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Islet β cell dysfunction and insulin resistance are the main pathogenesis of type 2 diabetes (T2D), but the mechanism remains unclear. Here we identify a rs3819316 C > T mutation in lncRNA Reg1cp mainly expressed in islets associated with an increased risk of T2D. Analyses in 16,113 Chinese adults reveal that Mut-Reg1cp individuals had higher incidence of T2D and presented impaired insulin secretion as well as increased insulin resistance. Mice with islet β cell specific Mut-Reg1cp knock-in have more severe β cell dysfunction and insulin resistance. Mass spectrometry assay of proteins after RNA pulldown demonstrate that Mut-Reg1cp directly binds to polypyrimidine tract binding protein 1 (PTBP1), further immunofluorescence staining, western blot analysis, qPCR analysis and glucose stimulated insulin secretion test reveal that Mut-Reg1cp disrupts the stabilization of insulin mRNA by inhibiting the phosphorylation of PTBP1 in β cells. Furthermore, islet derived exosomes transfer Mut-Reg1cp into peripheral tissue, which then promote insulin resistance by inhibiting AdipoR1 translation and adiponectin signaling. Our findings identify a novel mutation in lncRNA involved in the pathogenesis of T2D, and reveal a new mechanism for the development of T2D.

Medications used to treat hypertension may affect fracture risk. This study investigated fracture risk for users of angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB). Participants (899 men, median age 70.3 yr (59.9–79.1), range 50.0–96.6 yr; 574 women, median age 65.5 yr (58.1–75.4), range 50.1–94.6 yr) were from the Geelong Osteoporosis Study. Medication use was self-reported and incident fractures were ascertained using radiological reports. Bone mineral density (BMD) was measured at the femoral neck. Participants were divided into four groups: (1) non-users without hypertension, (2) non-users with hypertension, (3) ACEI users and (4) ARB users. Dosage was calculated using the defined daily dose (DDD) criteria. Participants were followed from date of visit to first fracture, death or 31 December 2016, whichever occurred first. Cox proportional hazards models were used for analyses. At least one incident fracture was sustained by 156 men and 135 women over a median(IQR) of 11.5(6.2–13.2) and 10.9(6.3–11.6) years of follow-up, respectively. In unadjusted analyses, compared to non-users without hypertension, men in all three other groups had a higher risk of fracture (Hazard Ratio (HR, 95%CI) 1.54, 1.00–2.37; 1.90, 1.18–3.05; 2.15, 1.26–3.66), for non-users with hypertension, ACEI and ARB users, respectively). Following adjustment for age, prior fracture and BMD, these associations became non-significant. A dose effect for ARB use was observed; men using lower doses had a higher risk of fracture than non-users without hypertension, in both unadjusted (2.66, 1.34–5.29) and adjusted (2.03, 1.01–4.08) analyses, but this association was not observed at higher doses. For women, unadjusted analyses showed a higher risk for ACEI users compared to non-users without hypertension (1.74, 1.07–2.83). This was explained after adjustment for age, alcohol consumption, prior fracture and BMD (1.28, 0.74–2.22). No other differences were observed. In men, lower dose (0

Hand, Foot and Mouth Disease (HFMD) is usually a self-limiting, mild childhood disease that is caused mainly by Coxsackie virus A16 (CVA16) and Enterovirus A71 (EV-A71), both members of the Picornaviridae family. However, recurring HFMD outbreaks and epidemics due to EV-A71 infection in the Western Pacific region, and the propensity of EV-A71 strains to cause severe neurological complications have made this neurotropic virus a serious public health concern in afflicted countries. High mutation rate leading to viral quasispecies combined with frequent intra- and inter-typic recombination events amongst co-circulating EV-A71 strains have contributed to the great diversity and fast evolution of EV-A71 genomes, making impossible any accurate prediction of the next epidemic strain. Comparative genome sequence analyses and mutagenesis approaches have led to the identification of a number of viral determinants involved in EV-A71 fitness and virulence. These viral determinants include amino acid residues located in the structural proteins of the virus, affecting attachment to the host cell surface, receptor binding, and uncoating events. Critical residues in non-structural proteins have also been identified, including 2C, 3A, 3C proteases and the RNA-dependent RNA polymerase. Finally, mutations altering key secondary structures in the 5’ untranslated region were also found to influence EV-A71 fitness and virulence. While our current understanding of EV-A71 pathogenesis remains fragmented, these studies may help in the rational design of effective treatments and broadly protective vaccine candidates.

To evaluate the cost-effectiveness of mepolizumab added to standard of care (SOC) compared with SOC alone among patients with severe uncontrolled eosinophilic asthma in the Singapore setting. A Markov model with three health states (asthma on mepolizumab and SOC, asthma on SOC alone, and death) was developed from a healthcare system perspective over a lifetime horizon. During each 4-week cycle, patients in the non-death health states could experience asthma exacerbations requiring oral corticosteroid burst, emergency department visit, or hospitalization. Asthma-related mortality following an exacerbation or all-cause mortality could also occur at each cycle. The model was populated using local costs while utilities were derived from international literature. Transition probabilities were obtained from a mixture of Singapore-specific and internationally published data. The base-case analysis comparing mepolizumab plus SOC with SOC alone resulted in an incremental cost-effectiveness ratio (ICER) of SGD335 486 (USD238 195) per quality-adjusted life-year (QALY) gained. Sensitivity analysis demonstrated that the ICER was most sensitive to the price of mepolizumab, followed by the proportion of exacerbations which required hospital intensive care. Despite restricting mepolizumab use to patients with a higher baseline exacerbation rate (3 in the past year) in a scenario analysis, the ICER remained high at SGD238 876 (USD 169 602) per QALY gained. At its current price, mepolizumab is not considered a cost-effective use of healthcare resources in Singapore. Substantial price reductions for mepolizumab are required to improve its cost-effectiveness to an acceptable range. These results will be useful to inform national funding decisions.

Nearly half of pregnancies worldwide are unintended mainly due to failure of contraception, resulting in negative effects on women's health. Male contraception techniques, primarily condoms and vasectomy, play a crucial role in birth control, but cannot be both highly effective and reversible at the same time. Herein, an ultrasound (US)-induced self-clearance hydrogel capable of real-time monitoring is utilized foriin situ/iinjection into the vas deferens, enabling effective contraception and noninvasive recanalization whenever needed. The hydrogel is composed of (i) sodium alginate (SA) conjugated with reactive oxygen species (ROS)-cleavable thioketal (SA-tK), (ii) titanium dioxide (TiOsub2/sub), which can generate a specific level of ROS after US treatment, and (iii) calcium chloride (CaClsub2/sub), which triggers the formation of the hydrogel. For contraception, the above mixture agents are one-time injected into the vas deferens, which can transform from liquid to hydrogel within 160 s, thereby significantly physically blocking the vas deferens and inhibiting movability of sperm. When fertility is needed, a noninvasive remedial ultrasound can make TiOsub2/subgenerate ROS, which cleaves SA-tK to destroy the network of the hydrogel. Owing to the recanalization, the refertility rate is restored to 100%. Meanwhile, diagnostic ultrasound (D-US, 22 MHz) can monitor the occlusion and recanalization process in real-time. In summary, the proposed hydrogel contraception can be a reliable, safe, and reversible male contraceptive strategy that addresses an unmet need for men to control their fertility.

