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Abstract Blockade of the binding between neonatal Fc receptor and IgG‐Fc reduces circulating IgG, and thus emerges as a potential therapy for IgG‐mediated autoimmune conditions. This was a double blind, randomized, single ascending dose study to evaluate the safety, pharmacokinetics, and pharmacodynamics of HBM9161 (a fully humanized Fc receptor monoclonal antibody) in healthy Chinese volunteers. Subjects were randomized to receive a single s.c. dose of HBM9161 or placebo in a 3:1 ratio in 3 dosing cohorts (340 mg, 510 mg, or 680 mg, respectively), and then followed up for 85 days. Study end points included incidence of adverse event (AE), serum drug concentration, IgG and its subclasses, and anti‐drug antibodies (ADAs). Twenty‐four subjects were randomized. Dose‐dependent reduction of total IgG occurred rapidly from baseline to reach nadir at day 11, then recovered steadily from day 11 to day 85. The mean maximum percentage reductions from baseline total IgG were 21.0 ± 9.3%, 39.8 ± 5.13%, and 41.2 ± 10.4% for subjects receiving HBM9161 340 mg, 510 mg, and 680 mg, respectively. The exposure of HBM9161 (areas under the curve [AUCs] and peak plasma concentration [Cmax]) increased in a more than dose‐proportional manner at the dose examined. All reported AEs were mild in severity. The most reported AEs in the HBM9161 groups were influenza‐like illness and rash. Two subjects developed ADA during the study period. A single s.c. dose of HBM9161 results in sustained and dose‐dependent IgG reduction, and was well‐tolerated at a dose up to 680 mg in Chinese subjects. The data warrant further investigation of its effects in IgG‐mediated autoimmune disorders.

Current guideline-recommended screening for pulmonary hypertension in patients with systemic sclerosis has not been evaluated in systemic lupus erythematosus (SLE), which is disproportionately prevalent in Asians. This multicentre, cross-sectional screening study aims to study the prevalence of pulmonary hypertension among SLE patients using these guidelines, and identify independent predictors and develop a prediction model for pulmonary hypertension in SLE patients. SLE patients from participating centres will undergo an echocardiography- and biomarker-based pulmonary hypertension screening procedure as in the DETECT study. Standard right heart catheterisation will be provided to patients with intermediate or high echocardiographic probability of pulmonary hypertension. Those with low echocardiographic probability will rescreen within 1 year. The primary measure will be the diagnosis and types of pulmonary hypertension and prevalence of pulmonary hypertension in SLE patients. The secondary measures will be the predictors and prediction models for pulmonary hypertension in SLE patients. The estimated sample size is approximately 895 participants. The results of the SOPHIE study will be an important contribution to the literature of SLE-related pulmonary hypertension and may be immediately translatable to real clinical practice. Ultimately, this study will provide the necessary evidence for establishing universal guidelines for screening of pulmonary hypertension in SLE patients.

OBJECTIVE:Androgen deprivation therapy (ADT) increases fracture risk in men with carcinoma of the prostate, but little is known about the fracture risk for different types of ADT. We studied the fracture risk amongst Chinese patients with carcinoma of the prostate prescribed different ADT regimens. SUBJECTS AND METHODS:This was a single-centered observational study that involved 741 patients with carcinoma of the prostate from January 2001 to December 2011. RESULTS:After a median follow-up of 5 years, 71.7% of the study cohort received ADT and the incidence rate of fracture was 8.1%. Multivariable Cox regression analysis revealed that use of ADT was significantly associated with risk of incident fracture (Hazard Ratio [HR] 3.60; 95% Confidence Interval [95% CI] 1.41-9.23; p = 0.008), together with aged >75 years and type 2 diabetes. Compared with no ADT, all three types of ADT were independently associated with the risk of incident fracture: anti-androgen monotherapy (HR 4.47; 95% CI 1.47-13.7; p = 0.009), bilateral orchiectomy ± anti-androgens (HR 4.01; 95% CI 1.46-11.1; p = 0.007) and luteinizing hormone-releasing hormone agonists ± anti-androgens (HR 3.16; 95% CI 1.18-8.43; p = 0.022). However, there was no significant difference in the relative risks among the three types of ADT. CONCLUSIONS:Fracture risk increases among all types of ADT. Clinicians should take into account the risk-benefit ratio when prescribing ADT, especially in elderly patients with type 2 diabetes.

