Prediction of standard cell types and functional markers from textual descriptions of flow cytometry gating definitions using machine learning.

BACKGROUND: A key step in clinical flow cytometry data analysis is gating, which involves the identification of cell populations. The process of gating produces a set of reportable results, which are typically described by gating definitions. The non-standardized, non-interpreted nature of gating definitions represents a hurdle for data interpretation and data sharing across and within organizations. Interpreting and standardizing gating definitions for subsequent analysis of gating results requires a curation effort from experts. Machine learning approaches have the potential to help in this process by predicting expert annotations associated with gating definitions. METHODS: We created a gold-standard dataset by manually annotating thousands of gating definitions with cell type and functional marker annotations. We used this dataset to train and test a machine learning pipeline able to predict standard cell types and functional marker genes associated with gating definitions. RESULTS: The machine learning pipeline predicted annotations with high accuracy for both cell types and functional marker genes. Accuracy was lower for gating definitions from assays belonging to laboratories from which limited or no prior data was available in the training. Manual error review ensured that resulting predicted annotations could be reused subsequently as additional gold-standard training data. CONCLUSIONS: Machine learning methods are able to consistently predict annotations associated with gating definitions from flow cytometry assays. However, a hybrid automatic and manual annotation workflow would be recommended to achieve optimal results.

Emerging leptospirosis in urban Sydney dogs: a case series (2017-2020).

Canine leptospirosis has not been reported in the Sydney dog population since 1976. However, between 2017 and 2020, leptospirosis was confirmed in 17 dogs, five of which were known to hunt rodents. Dogs infected between 2017 and 2019 lived within a 3 km radius in the Inner City of Sydney (n = 11). In 2020, cases emerged across a broader area of Sydney; Inner City (n = 1), Inner West (n = 3), Lower North Shore (n = 1) and Upper North Shore (n = 1). The disease was characterised by severe hepatorenal involvement resulting in an unusually high case fatality rate (88%). In conjunction with supportive clinical signs, diagnosis was confirmed by real-time PCR on whole blood (n = 1), kidney (n = 1), urine (n = 4), whole blood and urine (n = 9) or by seroconversion (n = 3). Antibody titres determined by Microscopic Agglutination Test (MAT) to Leptospira serovars were measured in 12 dogs: seven were positive for serovar Copenhageni, one was positive for serovar Hardjo, three were negative for all serovars, likely due to insufficient time for seroconversion before death and one had a low positive titre (1/50) for serovars Australis and Robinsoni. This sudden emergence of a highly fatal disease in pet dogs in Sydney has led to the introduction of Leptospira vaccination protocols for dogs living in inner Sydney using a monovalent vaccine containing serovar Copenhageni. The success of this vaccination program will require ongoing research to understand the emergence of leptospirosis in this region and the serovars involved.

Outcomes of robotic low anterior resection versus transanal total mesorectal excision for rectal cancer.

BACKGROUND: The quality of total mesorectal excision (TME) is regarded as a fundamental key to the oncological outcome of rectal cancer. Robotic low anterior resection (RLAR) and transanal TME (TaTME) were developed to overcome the technical challenges of conventional open TME. This study aimed to compare the short- and long-term outcomes of RLAR versus TaTME for rectal cancer. METHODS: Retrospective data from patients undergoing RLAR or TaTME at a colorectal unit in Singapore were analysed. The primary outcomes were the short-term clinical and pathological results including specimen margins and quality of TME. Secondary outcomes were recurrence, disease-free survival (DFS), and overall survival rates. RESULTS: A total of 80 patients who underwent either RLAR or TaTME were analysed. The TaTME group had a shorter operating time than the RLAR group (354 versus 481 min respectively; P < 0.001) and fewer stays in the high-dependency and intensive care units (38.1 versus 73.7 per cent; P = 0.010). There was a higher rate of readmissions at 30 days in the TaTME group (19.0 versus 0 per cent; P = 0.006). Specimens from TaTME had greater proximal (14.0 versus 10.0 cm; P = 0.045) and distal (2.50 versus 1.65 cm; P = 0.021) margins. Patients undergoing TaTME had borderline longer DFS (25.9 versus 15.7 months; P = 0.049). Subgroup analysis of patients with (y)pT3-4 tumours showed fewer positive circumferential resection margins with TaTME (0 versus 18.2 per cent; P = 0.019) and improved DFS (25.9 versus 15.7 months; P = 0.017). CONCLUSION: Superior margins were obtained with TaTME, especially in locally advanced tumours, although TaTME was associated with a higher readmission rate compared with RLAR.