Thrombin generation assays and activated partial thromboplastin time (aPTT)-based clot waveform analysis (CWA), are some examples of global coagulation assays. Each modality evaluates different aspects of the clot forming process to globally define haemostasis with exclusive measurement parameters. Data on CWA are emerging, but its performance against other haemostatic assays is yet to be ascertained. This study evaluates the correlation between aPTT-based CWA and CAT parameters across a range of INR in warfarin-treated patients.A prospective study consisting of patients on warfarin anticoagulation with varying INR levels. CWA and CAT were performed for the study subjects.54 samples were included covering an INR range from 1.33-6.89, with a mean of 4.31 +/- 1.13. For CAT parameters, endogenous thrombin potential (ETP) and peak thrombin were assessed. Both unadjusted and adjusted (adjusted for final plateau transmittance) aPTT-based CWA were evaluated for parameters min1 (maximum velocity), min2 (maximum acceleration) and max2 (maximum deceleration). Peak thrombin showed significant correlation with all CWA parameters (min1: r = 0.435,We demonstrated a modest correlation between CAT and CWA parameters. Adjusted CWA improved this correlation. These findings provide additional understanding of CWA and it's role in the evaluation of global haemostatic function.

Aseptic meningitis is a rare presentation of systemic lupus erythematosus (SLE). High index of suspicion is crucial when there is suboptimal response to the initial standard meningitis treatment and presence of connective tissue disease symptoms. We report 3 cases of aseptic meningitis as the main initial presentation of SLE. The diagnosis of SLE as the underlying cause of the aseptic meningitis was supported by the clinical, laboratory and radiological findings. All patients showed good response after treated with immunosuppressant therapy.

Current epidemiological and experimental studies have indicated the overlapping genetic foundation of epilepsy and depression. However, the detailed pleiotropic genetic etiology and neurobiological pathways have not been well understood, and there are many variants with underestimated effect on the comorbidity of the two diseases. Utilizing genome-wide association study (GWAS) summary statistics of epilepsy (15,212 cases and 29,677 controls) and depression (170,756 cases and 329,443 controls) from large consortia, we assessed the integrated gene-based association with both diseases by Multimarker Analysis of Genomic Annotation (MAGMA) and Fisher’s meta-analysis. On the one hand, shared genes with significantly altered transcripts in Gene Expression Omnibus (GEO) data sets were considered as possible pleiotropic genes. On the other hand, the pathway enrichment analysis was conducted based on the gene lists with nominal significance in the gene-based association test of each disease. We identified a total of two pleiotropic genes (CD3G and SLCO3A1) with gene expression analysis validated and interpreted twenty-five common biological process supported with literature mining. This study indicates the potentially shared genes associated with both epilepsy and depression based on gene expression, meta-data analysis, and pathway enrichment strategy along with traditional GWAS and provides insights into the possible intersecting pathways that were not previously reported.

Recent genetic approaches have demonstrated that genetic factors contribute to the pathologic origins of neuropsychiatric disorders. Nevertheless, the exact pathophysiological mechanism for most cases remains unclear. Recent studies have demonstrated alterations in pathways of protein homeostasis (proteostasis) and identified several proteins that are misfolded and/or aggregated in the brains of patients with neuropsychiatric disorders, thus providing early evidence that disrupted proteostasis may be a contributing factor to their pathophysiology. Unlike neurodegenerative disorders in which massive neuronal and synaptic losses are observed, proteostasis impairments in neuropsychiatric disorders do not lead to robust neuronal death, but rather likely act via loss- and gain-of-function effects to disrupt neuronal and synaptic functions. Furthermore, abnormal activation of or overwhelmed endoplasmic reticulum and mitochondrial quality control pathways may exacerbate the pathophysiological changes initiated by impaired proteostasis, as these organelles are critical for proper neuronal functions and involved in the maintenance of proteostasis. This perspective article reviews recent findings implicating proteostasis impairments in the pathophysiology of neuropsychiatric disorders and explores how neuronal and synaptic functions may be impacted by disruptions in protein homeostasis. A greater understanding of the contributions by proteostasis impairment in neuropsychiatric disorders will help guide future studies to identify additional candidate proteins and new targets for therapeutic development.

Aim N8‐GP (turoctocog alfa pegol) is a glycoPEGylated, extended half‐life human recombinant factor VIII (FVIII) shown to be an efficacious treatment for patients with haemophilia A. Accurate monitoring of replacement therapy helps ensure proper dosing, leading to better patient care. The objective of this field study was to evaluate the accuracy and intra‐ and inter‐laboratory variabilities of N8‐GP and rAHF (Advate®) FVIII activity (FVIII:C) measurements in clinical laboratories using their routine methods and reagents. Methods Laboratories measured plasma samples spiked with 0.03, 0.2, 0.6 and 0.9 IU/mL N8‐GP or rAHF. Samples were blinded, and laboratories were instructed to perform evaluations using their routine FVIII activity assays and calibrators. Results Of the 67 participating laboratories from 25 countries, 60 used a one‐stage assay, 36 used a chromogenic assay, and 29 used both one‐stage and chromogenic assays. Participating laboratories used nine different activated partial thromboplastin time (aPTT) reagents, the most common being SynthASil® and Actin® FS. Most aPTT reagents recovered N8‐GP close to target. Three silica‐based aPTT reagents (APTT‐SP, TriniCLOT™ and STA® PTT‐Automate) underestimated N8‐GP, recovering 40%‐83% of target concentration. For chromogenic assays, N8‐GP and rAHF recoveries were comparable at all concentrations, with overall mean recoveries for both products close to 130%. Assay variability was similar for both assay types and both products; inter‐laboratory variability was greater than intra‐laboratory variability and highest at 0.03 IU/mL. Conclusions Most clinical laboratories accurately measured N8‐GP and rAHF when using their in‐house one‐stage or chromogenic FVIII:C assays. However, three silica‐based aPTT reagents underestimated N8‐GP recovery.

