analyzed for rs9939609 genotyping, FTO gene methylation and leukocyte telomere length (LTL) measurement. RESULTS: In general linear models, rs9939609 AA genotypes were associated with increased fat percentage (3.15%, P=0.001), fat mass (4.16 kg, P=0.001), body mass index (BMI) (1.38, P=0.006) and waist circumference (3.35 cm, P=0.006), but not with FTO methylation or LTL in this overall population. However, when participants were stratified into higher and lower FTO methylation groups, the AA genotype possesses a 2.04-fold increased obesity risk in comparison to TT genotype (95%CI, 1.07-3.89, P=0.031) in participants with a higher FTO methylation level, but this association was absent in the lower FTO methylation sub-group. Moreover, AT and AA genotype carriers were associated with shorter LTL compared to TT carriers (P=0.020 and P=0.111, respectively) in the higher FTO methylation level group. However, this association was absent in the lower methylation group. Furthermore, FTO gene methylation level was significantly associated with LTL in the 942 samples (P=0.017). CONCLUSIONS: FTO rs9939609 is associated with obesity risk and LTL in this study, where this association is only observed at higher, but not lower, FTO methylation levels of participants. Our data suggest association of multiple factors, including FTO methylation level, may be involved in one of several mechanisms underlying the commonly reported obesity risk of this FTO polymorphism.

Local modulation of double optomechanically induced transparency and amplification.

We consider the probe absorption properties in a mechanically coupled optomechanical system in which the two coupled nanomechanical oscillators are driven by the time-dependent forces, respectively. It is found that the mechanical interaction splits the transparency window for a usual single-mode optomechanical system into two parts and then leads to appearance of the double optomechanically induced transparency. The distance between the two transparency positions (the frequency for the maximal transparency) is determined by the mechanical interaction amplitude. This can be explained by using optomechanical dressed-mode picture which is analogue to the interacting dark resonances in coherent atoms. When the mechanical resonators are driven by the external forces, the transparencies in the double-transparency spectrum can be increased into amplifications or be suppressed by tuning the amplitude of the forces. Additionally, it is shown that the double transparencies or the amplifications oscillate with the initial phases of the forces with a period of 2π. These investigations will be useful for more flexible controllability of multi-channel optical communication based on the optomechanical systems.

Slow and steady cell shrinkage reduces osmotic stress in bovine and murine oocyte and zygote vitrification.

STUDY QUESTION: Does the use of a new cryoprotectant agent (CPA) exchange protocol designed to minimize osmotic stress improve oocyte or zygote vitrification by reducing sublethal cryodamage? SUMMARY ANSWER: The use of a new CPA exchange protocol made possible by automated microfluidics improved oocyte and zygote vitrification with superior morphology as indicated by a smoother cell surface, higher sphericity, higher cytoplasmic lipid retention, less cytoplasmic leakage and higher developmental competence compared with conventional methods. WHAT IS KNOWN ALREADY: The use of more 'steps' of CPA exposure during the vitrification protocol increases cryosurvival and development in the bovine model. However, such an attempt to eliminate osmotic stress is limited by the practicality of performing numerous precise pipetting steps in a short amount of time. STUDY DESIGN, SIZE, DURATION: Murine meiotically competent germinal vesicle intact oocytes and zygotes were harvested from the antral follicles in ovaries and ampulla, respectively. Bovine ovaries were obtained from a local abattoir at random stages of the estrous cycle. A total of 110 murine oocytes, 802 murine zygotes and 52 bovine oocytes were used in this study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Microfluidic devices were fabricated using conventional photo- and soft-lithography. CPAs used were 7.5% ethylene glycol (EG) and 7.5% dimethyl sulfoxide (DMSO) for equilibration solution and 15% EG, 15% DMSO and 0.5 M sucrose for vitrification solution. End-point analyses include mathematical modeling using Kedem-Katchalsky equations, morphometrics assessed by conventional and confocal microscopy, cytoplasmic lipid quantification by nile red staining, cytoplasmic leakage quantification by fluorescent dextran intercalation and developmental competence analysis by 96 h embryo culture and blastomere quantification. MAIN RESULTS AND THE ROLE OF CHANCE: The automated microfluidics protocol decreased the shrinkage rate of the oocyte and zygote by 13.8 times over its manual pipetting alternative. Oocytes and zygotes with a lower shrinkage rate during CPA exposure experienced less osmotic stress resulting in better morphology, higher cell quality and improved developmental competence. This microfluidic procedure resulted in murine zygotes with a significantly smoother cell surface (P < 0.001), more spherical cellular morphology (P < 0.001), increased cytoplasmic lipid retention in vitrified and warmed bovine oocytes (P < 0.01), decreased membrane perforations and cytoplasmic leakage in CPA-exposed murine zygotes (P < 0.05) and improved developmental competence of vitrified and warmed murine zygotes (P < 0.05) than CPA exposure using the current clinically used manual pipetting method. LIMITATIONS, REASONS FOR CAUTION: It is necessary to design the microfluidic device to be more user-friendly for widespread use. WIDER IMPLICATIONS OF THE FINDINGS: The theory and approach of eliminating osmotic stress by decreasing shrinkage rate is complementary to the prevalent osmotic stress theory in cryobiology which focuses on a minimum cell volume at which the cells shrink. The auto-microfluidic protocol described here has immediate applications for improving animal and human oocyte, zygote and embryo cryopreservation. On a fundamental level, the clear demonstration that at the same minimum cell volume, cell shrinkage rate affects sublethal damage should be broadly useful for cryobiology. STUDY FUNDING/COMPETING INTERESTS: This project was funded by the National Institutes of Health and the University of Michigan Reproductive Sciences Program. The authors declare no conflicts of interest.

Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100.

BACKGROUND: Bevacizumab has broad anti-tumour activity, but substantial risk of hypertension. No reliable markers are available for predicting bevacizumab-induced hypertension. METHODS: A genome-wide association study (GWAS) was performed in the phase III bevacizumab-based adjuvant breast cancer trial, ECOG-5103, to evaluate for an association between genotypes and hypertension. GWAS was conducted in those who had experienced systolic blood pressure (SBP) >160 mm Hg during therapy using binary analysis and a cumulative dose model for the total exposure of bevacizumab. Common toxicity criteria (CTC) grade 3-5 hypertension was also assessed. Candidate SNP validation was performed in the randomised phase III trial, ECOG-2100. RESULTS: When using the phenotype of SBP>160 mm Hg, the most significant association in SV2C (rs6453204) approached and met genome-wide significance in the binary model (P=6.0 × 10(-8); OR=3.3) and in the cumulative dose model (P=4.7 × 10(-8); HR=2.2), respectively. Similar associations with rs6453204 were seen for CTC grade 3-5 hypertension but did not meet genome-wide significance. Validation study from ECOG-2100 demonstrated a statistically significant association between this SNP and grade 3/4 hypertension using the binary model (P-value=0.037; OR=2.4). CONCLUSIONS: A genetic variant in SV2C predicted clinically relevant bevacizumab-induced hypertension in two independent, randomised phase III trials.

Effects of newly developed chemotherapy regimens, comorbidities, chemotherapy-related toxicities on the changing patterns of the leading causes of death in elderly patients with colorectal cancer.

BACKGROUND: Abundant evidences have shown that newly developed chemotherapy regimens improved 5-year survival rate of colorectal cancer (CRC) patients over the past two decades. However, their impact on risk of death from leading causes among elderly patients is still poorly understood. PATIENTS AND METHODS: A retrospective cohort study of 69 718 elderly CRC patients with their first primary tumors in 1992-2009, identified from the 12 areas of Surveillance, Epidemiology, and End Results-Medicare linked database with their Medicare claims up to 2010. Multivariate Cox regression models were used to assess the effect of newly developed chemotherapy regimens, comorbidities, and chemotherapy related toxicities on cause-specific death and their temporal patterns among elderly CRC patients. RESULTS: The leading causes of death among CRC patients were CRC, circulation disorders, and secondary cancers, which accounted for 51.4%, 25%, and 4.6% of all-cause death, respectively. Patients diagnosed in more recent diagnostic time periods were significantly less likely to die of CRC [period 2: 5-year hazard ratio = 0.94, 95% confidence interval (CI) 0.90-0.97; period 3: 0.86, 0.83-0.90], circulation disorders (period 2: 0.94, 0.88-1.00; period 3: 0.80, 0.75-0.87), and more likely to die of secondary cancer (period 3: 1.42, 1.20-1.68) compared with those diagnosed in period 1. Charlson comorbidities index and the selected pre-existing comorbidities were significantly associated with increased 5-year risk of death from all three leading causes. Both hematological and gastric toxicity were associated with reduced risk of death from CRC and circulation disorders. The association between diagnostic time period and risk reduction in death from CRC depended on chemotherapy treatment (P < 0.0001). Subgroup analyses showed that the chemotherapy-dependent significant risk reduction was seen in patients with stage II-III CRC, patients without comorbidities, and patients without toxicities (P < 0.0001 for all). CONCLUSION: The newly developed chemotherapy regimens were associated with the decreased risk of mortality from CRC.