An enhanced prognostic score for overall survival of patients with cancer derived from a large real-world cohort.

BACKGROUND: By understanding prognostic biomarkers, we gain insights into disease biology and may improve design, conduct, and data analysis of clinical trials and real-world data. In this context, we used the Flatiron Health Electronic Health Record-derived deidentified database that provides treatment outcome and biomarker data from >280 oncology centers in the USA, organized into 17 cohorts defined by cancer type. PATIENTS AND METHODS: In 122 694 patients, we analyzed demographic, clinical, routine hematology, and blood chemistry parameters within a Cox proportional hazard framework to derive a multivariable prognostic risk model for overall survival (OS), the 'Real wOrld PROgnostic score (ROPRO)'. We validated ROPRO in two independent phase I and III clinical studies. RESULTS: A total of 27 variables contributed independently and homogeneously across cancer indications to OS. In the largest cohort (advanced non-small-cell lung cancer), for example, patients with elevated ROPRO scores (upper 10%) had a 7.91-fold (95% confidence interval 7.45-8.39) increased death hazard compared with patients with low scores (lower 10%). Median survival was 23.9 months (23.3-24.5) in the lowest ROPRO quartile Q1, 14.8 months (14.4-15.2) in Q2, 9.4 months (9.1-9.7) in Q3, and 4.7 months (4.6-4.8) in Q4. The ROPRO model performance indicators [C-index = 0.747 (standard error 0.001), 3-month area under the curve (AUC) = 0.822 (0.819-0.825)] strongly outperformed those of the Royal Marsden Hospital Score [C-index = 0.54 (standard error 0.0005), 3-month AUC = 0.579 (0.577-0.581)]. We confirmed the high prognostic relevance of ROPRO in clinical Phase 1 and III trials. CONCLUSIONS: The ROPRO provides improved prognostic power for OS. In oncology clinical development, it has great potential for applications in patient stratification, patient enrichment strategies, data interpretation, and early decision-making in clinical studies.

Resolution enhancement in an extended depth of field for volumetric two-photon microscopy.

The resolution enhancement over the extended depth of field (DOF) in the volumetric two-photon microscopy (TPM) is demonstrated by utilizing multiple orders of Bessel beams. Here the conventional method of switching laser modes (SLAM) in 2D is introduced to 3D, denoted as the volumetric SLAM (V-SLAM). The equivalent scanning beam in the TPM is a thin needle-like beam, which is generated from the subtraction between the needle-like 0th-order and the straw-like 1st-order Bessel beams. Compared with the 0th-order Bessel beam, the lateral resolution of the V-SLAM is increased by 28.6% and maintains over the axial depth of 56 µm. The V-SLAM performance is evaluated by employing fluorescent beads and a mouse brain slice. The V-SLAM approach provides a promising solution to improve the lateral resolutions for fast volumetric imaging on sparsely distributed samples.

The impact of community-based multimedia intervention on the new and repeated cervical cancer screening participation among South Asian women.