Background/objectives We compared the ex vivo haemostatic capacity of RTFP24 with FFP upon thawing and >24 h post-thaw. We included thrombin generation (TG) as few studies had compared global haemostatic function, and most did not directly compare RTFP24 with FFP >24 h post-thaw. Materials/methods Twenty units each of RTFP24 and FFP were measured for coagulation factors and thrombin generation upon thawing (D0) and 4 days post-thaw (D4). Labile factors were also measured from D1 to D3. 10 single cryoprecipitate units were each prepared from FFP and RTFP24, and measured for FXIII, FVIII and fibrinogen at D0. Results At D0, RTFP24 was comparable to FFP except for lower FV, protein S, endogenous thrombin potential (ETP) and higher FXIII. These differences were likely clinically insignificant since 95% and 80% of RTFP24 met our laboratory's reference ranges for FV/protein S and ETP, respectively. There were no differences between RTFP24- and FFP-derived cryoprecipitate. At D4, RTFP24 was comparable to FFP except for lower FV, ETP, and higher FXI and FXIII. More RTFP24 than FFP had ETP lower than our laboratory's reference range (45% vs 15%). Multiple coagulation factors and all TG parameters declined from their respective baselines. The percentage declines were comparable or less in RTFP24, except for protein C, fibrinogen and time to peak. Conclusion RTFP24 and FFP, and their derived cryoprecipitate have comparable haemostatic capacity upon thawing. RTFP24 has poorer TG potential than FFP >24 h post-thaw, not supporting universal extension of RTFP24's shelf life except to facilitate urgent transfusions for massive haemorrhage.

COVID-19 caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and other respiratory viral (non-CoV-2-RV) infections are associated with thrombotic complications. The differences in prothrombotic potential between SARS-CoV-2 and non-CoV-2-RV have not been well characterised. We compared the thrombotic rates between these two groups of patients directly and further delved into their coagulation profiles. In this single-center, retrospective cohort study, all consecutive COVID-19 and non-CoV-2-RV patients admitted between January 15th and April 10th 2020 were included. Coagulation parameters studied were prothrombin time and activated partial thromboplastin time and its associated clot waveform analysis (CWA) parameter, min1, min2 and max2. In the COVID-19 (n = 181) group there were two (1.0 event/1000-hospital-days) myocardial infarction events while one (1.8 event/1000-hospital-day) was reported in the non-CoV-2-RV (n = 165) group. These events occurred in patients who were severely ill. There were no venous thrombotic events. Coagulation parameters did not differ throughout the course of mild COVID-19. However, CWA parameters were significantly higher in severe COVID-19 compared with mild disease, suggesting hypercoagulability (min1: 6.48%/s vs 5.05%/s, P 2 vs 0.74%/s2, P = 0.033). In conclusion, the thrombotic rates were low and did not differ between COVID-19 and non-CoV-2-RV patients. The hypercoagulability in COVID-19 is a highly dynamic process with the highest risk occurring when patients were most severely ill. Such changes in haemostasis could be detected by CWA. In our population, a more individualized thromboprophylaxis approach, considering clinical and laboratory factors, is preferred over universal pharmacological thromboprophylaxis for all hospitalized COVID-19 patients and such personalized approach warrants further research.

LBD(lateral organ boundaries)transcription factors play an important role in the regulation of plant growth, development and secondary metabolism. In order to explore the function of LBD genes in cannabis, the Cannabis sativa genome and transcriptome were used to identify the C. sativa LBD gene family, and analyzed their expression patterns. Our results showed that the cannabis LBD contains 32 members, which were divided into two major categories, seven sub-families. Class Ⅰ was divided into 5 sub-families, named Class Ⅰ_a to Class Ⅰ_e, while Class Ⅱ was divided into 2 sub-families, including Class Ⅱ_a and Class Ⅱ_b. Analysis showed that the number of amino acids encoded LBDs was between 172 and 356, and the isoelectric point was between 4.92 and 9.43. The mole-cular weight of LBD was between 18 862.92 Da and 40 081.33 Da, and most members are located in the nucleus. Chromosome positioning of LBD showed that 32 members were unevenly distributed on 10 chromosomes of C. sativa LBD transcription factor domain, gene structure and motifs are relatively conservative, and the characteristics of different class members are similar. The upstream promoter region of the gene contains a variety of cis-acting elements related to plant hormones and environmental factors, C. sativa LBD genes have different expression patterns in the stems, leaves, and flowers of ZYS varieties(low tetrahydrocannabinol, high cannabidiol). The members of the LBD gene family are mainly expressed in the flowers and stems of ZYS varieties, while members expressed in the leaves very few; Class Ⅱ members CsLBD21 and CsLBD23 are expressed in flowers and stems, and CsLBD8 and CsLBD18 are expressed in flowers, stems and leaves. These genes may participate in the growth and development of cannabis and affect the biosynthesis of cannabinoids. This study laid the foundation for the subsequently functional research of the cannabis LBD gene family.

Angiotensin-converting enzyme inhibitor use in women was associated with lower femoral neck and lumbar spine bone mineral density as well as trabecular bone score compared to non-users. No differences were identified for men or for those who used ARB medications.Many individuals at high fracture risk use medications such as angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) that could affect bone; thus, this study aimed to investigate whether there are any differences in bone mineral density (BMD) and trabecular bone score (TBS) between ACEI users, ARB users, and non-users.Participants (685 men, 573 women) were from the Geelong Osteoporosis Study. Current medication use was self-reported. BMD at the femoral neck (FNBMD) and lumbar spine (LSBMD) were measured using DXA. TBS was calculated using TBS iNsight software. Linear regression models were used to investigate associations between ACEI or ARB use and bone measures, adjusting for other potential confounders. Due to interaction terms, data were stratified by age.There were 88 (12.8%) men and 41 (7.2%) women taking an ACEI medication, and 71 (10.4%) men and 76 (13.3%) women taking an ARB medication. Compared to non-users, ACEI use was associated with lower FNBMD (- 7.2%), LSBMD (- 12.2%), and TBS (- 9.0%) for women aged 65 years. Lower TBS was also observed for women aged ≥ 65 years (- 17.3%). No differences were identified for ARB use.Women who used an ACEI medication had lower values for FNBMD, LSBMD and TBS compared to non-users. No differences were identified for men or for those who used ARB medications.