Quality trait variations in [6°Co]-irradiated wheat and high-molecular-weight glutenin subunit mutant identification.

With 300 Gy of [(60)Co] γ-ray radiation of dry wheat seeds of Vortex 9722, the protein content, wet gluten content, sedimentation value, and hardness variation were analyzed in 341 lines in M4. Using over population mean ± 2X standard deviation as the screening standard, 8 lines with higher protein and wet gluten content and 4 lines with lower protein and wet gluten content were selected. In the M5 generation, the quality traits - silty parameters and high molecular weight glutenin subunits (HMW-GS) - were further analyzed in these 12 lines. The results showed that in the M5 generation, the quality traits in some variants were significantly different from those in the parents; the farinograms varied greatly. Eleven variants had significantly different HMW-GS bands compared to their parents. The parents had a HMW-GS composition of 5 + 14 + 15 + 12 + 9, and the variants had HMW-GS of 11 + 5 + 7 + 9 + 12 subunits or 1 + 5 + 7 + 8 + 12 subunits, indicating that the glutenin loci of these lines were mutated.

Development and evaluation of loop-mediated isothermal amplification (LAMP) for rapid detection of Clonorchis sinensis from its first intermediate hosts, freshwater snails.

Clonorchiasis, caused by Clonorchis sinensis, is a key foodborne zoonosis, which is mainly found in China, Korea and Vietnam. Detection of this parasite from the second intermediate host, the freshwater fish is the common method for epidemiological surveys of this parasite, but is time consuming, labour intensive and easily leads to misdiagnosis. In this study, we have developed a rapid, sensitive and reliable molecular method for the diagnosis of C. sinensis from its first intermediate hosts, freshwater snails, based on a loop-mediated isothermal amplification (LAMP) method. The specific amplified fragment from genomic DNA of C. sinensis did not cross-react with those from other relevant trematodes and a range of hosts (freshwater fish, shrimps and snails) of C. sinensis living in similar environments. The detection limit of the LAMP method was as low as 10 fg which was 1000 times more sensitive than conventional PCR, which was also demonstrated by successful application to field samples. These results show that the LAMP method is a more sensitive tool than conventional PCR for the detection of C. sinensis infection in the first intermediate hosts and, due to a simpler protocol, is an ideal molecular method for field-based epidemiological surveys of this parasite.

Potential gains in life expectancy from reducing heart disease, cancer, Alzheimer's disease, kidney disease or HIV/AIDS as major causes of death in the USA.

OBJECTIVES: Potential gains in life expectancy (PGLEs) that give proper consideration to competing risks are an effective indicator for measuring the impact of multiple causes of death on a defined population. This study aimed to assess PGLE by hypothetically reducing the major causes of death in the USA from 2001 to 2008. STUDY DESIGN: PGLEs due to the reduction and elimination of heart disease, cancer, Alzheimer's disease, kidney disease or human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) were calculated by age, gender and race. METHODS: Age-specific mortality rates for the above diseases from the National Center for Health Statistics were used, and multiple decremental life tables were constructed to compute the corresponding PGLEs. RESULTS: PGLEs due to the elimination of heart disease, cancer or HIV/AIDS decreased from 2001 to 2008, but PGLEs due to the elimination of Alzheimer's disease or kidney disease increased over time. For heart disease, PGLE in 2001-2008 for all races was 2.78-2.15 for females vs 2.41-2.06 for males. For cancer, PGLE in 2001-2008 for all races was 2.97-2.81 for females vs 3.02-2.85 for males. HIV/AIDS has a greater impact on people of working age, whereas Alzheimer's disease has a greater impact on the elderly population. To compare the impacts of these diseases on life expectancy, partial multiple decremental life tables were constructed, and PGLEs were computed by a partial reduction or complete elimination of various causes of death for the entire life span as well as for certain working ages. CONCLUSION: This study outlined a picture of how each category of diseases could affect life expectancy in the US population by age, race or sex. The findings may assist in evaluating current public health improvements, and also provide useful information for directing future research and disease control programmes.