OBJECTIVES: The objectives of this study were to reveal the screening uptake of South Asian women who had participated in the community-based multimedia intervention and to identify the reasons among those women who remained unscreened after receiving the intervention. STUDY DESIGN: This was a cross-sectional study. METHODS: South Asian women (Indian, Pakistani and Nepalese) who had attended a community-based multimedia intervention and who agreed to participate in a follow-up telephone survey were contacted. A structured telephone survey was conducted to collect data on their screening uptake status. RESULTS: There were altogether 371 women who completed the survey. Before attending the intervention, 220 of them had never had a Pap test. After the intervention, 75 of those 220 women (34.1%) decided to attend screening, of which 43 underwent their first Pap test, while 32 made their first Pap test appointment. Among those 151 women who previously underwent screening, 76 of them completed the screening or had scheduled a repeated test. Perceived barriers to screening such as lack of time, language barriers and perception that it was unnecessary to attend screening remained the major reasons for women who were not screened. CONCLUSION: Some South Asian women started to have their first Pap test, while some continued to attend screening after the intervention. As barriers that affect women's screening participation still exist, continuous and sustainable efforts should be made to improve the overall screening uptake.

Insulin glargine compared to neutral protamine Hagedorn (NPH) insulin in patients with type-2 diabetes uncontrolled with oral anti-diabetic agents alone in Hong Kong: a cost-effectiveness analysis.

BACKGROUND: International guidelines recommend using basal insulin in patients with type-2 diabetes mellitus if glycaemic target cannot be attained on non-insulin anti-diabetic drugs. Available choices of basal insulin include intermediate-acting neutral protamine Hagedorn (NPH) insulin and long-acting insulin analogues like insulin glargine U100. Despite clear advantages of glargine U100, the existing practice in Hong Kong still favours NPH insulin due to lower immediate drug costs. OBJECTIVES: The objective of this study was to assess the cost-effectiveness of insulin glargine U100 compared to NPH insulin in patients with type-2 diabetes uncontrolled with non-insulin anti-diabetic agents alone in Hong Kong. METHODS: The IQVIA™ Core Diabetes Model (CDM) v9.0 was used to conduct the cost-effectiveness analysis of glargine U100 versus NPH. Baseline characteristics were collected from the Hong Kong Diabetes Registry. Efficacy rates were extracted from a published study comparing glargine U100 and NPH in Asia, utilities from published literature, and costs constructed using the Hong Kong Hospital Authority (HA) Gazette (public healthcare setting). The primary outcome was an incremental cost-effectiveness ratio (ICER). RESULTS: Insulin glargine U100 resulted in an ICER of HKD 98,663 per Quality Adjusted Life Year (QALY) gained. The incremental gains in QALY and costs were 0.217 years and HKD 21,360 respectively. Results from scenario and probabilistic sensitivity analyses were consistent with that from base case analysis. CONCLUSION: Insulin glargine U100 is a cost-effective treatment for patients with type 2 diabetes compared to NPH insulin in setting in Hong Kong. This was mainly driven by the significantly lower rates of hypoglycaemia of insulin glargine U100 than NPH insulin.

Lack of UGT polymorphism association with idasanutlin pharmacokinetics in solid tumor patients.

PURPOSE: Idasanutlin is a selective small-molecule MDM2 antagonist. It activates the tumor suppressor TP53 and is in phase 3 clinical trial for acute myeloid leukemia. Nonclinical studies have shown that glucuronidation is the major metabolizing mechanism for idasanutlin and UGT1A3 is the major metabolizing enzyme. There are reported examples of UGT polymorphisms associated with drug metabolism or response. Thus, the aim of this analysis is to investigate if UGT polymorphism is associated with idasanutlin pharmacokinetics. METHOD: Idasanutlin clearance was derived and normalized from two phase I studies. Its clearance level was compared between patients with different genotypes at 44 non-monomorphic UGT SNPs. Several single-locus and multi-locus association analysis, including haplotype association analysis and pairwise SNP interaction (epistasis) analyses were performed to investigate if there is any association between UGT genotypes and idasanutlin clearance. RESULTS AND CONCLUSION: A total of 69 patients who have both idasanutlin pharmacokinetic data and UGT genotyping data were analyzed for association. The major clearance enzyme for idasanutlin, UGT1A3, has no association with idasanutlin clearance. Further single-locus and multi-locus association analyses also suggest that no significant UGT polymorphism association with idasanutlin clearance can be detected with the current datasets. However, the possibility of association with rare allele(s) of UGT family genes cannot be excluded due to the limited sample size of the current phase I studies.