Forceps-assisted deliveries are an established risk factor for pelvic organ prolapse and pelvic floor injury. However, specific comparison of incontinence outcomes between vacuum-assisted and forceps-assisted deliveries are scarce in the literature. We aimed to compare the initial impact of vacuum and forceps deliveries on new-onset urinary and faecal incontinence as well as pelvic floor muscle strength, with the hypothesis that incontinence outcomes were poorer after forceps- than after vacuum-assisted delivery. This is a retrospective cohort study of incontinence outcomes in patients who had primary vacuum- or forceps-assisted delivery. The study population included 108 postpartum patients who had undergone operative vaginal delivery (63 vacuum-assisted, 45 forceps-assisted), met the inclusion criteria and attended the postpartum assessment service. Outcomes studied were the presence and severity of symptoms manifesting beyond 1 month postpartum — faecal incontinence and stress, urgency and mixed urinary incontinence — as well as pelvic floor muscle strength scores based on the modified Oxford scale. Prevalence of new-onset urinary and faecal incontinence was 35.6% in the forceps group and 30.2% in the vacuum group. The data suggest that there is no significant difference in the prevalence of new-onset incontinence symptoms (p = 0.70, difference in prevalence [forceps − vacuum]: 5.4%, 95% CI −0.25, +0.15), frequency (p = 0.40) and amount (p = 0.48) of urine leakage or mean muscle strength scores (p = 0.89). In our maternity unit, we observed that type of operative vaginal delivery was not associated with significant differences in urinary incontinence and pelvic floor muscle strength outcomes.

FVIII activity in samples taken at various time points from 21 patients treated with N8-GP (Esperoct

Infections cause varying degrees of haemostatic dysfunction which can be detected by clot waveform analysis (CWA), a global haemostatic marker. CWA has been shown to predict poor outcomes in severe infections with disseminated intravascular coagulopathy. The effect of less severe bacterial and viral infections on CWA has not been established. We hypothesized that different infections influence CWA distinctively. Patients admitted with bacterial infections, dengue and upper respiratory tract viral infections were recruited if they had an activated partial thromboplastin time (aPTT) measured on admission. APTT-based CWA was performed on Sysmex CS2100i automated analyser using Dade Actin FSL reagent. CWA parameters [(maximum velocity (min1), maximum acceleration (min2) and maximum deceleration (max2)] were compared against control patients. Infected patients (n = 101) had longer aPTT than controls (n = 112) (34.37 ± 7.72 s vs 27.80 ± 1.59 s, p 2; 0.74 ± 0.16%/s2), bacterial infection has higher CWA results (6.92 ± 1.60%/s; 1.04 ± 0.28%/s2; 0.82 ± 0.24%/s2, all p 2; 0.43 ± 0.14%/s2, all p 2; 0.73 ± 0.18%/s2, all p > 0.05). CWA parameters demonstrated positive correlation with C-reactive protein levels (min1: r = 0.54, min2: r = 0.44, max2: r = 0.34; all p

A total of 22

The prognostic value of histologic grading and the Ki-67 proliferation index in follicular lymphoma (FL) is controversial. This study investigated the clinical usefulness of these two factors in Asian FL patients. Four hundred and thirty-three patients diagnosed with FL were retrospectively reviewed with a median follow-up time of 47.0 months (range, 24.0-168.0). The 10-year overall survival (OS) rate and progression-free survival (PFS) rate were 91.0% and 47.1%, respectively. Grade 3B and grade 3B with diffuse large B cell lymphoma (DLBCL) showed a better PFS than grade 1-3A (P < 0.001), and similar findings were noted in patients who received rituximab-containing regimens (P = 0.002). In contrast, no significant differences in terms of OS or PFS were observed between grades 1-2 and 3A. In addition, patients with Ki-67 ≥ 30% had a significantly better PFS than patients with Ki-67 < 30% (P = 0.014), although the difference was eliminated in the multivariate analysis. Both grade and Ki-67 index had no impact on prognosis in patients who did not receive rituximab treatment. In conclusion, grade 3A is closely related to grade 1-2, as reflected by a similar indolent clinical course and a lower PFS rate than grade 3B/3B + DLBCL. In addition, a higher Ki-67 index seems to have a positive effect on PFS in FL patients.

Introduction Prophylaxis with replacement factor IX (FIX) reduces bleeding frequency and improves quality of life in haemophilia B patients. With prophylaxis, the likelihood of bleeding is lowered with increasing trough levels. New products with extended half-life (EHL) can maintain high factor activity levels over prolonged periods, compared with standard FIX products. Aim To evaluate the safety, efficacy and pharmacokinetics of the new recombinant FIX EHL product, nonacog beta pegol (N9-GP), using pooled data, with a focus on-but not limited to-prophylaxis at 40 IU/kg. Methods N9-GP has been investigated in males with congenital haemophilia B and FIX activity ≤2% in the paradigm™ clinical trial programme. This analysis includes pooled data from five completed paradigm™ trials conducted in previously treated adults, adolescents and children, focusing on results of prophylaxis with 40 IU/kg once-weekly intravenous dosing. Results In total, 115 previously treated patients were exposed to N9-GP. Of 54 patients (47%) treated with N9-GP 40 IU/kg once-weekly prophylaxis, 72% experienced no spontaneous bleeds over 1 year. In all patients receiving 40 IU/kg once-weekly, median overall annualized bleeding rate (ABR) was 1.03 (interquartile range 0.00; 2.89); median spontaneous ABR was 0.00 (0.00; 0.80). No patients developed inhibitors. Estimated mean steady-state trough levels with N9-GP 40 IU/kg once-weekly were ≥15% overall; 27.3% in adolescents and adults. Conclusion N9-GP 40 IU/kg once-weekly was well tolerated and effective in preventing bleeding, maintaining mean FIX activity levels ≥15% across all age groups. N9-GP may provide a new treatment option for preventing bleeding in haemophilia B patients.

A novel tetrahydrofuran derivative, trigonohowine (1), together with five known tetrahydrofuran derivatives (2–6), were isolated from the stems and leaves of Trigonostemon howii. The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons with the data reported in literature. Among them, trigonohowine (1) represents the first example of a new type of tetrahydrofuran derivative, possessing an unprecedented carbon skeleton containing 23 carbon atoms on the carbon skeleton and the known compouds (2–6) are rare tetrahydrofuran derivatives in the plant kingdom with various carbon skeletons. All isolated compounds were evaluated for their anti-HIV-1 activities. Compounds 1–6 showed significant anti-HIV-1 activities with EC50 ranged from 0.08 to 1.03 µM. These findings suggest that the discoveries of these tetrahydrofuran derivatives with significant anti-HIV-1 activities isolated from T. howii could be of great importance to the development of new anti-HIV agents.