Trajectories of Intrinsic Capacity: Determinants and Associations with Disability.

OBJECTIVES: Intrinsic capacity (IC) declines progressively with age, thereby increasing the risk of disability. However, it is less known whether IC trajectories are associated with disability. This study aims to identify the different patterns of IC trajectories in older people, and examine their determinants and associations with Instrumental Activities of Daily Living (IADL). DESIGN: Cohort study. SETTING: Community centres in different regions in Hong Kong. PARTICIPANTS AND MEASUREMENTS: Longitudinal data from community-dwelling older people aged 60 years or above (n = 1371) collected between 2016 and 2021 was analysed. Their mean age was 74.5 years, and 78.7% of them were female. Repeated measurements of a set of 14 self-reported items were used to generate IC scores at four time points using a bi-factor model. Latent class growth analysis was performed to identify classes with distinct IC trajectories. The association between class membership and IADL disability was then examined using logistic regression. RESULTS: Three distinct IC trajectories were identified. The 1st class included those with the highest level of baseline IC and the least declining trajectory, whereas the 3rd class was composed by those with the lowest level of baseline IC and the most declining trajectory. Older age, female gender, lower perceived financial adequacy, living in public or subsidized housing, and chronic diseases were associated with the 3rd class. After adjusting for demographic factors, socioeconomic status, and the number of chronic diseases, the 1st class was more likely to preserve IADL when compared against the 2nd class, with OR being 3.179 (95% CI: 2.152-4.793), whereas for the 3rd class, the OR was 0.253 (95% CI: 0.178-0.359). CONCLUSION: Monitoring IC trajectories is of relevance to clinical practice, as it helps shift the focus from treating acute episodes of illness to preserving the functional ability of older people.

A Dyadic Cooking-Based Intervention for Improving Subjective Health and Well-Being of Older Adults with Subjective Cognitive Decline and Their Caregivers: A Randomized Controlled Trial.

OBJECTIVES: Evidence on the effectiveness of cooking activities as a well-being promotion intervention for older adults with subjective cognitive decline (SCD) and their caregivers is scarce. In view of this, a randomized controlled trial was conducted to examine whether a dyadic cooking-based intervention can improve the subjective health and well-being of older adults with SCD and their caregivers, as well as the cooking competence of the former group. DESIGN: Randomized controlled trial. SETTING: Community. PARTICIPANTS: Sixty pairs of community-dwelling older adults aged 60 years or above with SCD (mean age = 78.4 years) and their caregivers (mean age = 65.3 years) were randomly assigned to the intervention group (N = 30 pairs) and the wait-list control group (N = 30 pairs). INTERVENTION: The intervention was an innovative 5-week (two hours per week) dyadic cooking-based intervention employing procedural learning methods specifically adapted for older adults with SCD. MEASUREMENTS: The outcome measures included 1) a well-being index composed by four indicators: life satisfaction, feeling of happiness, sense of purpose and meaning in life, and perceived health, and 2) cooking competence. RESULTS: For both older adults with SCD and their caregivers, the increases in the well-being index were significantly greater in the intervention group than in the control group (ß = 0.508, 95% CI [0.036, 0.980]). For older adults with SCD, the increases in the cooking competence score were significantly greater in the intervention group than in the control group (ß = 1.629, 95% CI [0.165, 3.071]). CONCLUSION: The dyadic cooking-based intervention resulted in improvements in the cooking competence and well-being of older adults with SCD, as well as the well-being of caregivers.

Assessing the Readiness for Implementing the World Health Organization's ICOPE Approach in Hong Kong: Perspectives from Social Care and Policy Stakeholders.

Although integrated care has been considered a key strategy in reforming health systems around the world, it seems hard to realise in practice, particularly in the part of medical social integration. Worse still, little is known about the capacity of social care professionals who implement it, or their perceived roles and responsibilities, as well as the barriers and facilitators that stakeholders from the health and social sectors identify as factors affecting the ICOPE implementation process. Therefore, the present study was performed to probe into these issues. Data were collected from an online survey based on the WHO ICOPE scorecard (N = 34), and focus groups with policy makers, managers, health and social care professionals (N = 47). Inductive analyses were performed in accordance with the service and system levels within the WHO ICOPE implementation framework. While the findings from the scorecard survey highlight the gap in actualizing the ICOPE approach within the existing social services and care structures, we found support for a model of integrated care underpinned by the WHO ICOPE approach. Factors that may hinder and facilitate ICOPE implementation include workforce capacity-building, coordinated networks and partnerships, and financial mechanisms. This finding can help inform subsequent actions that further support health and social care advancement and collaboration, and the implementation of the ICOPE approach.