Background: Little is known about the impact of the provision of handheld point-of-care ultrasound (POCUS) devices on physical examination skills of medical students.Methods: We describe an educational initiative that comprised a POCUS workshop followed by allocation of a POCUS device to medical students for use over the subsequent 8 weeks. They were encouraged to scan patients and correlate their physical examination findings. A mobile instant messaging group discussion platform was set to provide feedback from instructors. Physical examination skills were assessed by means of clinical examination.Results: 210 final-year medical students from the University of Hong Kong participated in the programme. 46.3% completed the end of programme electronic survey: 74.6% enjoyed using the POCUS device, 50.0% found POCUS useful to validate physical examination findings and 47.7% agreed that POCUS increased their confidence with physical examination. 93.9% agreed that the programme should be incorporated into the medical curriculum and 81.9% would prefer keeping the device for longer time from 16 weeks (45.6%) to over 49 weeks (35.3%). Medical students who participated in the POCUS programme had a higher mean score for abdominal examination compared with those from the previous academic year with no POCUS programme (3.65±0.52 vs 3.21±0.80, p=0.014), but there was no statistically significant difference in their mean score for cardiovascular examination (3.62±0.64 vs 3.36±0.93, p=0.203).Conclusion: The POCUS programme that included provision of a personal handheld POCUS device improved students' attitude, confidence and ability to perform a physical examination. [ABSTRACT FROM AUTHOR]

Background: Patients who survive non-ST-elevation myocardial infarction (NSTEMI) are at heightened risk of recurrent cardiovascular events. Data on long-term secondary atherothrombotic risk stratification are limited.Objectives: To stratify post-NSTEMI patients for risk of recurrent cardiovascular events to maximise benefit from aggressive secondary prevention strategies using the TIMI Risk Score for Secondary Prevention (TRS 2°P) score in a real-world cohort of NSTEMI patients.Methods and Results: This was a single-centre observational study of 891 post-NSTEMI patients (73.7 ± 12.7 years; male: 54.2%). The TRS 2°P is a nine-point risk stratification tool to predict cardiovascular events in patients with established cardiovascular disease. The primary outcome was a composite endpoint of cardiovascular death, non-fatal MI and non-fatal ischaemic stroke. After a median follow-up of 31 months (IQR: 11.4 - 60.2), 281 patients (31.5%) had developed a primary outcome (13.3%/year) including 196 cardiovascular deaths, 94 non-fatal MIs and 22 non-fatal strokes. The TRS 2°P score was strongly associated with the primary outcome. The annual incidence of primary composite endpoint for patients with TRS 2°P score =0 was 1.6%, and increased progressively to 47.4% for those with a TRS 2°P score ≥6 (HR: 20.18, 95% CI: 4.85 to 84.05, p<0.001). Similar associations were also observed between the TRS 2°P score and cardiovascular death and MI (fatal and non-fatal), but not non-fatal ischaemic stroke.Conclusion: The TRS 2°P score stratified post-NSTEMI patients for risk of future cardiovascular events and potentially help guide the selection of more aggressive secondary prevention therapy. [ABSTRACT FROM AUTHOR]