Race is touted as an independent risk factor for venous thromboembolism (VTE), although the basis for this is varied and contentious. Comparison of plasma thrombin generation (TG) using calibrated automated thrombogram (CAT) across races offers a modality that objectively measures global hemostatic function to evaluate this influence. Direct comparative data across races are currently not available. Aim is to establish the influence of race on plasma TG. Sixty normal participants, matched for age and gender, equally representing 4 races—Caucasian, Chinese, Indian, and Malay—were recruited. Thrombin generation parameters (lag time, time to peak, peak, and endogenous thrombin potential [ETP]) in platelet-poor plasma were measured using CAT. The mean ETP (standard deviation) for the different races were Caucasians: 1338.18 (194.19) nM·min; Chinese, 1318.91 (108.90) nM·min; Indians, 1389.81 (182.61) nM·min; and Malays, 1436.21 (184.24) nM·min. Caucasians had the longest mean lag time of 2.59 ± 0.37 seconds; Indians had the highest mean peak of 284.22 ± 30.74 nM, and Malays had the longest mean time to peak of 5.47 ± 0.59 seconds. Analysis based on race did not demonstrate any significant difference for all TG parameters. The greatest mean difference of ETP between any 2 races (Malays and Chinese) was 117.30 nM·min (95% confidence interval: −45.86 to 280.46 nM·min) which was within the predefined limit of equivalence. In a cohort of healthy participants, TG mediated by plasma factors is not influenced by race and does not explain the reported racial differences in VTE incidence. For the 4 racial groups studied, the use of separate normal ranges for plasma TG might not be essential.

The current study observed the percentage of peripheral blood (PB) CD4+CD25+ regulatory T cells (Tregs) and the influence of CD4+CD25+ Tregs on the proliferation of naïve CD4 T cells in patients with hyperthyroidism. Furthermore, preliminary discussions are presented on the action mechanism of CD4+CD25+ Tregs on hyperthyroidism attacks. The present study identified that compared with the percentage of PB CD4+CD25+ Tregs in healthy control subjects, no significant changes were observed in the percentage of PB CD4+CD25+ Tregs in patients with hyperthyroidism (P>0.05). For patients with hyperthyroidism, CD4+CD25+ Tregs exhibited significantly reduced inhibition of the proliferation of naïve CD4 T cells and decreased secretion capacity on the cytokines of CD4 T cells, compared with those of healthy control subjects (P0.05). In the patients with hyperthyroidism, following treatment, CD4+CD25+ Tregs exhibited significantly increased inhibition of the proliferation of naïve CD4 T cells and increased secretion capacity of CD4 T cell cytokines, compared with those of the patients with hyperthyroidism prior to treatment (P

A new indole alkaloid, nauclorienine (1), along with seven known alkaloids (2–8), were isolated from the stems and leaves of Nauclea orientalis. Among them, nauclorienine (1) was a new indole alkaloid holding a rare corynanthe-type skeleton, and the known compounds (2–8) were isolated from N. orientalis for the first time. Their structures were elucidated on the basis of extensive spectroscopic data analyses. All isolated compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Alkaloids 1–4 exhibited significant inhibitory effects against various human cancer cell lines with IC50 values comparable to those of cisplatin.

Introduction Nonacog beta pegol (N9-GP) is a glycoPEGylated recombinant factor IX (FIX) with an extended half-life developed for routine prophylaxis and the prevention and treatment of bleeding episodes in patients with haemophilia B. Aim The aim of this study was to evaluate the pharmacokinetics (PK) of N9-GP. Methods Data from 41 previously treated haemophilia B patients, enrolled globally (16 adolescents/adults and 25 children; FIX activity ≤0.02 IU mL−1) with no history of FIX inhibitors, were included. N9-GP was administered once-weekly as 10 IU kg−1 or 40 IU kg−1 in adolescents/adults and 40 IU kg−1 in children. Blood was sampled up to 168 h (1 week) post dose. Standard PK was estimated on the basis of plasma FIX activity vs. time (PK profiles) using non-compartmental methods. Furthermore, a population PK analysis and FIX activity predictions were performed. Results Incremental recoveries were 0.02 (IU mL−1)/(IU kg−1) in both adolescents/adults and children. The extended half-life resulted in mean trough levels of 0.27 IU mL−1 for adolescents/adults and 0.17 IU mL−1 for children at steady-state after weekly dosing at 40 IU kg−1. The population PK analysis confirmed a mono-exponential decay in FIX activity and allowed for predictions of FIX activity for adolescents/adults above 0.15 IU mL−1 at all times and 6.4 days week−1 in children. Conclusion N9-GP has the potential to shift previously treated haemophilia B patients from a severe/moderate disease state into a mild- or non-haemophilic range for most of the dosing interval, which is expected to reduce the number of bleeding episodes.

Background: B cells can function as antigen-presenting cells by presenting antigens captured by the B-cell receptor (BCR) on Class II Major Histocompatibility Complex (MHC II) to T cells. In addition, B-cells can also maintain immune homeostasis by expressing PD-L1 and suppressing T-cell activity. Epstein-Barr virus (EBV) infection can disrupt B-cell function and lead to B cell malignancies, including diffuse large B-cell lymphoma (DLBCL). Here we show that EBV-positive DLBCL (EBV+ DLBCL) has decreased expression of BCR and MHC II, but over-expressed PD-L1, which may lead to immune evasion. Methods: An EBV+ DLBCL cohort (n = 30) and an EBV- DLBCL control cohort (n = 83) were established. Immunostaining of PD-L1, MHC II, MHC II Transactivator (CIITA) and pBTK was performed on automated stainer. H-score was used to denote the results of staining of PD-L1 and pBTK. Break apart and deletion of CIITA locus was studied by fluorescent in situ hybridization. Surface immunoglobulin mean fluorescent insensitivity (MFI) was detected by flow cytometry to demonstrate the level BCR. Results: EBV+ DLBCL showed significantly lower expression of CIITA and MHC II compared to EBV- DLBCL. Genetic aberrations involving CIITA were also more common in EBV+ DLBCL, with 23% break apart events and 6% deletion events, comparted to 2% break apart and 0% deletion in EBV- DLBCL. In addition to the loss of antigen presentation molecule, the antigen capture receptor, BCR, was also down-regulated in EBV+ DLBCL. Accordingly, BCR signaling was also significantly decreased in EBV+ DLBCL as denoted by the respective pBTK levels. Conclusions: EBV+ DLBCL shows over expression of the T-cell inhibitory ligand, PD-L1. Antigen capture and presentation system were disrupted, and T-cell inhibitory molecule was hijacked in EBV+ DLBCL, which may contribute to immune escape in this high risk disease. Therapies targeting these aberrations may improve the outcome of patients with EBV+ DLBCL.