Moving towards the ICOPE Approach: Evaluation of Community-Based Intervention Activities on Improving Intrinsic Capacity.

OBJECTIVES: Different types of community-based intervention activities may have differential effects in improving the intrinsic capacity (IC) of older people. This study aims to (i) identify subgroups of older people based on their IC impairments, (ii) examine the differential associations between different types of activity participations and change in IC across subgroups, and (iii) assess whether the activity participation patterns of older people align with the way that would benefit them the most. METHODS: Participants were community-dwelling older people aged 60 years or above. They were screened for IC impairments at baseline, and their participation records of different types (cognitive, physical, nutritional, mental, and social) of intervention activities were collected for one year. An aggregated IC score was created based on four IC domains including cognitive (self-rated memory), locomotor (self-rated difficulties in walking), vitality (self-rated weight loss), and psychological (subjective well-being). Cluster analysis was used to group homogenous participants. Mixed-effects regression was used to examine the associations between activity counts (i.e., number of sessions participated) and change in IC. Activity participation patterns were also compared across subgroups. RESULTS: Data were obtained from 7,357 participants (mean age = 74.72 years). Four clusters were identified, including those who were relatively robust (cluster 1, N = 4,380, 59.5%), those who had cognitive decline (cluster 2, N = 2,134, 29.0%), those who had impaired mobility and vitality (cluster 3, N = 319, 4.3%), and those with poor psychological well-being (cluster 4, N = 524, 7.1%). Overall, activity count was associated with IC improvement (ß = 0.073, 95% CI [0.037, 0.108]). However, as regards the cluster-specific results, different types of activities were associated with IC improvement for different specific clusters. For instance, cognitive activity count was associated with IC improvement only for cluster 2 (ß = 0.491, 95% CI [0.258, 0.732]). Notably, none of the activity types were associated with IC improvement for cluster 1. Regarding the activity participation patterns, there were no significant differences across the four clusters (Wilk's Λ = 0.997, F = 1.400, p = .138). CONCLUSIONS AND IMPLICATIONS: IC improvement depended on the activity types and IC status of older people. In view of this, a people-centred and targeted approach should be adopted to maximize the overall benefits of intervention activities.

miR-21, miR-17 and miR-19a induced by phosphatase of regenerating liver-3 promote the proliferation and metastasis of colon cancer.

BACKGROUND: Phosphatase of regenerating liver-3 (PRL-3) is an oncogene known to promote tumour metastasis, especially in colorectal cancer (CRC). Here, we demonstrate that the miR-21, miR-17 and miR-19a expressions induced by PRL-3 are involved in the proliferation and metastasis of colon cancer. METHODS: Microarray analysis and quantitative reverse-transcription polymerase chain reactions (qRT-PCR) were used to investigate the changes in miRNA expression due to the overexpression of PRL-3. Transwell chamber invasion assays, CCK-8 proliferation assays and RNA interference assays were used to explore the effects of PRL-3 on miR-21, miR-17 and miR-19a expression in colon cancer cells. Immunohistochemistry and qRT-PCR were performed in colon cancer tissues to evaluate the expression of PRL-3, signal transducer and activator of transcription 3 (STAT3), miR-21, miR-17 and miR-19a. RESULTS: Our study demonstrated that the overexpression of PRL-3 in colon cancer cells induced the expression of miR-21, miR-17 and miR-19a by activating STAT3. Subsequently, these microRNAs contributed to the increased proliferation and invasiveness of the colon cancer cells. Positive correlations between PRL-3 and these microRNAs were also observed in matched primary colon cancer tissues and metastatic lesions. CONCLUSION: miR-21, miR-17 and miR-19a induced by PRL-3 contribute to the proliferation and invasion of colon cancer.

Imaging of highly malignant osteosarcoma with iodine-123-vascular endothelial growth factor.