Diabetes in older people: position statement of The Hong Kong Geriatrics Society and the Hong Kong Society of Endocrinology, Metabolism and Reproduction.

Following a survey on the clinical practice of geriatricians in the management of older people with diabetes and a study of hypoglycaemia in diabetic patients, a round-table discussion with geriatricians and endocrinologists was held in January 2015. Consensus was reached for six domains specifically related to older diabetic people: (1) the considerations when setting an individualised diabetic management; (2) inclusion of geriatric syndrome screening in assessment; (3) glycaemic and blood pressure targets; (4) pharmacotherapy; (5) restrictive diabetic diet; and (6) management goals for nursing home residents.

Mapping unmet supportive care needs, quality-of-life perceptions and current symptoms in cancer survivors across the Asia-Pacific region: results from the International STEP Study.

Background: To assess the supportive care needs, quality of life (QoL) and symptoms of patients with cancer after the end of first-line treatments and into survivorship in Asian countries using Australian data as benchmark. Patients and methods: A cross-sectional survey was carried out in Australia and eight high-income (HICs) and low-/middle-income (LMICs) Asian countries (China, Japan, Hong Kong SAR, South Korea, Myanmar, Thailand, India, Philippines) using validated scales (Cancer Survivors Unmet Needs scale), physical-symptom concerns (Cancer Survivors Survey of Needs subscale) and a single-item measure of global QoL perception. Results: Data were collected from 1873 patients. QoL was highest in Australia and all other countries had significantly lower QoL than Australia (all P < 0.001). One-quarter of the patients reported low QoL (scores 1-3/10). The most frequently reported symptoms were fatigue (66.6%), loss of strength (61.8%), pain (61.6%), sleep disturbance (60.1%), and weight changes (57.7%), with no difference in symptom experience between Australian data and all other countries, or between HICs and LMICs. Unmet needs of moderate/strong level were particularly high in all aspects assessed, particularly in the area of existential survivorship (psychosocial care) and receiving comprehensive cancer care. Australia and HICs were similar in terms of unmet needs (all low), but LMICs had a significantly higher number of needs both compared with Australia and HICs (all P < 0.001). Conclusion: Health care systems in Asian countries need to re-think and prioritize survivorship cancer care and put action plans in place to overcome some of the challenges surrounding the delivery of optimal supportive cancer care, use available resource-stratified guidelines for supportive care and test efficient and cost-effective models of survivorship care.

High risk of conversion to diabetes in first-degree relatives of individuals with young-onset type 2 diabetes: a 12-year follow-up analysis.

AIM: Family history of diabetes is an established risk factor for Type 2 diabetes, but the impact of a family history of young-onset diabetes (onset < 40 years) on future risk of diabetes among first-degree relatives is unclear. In this prospective study, we examined the influence of family history of late- versus young-onset diabetes on the development of diabetes in a young to middle-aged Chinese population. METHODS: Some 365 siblings identified through probands with Type 2 diabetes and 452 participants from a community-based health awareness project (aged 18-55 years) who underwent metabolic assessment during the period 1998-2002 were followed to 2012-2013 to determine their glycaemic status. Multivariate logistic regression was performed to investigate the association of family history of diabetes presented at different age categories with development of diabetes. RESULTS: In this cohort, 53.4% (n = 167) of participants with a family history of young-onset diabetes, 30.1% (n = 68) of those with a family history of late-onset diabetes and 14.4% (n = 40) of those without a family history developed diabetes. Using logistic regression, family history of diabetes presented at ages ≥ 50, 40-49, 30-39 and < 30 years, increased conversion to diabetes with respective odds ratios of 2.4, 5.8, 9.4 and 7.0 (P < 0.001 for all), after adjustment for socio-economic status, smoking, obesity, hypertension and dyslipidaemia. Among participants without diabetes at baseline, risk association of family history of late-onset diabetes with incident diabetes was not sustained, whereas that of family history of young-onset diabetes remained robust on further adjustment for baseline glycaemic measurements. CONCLUSIONS: First-degree relatives of people with Type 2 diabetes, especially relatives of those with young-onset diabetes, are at high risk for diabetes.