Introduction: A hypercoagulable state is a predisposition for venous thromboembolism (VTE). The activated partial thromboplastin time (aPTT)-based clot waveform analysis (CWA) is a global haemostatic measure but its role in assessment of hypercoagulability and thrombotic disorders is uncertain. We aimed to study the changes of CWA parameters in acute VTE. We hypothesized that patients with acute VTE would demonstrate higher CWA values than control patients without VTE and having elevated CWA parameters is associated with acute VTE. Materials and methods: Clot waveform analysis data from patients (N = 45) with objectively proven acute VTE who had an aPTT performed prior to initiation of anticoagulation were compared with controls (N = 111). The CWA parameters measured were min1, min2, max2 and delta change. Results: While the mean aPTT between VTE patients and controls did not differ (P = 0.830), the mean CWA parameters were significantly higher among VTE patients than controls (min1, P < 0.001; min2, P = 0.001; max2, P = 0.002; delta change, P < 0.001). There were significantly more cases within the VTE group exhibiting CWA values above their reference intervals than the control group (all P < 0.001), with the odds ratios for VTE of 8.0, 5.2, 4.8 and 18.6 for min1, min2, max2 and delta change, respectively (all P < 0.001). Conclusions: Patients with acute VTE had elevated aPTT-based CWA parameters than controls. Higher CWA parameters were significantly associated with acute VTE.

Background and aim Most previous attention-deficit/hyperactivity disorder (ADHD) studies have used only a single sensory modality (usually vision) to investigate attentional problems, although patients with ADHD might display deficits of auditory attention similar to their visual attention. This study explored intraindividual auditory and visual attention in children with and without ADHD to examine the relationship between these two dimensions of attention. Methods Attentional performances of 140 children (70 children with ADHD and 70 typically developing peers) were measured through the Test of Variables of Attention (TOVA) in the present study. Results For both groups, most attentional indices showed significant differences between the two modalities (d ranging from 0.32 to 0.72). The correlation coefficients of most of the attentional variables in children with ADHD were lower than their typically developing peers. All attentional indices of children with ADHD (ranging from 12.8%–55.7%) were much higher than those of their typically developing peers (ranging from 1.4%–8.6%). Conclusion These results not only indicate that typically developing children display more consistent attentional performance, but also support the view that children with ADHD may show attention deficiency in one modality but not necessarily in the other.

Introduction: Direct oral anticoagulants (DOACs) are establishing themselves as principle choices for the treatment of a variety of thrombotic disorders. DOACs are also known to affect common coagulation tests which are routinely performed for patients in clinical practice. An understanding of their varied effects is crucial for the appropriate ordering of coagulation tests and their interpretation. Materials and Methods: Laboratories in public and private healthcare institutions and commercial sectors were surveyed on coagulation tests offered and their methods. A Medline and bibliography search, including a search on search engines, was performed for publications reporting the effects of dabigatran, apixaban and rivaroxaban on these coagulation tests. These papers were reviewed and summarised for consensus recommendations. Results: Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are variably affected by the DOACs and dependent of the coagulation assays used. Clinicians must know which laboratory has performed these tests to logically interpret test results. A normal PT or aPTT does not exclude the presence of residual DOACs effect. The thrombin time is sensitive to dabigatran but not apixaban or rivaroxaban. Specialised coagulation tests such as thrombophilia tests are also variably affected by the DOACs. All laboratories in Singapore however, employ similar test methods permitting a common set of recommendations for specialised coagulation testing. Conclusion: Knowledge of the effects of DOACs on coagulation testing is essential to determine the appropriateness of performing such tests and interpreting them coherently. Practical recommendations which are tests and location-specific are set out in this paper. Key words: Apixaban, Dabigatran, Laboratory testing, Rivaroxaban

To develop a Tablet-based Symbol Digit Modalities Test (T-SDMT) and to examine the test-retest reliability and concurrent validity of the T-SDMT in patients with stroke.The study had two phases. In the first phase, six experts, nine college students and five outpatients participated in the development and testing of the T-SDMT. In the second phase, 52 outpatients were evaluated twice (2 weeks apart) with the T-SDMT and SDMT to examine the test-retest reliability and concurrent validity of the T-SDMT.The T-SDMT was developed via expert input and college student/patient feedback. Regarding test-retest reliability, the practise effects of the T-SDMT and SDMT were both trivial (d=0.12) but significant (p≦0.015). The improvement in the T-SDMT (4.7%) was smaller than that in the SDMT (5.6%). The minimal detectable changes (MDC%) of the T-SDMT and SDMT were 6.7 (22.8%) and 10.3 (32.8%), respectively. The T-SDMT and SDMT were highly correlated with each other at the two time points (Pearson's r=0.90-0.91).The T-SDMT demonstrated good concurrent validity with the SDMT. Because the T-SDMT had a smaller practise effect and less random measurement error (superior test-retest reliability), it is recommended over the SDMT for assessing information processing speed in patients with stroke. Implications for Rehabilitation The Symbol Digit Modalities Test (SDMT), a common measure of information processing speed, showed a substantial practise effect and considerable random measurement error in patients with stroke. The Tablet-based SDMT (T-SDMT) has been developed to reduce the practise effect and random measurement error of the SDMT in patients with stroke. The T-SDMT had smaller practise effect and random measurement error than the SDMT, which can provide more reliable assessments of information processing speed.

SARS-CoV-2 has caused a pandemic coronavirus disease 2019 (COVID-19), claiming over a million worldwide lives of people among whom those with cardiovascular disease or hypertension are over-represented. Understanding the mechanism by which coronavirus threatens human health is vital for reducing the current disease burden and even for preventing future attacks. Inspired by the temporal relationship between three coronavirus outbreaks in humans since 2000 and hypertension medications gaining popularity since 2000, we discuss here how hypertension medications might contribute to the COVID-19 pandemic and mortality with a focus on inhibitors of the renin-angiotensin-aldosterone system (RAAS). The fact that RAAS inhibitors increase angiotensin converting enzyme-2 (ACE2) expression in respiratory epithelial cells, the kidneys and heart has stirred a surge of interest in the discussion of the role of RAAS inhibitors in COVID-19 disease, all related to ACE2-mediated effects [1–5]. Here, we abstain from contributing further to this extensive discussion, but expand this discussion beyond ACE2 and centre on how RAAS blockade influences human interaction with SARS-CoV-2 by altering acid-base balance. This expansion is based on our previous experimental work conducted on aldosterone deficient mice [6] and on the fact, supported by accumulated groundwork in physiology, that acid-base homeostasis is maintained by the coordinated work of kidneys and lungs, and is vital for normal physiology and health. RAAS evolved to facilitate humans’ adaptation to land life by conserving salt and water in the intestine and kidney, and facilitating renal acid and other water-soluble waste elimination. As renal acid-excretion effects are largely dependent on the RAAS, inhibiting renal salt absorption by RAAS inhibitors in attempt to reduce blood pressure also slows renal acid elimination (see fig. 1 below).