Elevated circulating levels of pigment epithelium-derived factor (PEDF) have been reported in patients with type 2 diabetes (T2D) and its associated microvascular complications. This study aimed to 1) identify the genetic determinants influencing circulating PEDF levels in a clinical setting of T2D, 2) examine the relationship between circulating PEDF and diabetes complications, and 3) explore the causal relationship between PEDF and diabetes complications. An exome-chip association study on circulating PEDF levels was conducted in 5,385 Chinese subjects with T2D. A meta-analysis of the association results of the discovery stage (n = 2,936) and replication stage (n = 2,449) was performed. The strongest association was detected at SERPINF1 (p.Met72Thr; Pcombined = 2.06 × 10-57; β [SE] -0.33 [0.02]). Two missense variants of SMYD4 (p.Arg131Ile; Pcombined = 7.56 × 10-25; β [SE] 0.21 [0.02]) and SERPINF2 (p.Arg33Trp; Pcombined = 8.22 × 10-10; β [SE] -0.15 [0.02]) showed novel associations at genome-wide significance. Elevated circulating PEDF levels were associated with increased risks of diabetic nephropathy and sight-threatening diabetic retinopathy. Mendelian randomization analysis showed suggestive evidence of a protective role of PEDF on sight-threatening diabetic retinopathy (P = 0.085). Our study provided new insights into the genetic regulation of PEDF and further support for its potential application as a biomarker for diabetic nephropathy and sight-threatening diabetic retinopathy. Further studies to explore the causal relationship of PEDF with diabetes complications are warranted. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 21 (FGF21) is increasingly recognized as an important metabolic regulator of glucose homeostasis. Here, we conducted an exome-chip association analysis by genotyping 5,169 Chinese individuals from a community-based cohort and two clinic-based cohorts. A custom Asian exome-chip was used to detect genetic determinants influencing circulating FGF21 levels. Single-variant association analysis interrogating 70,444 single nucleotide polymorphisms identified a novel locus, GCKR, significantly associated with circulating FGF21 levels at genome-wide significance. In the combined analysis, the common missense variant of GCKR, rs1260326 (p.Pro446Leu), showed an association with FGF21 levels after adjustment for age and sex (P = 1.61 × 10-12; β [SE] = 0.14 [0.02]), which remained significant on further adjustment for BMI (P = 3.01 × 10-14; β [SE] = 0.15 [0.02]). GCKR Leu446 may influence FGF21 expression via its ability to increase glucokinase (GCK) activity. This can lead to enhanced FGF21 expression via elevated fatty acid synthesis, consequent to the inhibition of carnitine/palmitoyl-transferase by malonyl-CoA, and via increased glucose-6-phosphate-mediated activation of the carbohydrate response element binding protein, known to regulate FGF21 gene expression. Our findings shed new light on the genetic regulation of FGF21 levels. Further investigations to dissect the relationship between GCKR and FGF21, with respect to the risk of metabolic diseases, are warranted. [ABSTRACT FROM AUTHOR]

Aims: Little is known about the ischaemic stroke risk and benefit of warfarin therapy for stroke prevention in chronic kidney disease (CKD) patients on peritoneal dialysis (PD) with concomitant atrial fibrillation (AF). Our objective was to determine the risk of ischaemic stroke in a 'real-world' cohort of PD patients with AF, and clinical benefit or harm of aspirin and warfarin.Methods and Results: This is a single-centred observational study of Chinese patients with non-valvular AF. Hospitalizations with ischaemic stroke and intracranial haemorrhage (ICH) were recorded. Of 9810 patients from a hospital-based AF registry, 271 CKD patients on PD with AF (76.8 ± 12.5 years, CHA2DS2-VASc: 3.69 ± 1.83, and HAS-BLED: 2.07 ± 0.97) were identified. Amongst these PD patients, 24.7% received warfarin; 31.7% received aspirin; and 43.5% received no antithrombotic therapy. Amongst patients with no antithrombotic therapy, annual incidence of ischaemic stroke in PD patients was comparable with those non-CKD counterparts (9.32 vs. 9.30%/year). Similar to non-CKD patients, annual incidence of ischaemic stroke increased with increasing CHA2DS2-VASc score (CHA2DS2-VASc = 0-1: 5.76 vs. 5.70%/year, P = 1.00; and CHA2DS2-VASc ≥ 2: 10.80 vs. 9.94%/year, P = 0.78). Amongst PD patients, warfarin therapy was associated with lower risk of ischaemic stroke compared with aspirin [Hazard ratio (HR): 0.16, 95% confidence interval (CI): 0.04-0.66, P = 0.01] and no therapy (HR: 0.19, 95% CI: 0.06-0.65, P = 0.01), but not associated with a higher risk of ICH.Conclusion: In CKD patients on PD with AF, who had similar ischaemic stroke risk as non-CKD counterparts, warfarin therapy is associated with reduction in risk of ischaemic stroke without a higher risk of ICH. [ABSTRACT FROM AUTHOR]