OBJECTIVE: Vascular endothelial growth factor (VEGF) is an important angiogenic factor, and its receptors have been shown to be overexpressed in various human carcinomas. In this study, we investigated the role of scanning with iodine-123 ((123)I)-labelled VEGF(165) in patients with highly malignant osteosarcoma. METHODS: Two patients (a 15-year-old female and a 14-year-old male) with osteosarcoma were injected with 140 MBq [<130 pmol (<5 µg) VEGF(165) per patient] of (123)I-VEGF(165). Dynamic acquisition was initiated immediately after administration and carried out until 30 min after injection. Whole-body images were done in anterior and posterior views at various time points. All patients underwent single-photon emission tomography imaging. RESULTS: (123)I-VEGF(165) scans were positive in these patients. Sequential images clearly showed increased (123)I-VEGF(165) activity in osteosarcoma lesions. The tumour lesions were still visualized in whole-body images and single-photon emission tomography examinations 2 h after injection. Intravenous injection of (123)I-VEGF(165) did not cause any side effects. CONCLUSION: Our results suggest that (123)I-VEGF(165) receptor scintigraphy may be useful for the visualization of highly malignant osteosarcoma and/or metastasis and the angiogenic activity of the tumour.

Schizophrenia-related endophenotypes in heterozygous neuregulin-1 'knockout' mice.

Neuregulin-1 (NRG1) has been shown to play a role in glutamatergic neurotransmission and is a risk gene for schizophrenia, in which there is evidence for hypoglutamatergic function. Sensitivity to the behavioural effects of the psychotomimetic N-methyl-D-aspartate receptor antagonists MK-801 and phencyclidine (PCP) was examined in mutant mice with heterozygous deletion of NRG1. Social behaviour (sociability, social novelty preference and dyadic interaction), together with exploratory activity, was assessed following acute or subchronic administration of MK-801 (0.1 and 0.2 mg/kg) or PCP (5 mg/kg). In untreated NRG1 mutants, levels of glutamate, N-acetylaspartate and GABA were determined using high-performance liquid chromatography and regional brain volumes were assessed using magnetic resonance imaging at 7T. NRG1 mutants, particularly males, displayed decreased responsivity to the locomotor-activating effects of acute PCP. Subchronic MK-801 and PCP disrupted sociability and social novelty preference in mutants and wildtypes and reversed the increase in both exploratory activity and social dominance-related behaviours observed in vehicle-treated mutants. No phenotypic differences were demonstrated in N-acetylaspartate, glutamate or GABA levels. The total ventricular and olfactory bulb volume was decreased in mutants. These data indicate a subtle role for NRG1 in modulating several schizophrenia-relevant processes including the effects of psychotomimetic N-methyl-D-aspartate receptor antagonists.

Synthetic evaluation of the effect of health promotion: impact of a UNICEF project in 40 poor western counties of China.

OBJECTIVE: To synthetically evaluate the effects of a health promotion project launched by the Ministry of Health of China and the United Nations Children's Fund (UNICEF) in 40 poor western counties of China. STUDY DESIGN: The two surveys were cross-sectional studies. Stratified multistage random sampling was used to recruit subjects. METHODS: Data were collected through two surveys conducted in the 40 'UNICEF project counties' in 1999 and 2000. After categorizing the 27 evaluation indicators into four aspects, a hybrid of the Analytic Hierarchy Process, the Technique for Order Preference by Similarity to Ideal Solution, and linear weighting were used to analyse the changes. The 40 counties were classified into three different levels according to differences in the synthetic indicator derived. Comparing the synthetic evaluation indicators of these two surveys, issues for implementation of the project were identified and discussed. RESULTS: The values of the synthetic indicators were significantly higher in 2000 than in 1999 (P=0.02); this indicated that the projects were effective. Among the 40 counties, 11 counties were at a higher level in 2000, 10 counties were at a lower level, and others were in the middle level. Comparative analysis showed that 36% of village clinics were not licensed to practice medicine, nearly 50% of village clinics had no records of medicine purchases, nearly 20% of village clinics had no pressure cooker for disinfection, and 20% of pregnant women did not receive any prenatal care. CONCLUSIONS: The health promotion projects in the 40 counties were effective. Health management, medical treatment conditions, maternal health and child health care have improved to some extent. However, much remains to be done to improve health care in these 40 poor counties. The findings of this study can help decision makers to improve the implementation of such improvements.