Point-of-care testing (POCT) of the international normalised ratio (INR) is recognised as a rapid and reliable alternative to venous INR measurement for titration and monitoring of patients anticoagulated with vitamin K antagonists.1–4 Besides empowering patient self-testing and self-management,5–7 POCT coagulometers are now widely used in healthcare institutions for bedside anticoagulation management and have replaced venous INR sampling in many anticoagulation clinics (ACCs).8–10 For the past decade, our institution has been using the CoaguChek XS system (Roche Diagnostics, Basel, Switzerland) for INR testing at our outpatient ACC and inpatient anticoagulation service. This followed a validation study conducted by our group which showed excellent correlation with venous INR below a reading of 3.5.11 A tendency for a higher INR on the POCT platform above this threshold prompted us to introduce a mechanism that rejected results above 3.5 on the CoaguChek XS system and mandating repeat testing with venous INR. This test protocol remains in effect today. Recently, two new fourth-generation coagulometers were introduced on the CoaguChek platform. The CoaguChek Pro II is designed for institutional use with the added capability of measuring activated partial thromboplastin time while the CoaguChek INRange is targeted at patients performing home INR monitoring. These machines have the same detection system as the CoaguChek XS devices but uses the new CoaguChek PT Test strip which has a broader intended use compared with the XS devices’ test strip.12 We evaluated the performance of these two coagulometers for INR testing with a validation study comparing their performance against the old CoaguChek XS Pro and standard venous INR. The results were intended for us to conduct a review of our current POCT INR test protocol. This paper reports the findings of our efforts. ### Study design and study population This prospective validation study comparing three different POCT coagulometers against venous INR was …

Non-transfusion-dependent thalassaemia (NTDT) is associated with a hypercoagulable state with thrombotic risk highest after splenectomy. Various mechanisms have been proposed. Although an antiplatelet agent is commonly recommended as thromboprophylaxis in NTDT, the role of platelets contributing to this hypercoagulable state is not well-defined. This study aims to evaluate the role of platelets contributing to hypercoagulability in NTDT patients using thrombin generation (TG). Platelet-rich (PRP) and platelet-poor plasma (PPP) were collected from NTDT patients (n = 30) and normal controls (n = 20) for TG measurement and compared. Controls had higher endogenous thrombin potential (ETP) in PPP (1204.97 nM.min vs 911.62 nM.min, p

Purpose The purpose of this study was to apply Rasch analysis to examine the unidimensionality and reliability of the General Self-Efficacy Scale (GSE) in workers with traumatic limb injuries. Furthermore, if the items of the GSE fitted the Rasch model's assumptions, we transformed the raw sum ordinal scores of the GSE into Rasch interval scores. Methods A total of 1076 participants completed the GSE at 1 month post injury. Rasch analysis was used to examine the unidimensionality and person reliability of the GSE. The unidimensionality of the GSE was verified by determining whether the items fit the Rasch model's assumptions: (1) item fit indices: infit and outfit mean square (MNSQ) ranged from 0.6 to 1.4; and (2) the eigenvalue of the first factor extracted from principal component analysis (PCA) for residuals was

Five new carbazole alkaloids, clausehainanines A-E (1-5), together with seven known analogues (6-12) were isolated from the stems and leaves of C. hainanensis. Their structures were elucidated by extensive spectroscopic methods. Among them, compounds 1-5 were an unusual type of carbazole alkaloids, possessing diverse isopentenyl derivatives as substituents at C-2. All isolated compounds were evaluated for their antiproliferative activities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Alkaloids 1-12 showed significant antiproliferative effects against various human cancer cell lines with IC50 values ranging from 0.12 to 15.56 μM. These findings suggest that the discoveries of these carbazole alkaloids with significant cytotoxic activities isolated from C. hainanensis could be of great importance to the development of new anticancer agents.

A new furanocoumarin, clauhainanin A (1), together with seven known furanocoumarins (2-8), were isolated from the stems and leaves of Clausena hainanensis. The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons with data reported in the literature. All known compounds (2-8) were isolated from C. hainanensis for the first time. All isolated compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1-8 exhibited significant inhibitory effects with IC50 values ranging from 1.36 to 18.96 μM.

We aimed to compare the test-retest agreement, random measurement error, practice effect, and ecological validity of the original and Tablet-based Symbol Digit Modalities Test (T-SDMT) over five serial assessments, and to examine the concurrent validity of the T-SDMT in patients with schizophrenia. Sixty patients with chronic schizophrenia completed five serial assessments (one week apart) of the SDMT and T-SDMT and one assessment of the Activities of Daily Living Rating Scale III at the first time point. Both measures showed high test-retest agreement, similar levels of random measurement error over five serial assessments. Moreover, the practice effects of the two measures did not reach a plateau phase after five serial assessments in young and middle-aged participants. Nevertheless, only the practice effect of the T-SDMT became trivial after the first assessment. Like the SDMT, the T-SDMT had good ecological validity. The T-SDMT also had good concurrent validity with the SDMT. In addition, only the T-SDMT had discriminative validity to discriminate processing speed in young and middle-aged participants. Compared to the SDMT, the T-SDMT had overall slightly better psychometric properties, so it can be an alternative measure to the SDMT for assessing processing speed in patients with schizophrenia.

BACKGROUND A lack of evidence on the test-retest reliability and responsiveness limits the utility of the BI-based Supplementary Scales (BI-SS) in both clinical and research settings. AIM To examine the test-retest reliability and responsiveness of the BI-based Supplementary Scales (BI-SS) in patients with stroke. DESIGN A repeated-assessments design (1 week apart) was used to examine the test-retest reliability of the BI-SS. For the responsiveness study, the participants were assessed with the BI-SS and BI (treated as an external criterion) at admission to and discharge from rehabilitation wards. SETTING Seven outpatient rehabilitation units and one inpatient rehabilitation unit. POPULATION Outpatients with chronic stroke. METHODS Eighty-four outpatients with chronic stroke participated in the test-retest reliability study. Fifty-seven inpatients completed baseline and follow-up assessments in the responsiveness study. RESULTS For the test-retest reliability study, the values of the intra-class correlation coefficient and the overall percentage of minimal detectable change for the Ability Scale and Self-perceived Difficulty Scale were 0.97, 12.8%, and 0.78, 35.8%, respectively. For the responsiveness study, the standardized effect size and standardized response mean (representing internal responsiveness) of the Ability Scale and Self-perceived Difficulty Scale were 1.17 and 1.56, and 0.78 and 0.89, respectively. Regarding external responsiveness, the change in score of the Ability Scale had significant and moderate association with that of the BI (r=0.61, P