The Potential Roles of Radionanomedicine and Radioexosomics in Prostate Cancer Research and Treatment.

The artificial nanostructures such as nanoparticles and natural nanostructures such as secreted nanosized extracellular vesicles known as exosomes are promising tools for the realization of personalized medicine. Radionanomedicine is a recently coined term for the simultaneous application of either radiation technology or nuclear medicine with nanomedicine. In addition, radioexosomics is our suggested term for the study of exosomes functions, cytotoxicity, cancerogenicity, and biodistribution using radiation technology and nuclear medicine tracing technology. Prostate cancer (PCa) is the most commonly diagnosed cancer in males and a big majority of patients with PC progress to castration-resistant prostate cancer (CRPC) mostly. The mechanisms leading to development of CRPC remain poorly understood and there is still a need to improve the therapeutic options available for PCa. In this review, a wide variety of nanostructure-based prostate cancer research using radiation technology and nuclear medicine is discussed. In addition, we will present what is currently known about the function of exosomes in PCa. The review concludes by summarizing the current status and future perspectives of radionanomedicine and radioexosomics for understanding PCa biology, as well as PCa enhancement of targeting strategies, drug delivery, molecular imaging and therapy.

A multicentre demonstration project to evaluate the effectiveness and acceptability of the web-based Joint Asia Diabetes Evaluation (JADE) programme with or without nurse support in Chinese patients with Type 2 diabetes.

AIMS: To test the hypothesis that delivery of integrated care augmented by a web-based disease management programme and nurse coordinator would improve treatment target attainment and health-related behaviour. METHODS: The web-based Joint Asia Diabetes Evaluation (JADE) and Diabetes Monitoring Database (DIAMOND) portals contain identical built-in protocols to integrate structured assessment, risk stratification, personalized reporting and decision support. The JADE portal contains an additional module to facilitate structured follow-up visits. Between January 2009 and September 2010, 3586 Chinese patients with Type 2 diabetes from six sites in China were randomized to DIAMOND (n = 1728) or JADE, plus nurse-coordinated follow-up visits (n = 1858) with comprehensive assessments at baseline and 12 months. The primary outcome was proportion of patients achieving ≥ 2 treatment targets (HbA1c < 53 mmol/mol (7%), blood pressure < 130/80 mmHg and LDL cholesterol < 2.6 mmol/l). RESULTS: Of 3586 participants enrolled (mean age 57 years, 54% men, median disease duration 5 years), 2559 returned for repeat assessment after a median (interquartile range) follow-up of 12.5 (4.6) months. The proportion of participants attaining ≥ 2 treatment targets increased in both groups (JADE 40.6 to 50.0%; DIAMOND 38.2 to 50.8%) and there were similar absolute reductions in HbA1c [DIAMOND -8 mmol/mol vs JADE -7 mmol/mol (-0.69 vs -0.62%)] and LDL cholesterol (DIAMOND -0.32 mmol/l vs JADE -0.28 mmol/l), with no between-group difference. The JADE group was more likely to self-monitor blood glucose (50.5 vs 44.2%; P = 0.005) and had fewer defaulters (25.6 vs 32.0%; P < 0.001). CONCLUSIONS: Integrated care augmented by information technology improved cardiometabolic control, with additional nurse contacts reducing the default rate and enhancing self-care. (Clinical trials registry no.: NCT01274364).