Fibroblast migration is a central process in skin wound healing, which requires the coordination of several types of growth factors. bFGF, a well-known fibroblast growth factor (FGF), is able to accelerate fibroblast migration; however, the underlying mechanism of bFGF regulation fibroblast migration remains unclear. Through the RNA-seq analysis, we had identified that the hedgehog (Hh) canonical pathway genes including Smoothened (Smo) and Gli1, were regulated by bFGF. Further analysis revealed that activation of the Hh pathway via up-regulation of Smo promoted fibroblast migration, invasion, and skin wound healing, but which significantly reduced by GANT61, a selective antagonist of Gli1/Gli2. Western blot analyses and siRNA transfection assays demonstrated that Smo acted upstream of phosphoinositide 3-kinase (PI3K)-c-Jun N-terminal kinase (JNK)-β-catenin to promote cell migration. Moreover, RNA-seq and qRT-PCR analyses revealed that Hh pathway genes including Smo and Gli1 were under control of β-catenin, suggesting that β-catenin turn feedback activates Hh signaling. Taken together, our analyses identified a new bFGF-regulating mechanism by which Hh signaling regulates human fibroblast migration, and the data presented here opens a new avenue for the wound healing therapy.

Turoctocog alfa pegol (N8-GP) is a novel glycoPEGylated extended half-life recombinant factor VIII (FVIII) product developed for prophylaxis and treatment of bleeds in patients with haemophilia A, to enable higher activity levels with less frequent injections compared with standard FVIII products. This phase III (NCT01480180), multinational, open-label, non-randomised trial evaluated the safety and clinical efficacy of N8-GP when administered for treatment of bleeds and for prophylaxis, in previously treated patients aged ≥12 years with severe haemophilia A. Patients were allocated to receive N8-GP for prophylaxis or on-demand treatment for up to 1.8 years. Patients on prophylaxis were administered one dose of 50 IU/kg of N8-GP every fourth day. Bleeds were treated with doses of 20-75 IU/kg. Total exposure to N8-GP in the trial was 14,114 exposure days (159 patient-years). For the prophylaxis arm (n=175), the median annualised bleeding rate (ABR) was 1.33 (interquartile range, 0.00-4.61), the mean ABR was 3.70 (95 % confidence interval 2.94-4.66) and 70 (40 %) patients had no bleeds during the trial. Across treatment arms, 83.6 % of bleeds resolved with one injection and 95.5 % with up to two injections. N8-GP had a favourable safety profile and was well tolerated. The frequency and types of adverse events reported were as expected in this population. One patient developed inhibitory antibodies against FVIII (≥0.6 Bethesda units [BU]) after 93 N8-GP exposure days. No clinically significant safety concerns were identified and N8-GP was effective for prophylaxis and treatment of bleeds in previously treated patients. Turoctocog alfa pegol (N8-GP) is a novel glycoPEGylated extended half-life recombinant factor VIII (FVIII) product developed for prophylaxis and treatment of bleeds in patients with haemophilia A, to enable higher activity levels with less frequent injections compared with standard FVIII products. This phase III (NCT01480180), multinational, open-label, non-randomised trial evaluated the safety and clinical efficacy of N8-GP when administered for treatment of bleeds and for prophylaxis, in previously treated patients aged ≥12 years with severe haemophilia A. Patients were allocated to receive N8-GP for prophylaxis or on-demand treatment for up to 1.8 years. Patients on prophylaxis were administered one dose of 50 IU/kg of N8-GP every fourth day. Bleeds were treated with doses of 20-75 IU/kg. Total exposure to N8-GP in the trial was 14,114 exposure days (159 patient-years). For the prophylaxis arm (n=175), the median annualised bleeding rate (ABR) was 1.33 (interquartile range, 0.00-4.61), the mean ABR was 3.70 (95 % confidence interval 2.94-4.66) and 70 (40 %) patients had no bleeds during the trial. Across treatment arms, 83.6 % of bleeds resolved with one injection and 95.5 % with up to two injections. N8-GP had a favourable safety profile and was well tolerated. The frequency and types of adverse events reported were as expected in this population. One patient developed inhibitory antibodies against FVIII (≥0.6 Bethesda units [BU]) after 93 N8-GP exposure days. No clinically significant safety concerns were identified and N8-GP was effective for prophylaxis and treatment of bleeds in previously treated patients.

Objective To examine the intrarater reliability, interrater reliability, and responsiveness of the Activities of Daily Living Computerized Adaptive Testing system (ADL CAT) in patients with stroke. Design One repeated-measures design (at an interval of 7d) was used to examine the intrarater reliability and interrater reliability of the ADL CAT. For the responsiveness study, participants were assessed with the ADL CAT at admission to the rehabilitation ward and at discharge from the hospital. Setting Eight rehabilitation units. Participants Three different (nonoverlapping) groups of patients (N=157) were recruited. Fifty-five and 42 outpatients with chronic stroke participated in the intrarater and interrater reliability studies, respectively; 60 inpatients who had recently had a stroke participated in the responsiveness study. Interventions Not applicable. Main Outcome Measure ADL CAT. Results The intraclass correlation coefficient values were .94 and .80 for the ADL CAT in the intrarater reliability and interrater reliability studies, respectively. The classical test theory–based minimal detectable change values were 6.5 and 9.5 for the ADL CAT in the intrarater reliability and interrater reliability studies, respectively. The Kazis' effect size and standardized response mean of the ADL CAT were moderate (.62–.73). Conclusions The ADL CAT has good intrarater reliability and interrater reliability in outpatients with chronic stroke, and sufficient responsiveness in inpatients with stroke undergoing inpatient rehabilitation. Further investigations on the responsiveness of the ADL CAT in outpatients are needed to obtain more evidence on the utility of the ADL CAT.

Objectives. To investigate the association of indoor air pollution with the respiratory health of children, we evaluated the associations of children’s respiratory symptoms with asthma and recent home renovation. Methods. We conducted a cross-sectional survey in a school recruitment sample of 31 049 children aged 2 to 14 years in 25 districts of 7 cities of northeast China in 2008–2009. The children’s parents completed standardized questionnaires characterizing the children’s histories of respiratory symptoms and illness, recent home renovation information, and other associated risk factors. Results. The effects of home renovation in the past 2 years were significantly associated with cough, phlegm, current wheeze, doctor-diagnosed asthma, and current asthma. The associations we computed when combining the status of home renovation and family history of atopy were higher than were those predicted from the combination of the separate effects. However, the interactions between home renovation and family history of atopy on a multiplicative scale were not statistically significant (P > .05). Conclusions. Home renovation is associated with increases in the prevalence of respiratory symptoms and asthma in children. The effects of different renovation materials on child respiratory health should be studied further.