Background: The optimal screening interval for diabetic retinopathy (DR) remains controversial. This study aimed to develop a risk algorithm to predict the individual risk of referable sight-threatening diabetic retinopathy (STDR) in a mainly Chinese population and to provide evidence for risk-based screening intervals. Methods: The retrospective cohort data from 117,418 subjects who received systematic DR screening in Hong Kong between 2010 and 2016 were included to develop and validate the risk algorithm using a parametric survival model. The risk algorithm can be used to predict the individual risk of STDR within a specific time interval, or the time to reach a specific risk margin and thus to allocate a screening interval. The calibration performance was assessed by comparing the cumulative STDR events versus predicted risk over 2 years, and discrimination by using receiver operative characteristics (ROC) curve. Results: Duration of diabetes, glycosylated hemoglobin, systolic blood pressure, presence of chronic kidney disease, diabetes medication, and age were included in the risk algorithm. The validation of prediction performance showed that there was no significant difference between predicted and observed STDR risks in males (5.6% vs. 5.1%, P=0.724) or females (4.8% vs. 4.6%, P=0.099). The area under the receiver operating characteristic curve was 0.80 (95% confidence interval [CI], 0.78 to 0.81) for males and 0.81 (95% CI, 0.79 to 0.83) for females. Conclusion The risk algorithm has good prediction performance for referable STDR. Using a risk-based screening interval allows us to allocate screening visits disproportionally more to those at higher risk, while reducing the frequency of screening of lower risk people.

Background: The optimal screening interval for diabetic retinopathy (DR) remains controversial. This study aimed to develop a risk algorithm to predict the individual risk of referable sight-threatening diabetic retinopathy (STDR) in a mainly Chinese population and to provide evidence for risk-based screening intervals. Methods: The retrospective cohort data from 117,418 subjects who received systematic DR screening in Hong Kong between 2010 and 2016 were included to develop and validate the risk algorithm using a parametric survival model. The risk algorithm can be used to predict the individual risk of STDR within a specific time interval, or the time to reach a specific risk margin and thus to allocate a screening interval. The calibration performance was assessed by comparing the cumulative STDR events versus predicted risk over 2 years, and discrimination by using receiver operative characteristics (ROC) curve. Results: Duration of diabetes, glycosylated hemoglobin, systolic blood pressure, presence of chronic kidney disease, diabetes medication, and age were included in the risk algorithm. The validation of prediction performance showed that there was no significant difference between predicted and observed STDR risks in males (5.6% vs. 5.1%, P=0.724) or females (4.8% vs. 4.6%, P=0.099). The area under the receiver operating characteristic curve was 0.80 (95% confidence interval [CI], 0.78 to 0.81) for males and 0.81 (95% CI, 0.79 to 0.83) for females. Conclusion The risk algorithm has good prediction performance for referable STDR. Using a risk-based screening interval allows us to allocate screening visits disproportionally more to those at higher risk, while reducing the frequency of screening of lower risk people.

Background: The optimal screening interval for diabetic retinopathy (DR) remains controversial. This study aimed to develop a risk algorithm to predict the individual risk of referable sight-threatening diabetic retinopathy (STDR) in a mainly Chinese population and to provide evidence for risk-based screening intervals. Methods: The retrospective cohort data from 117,418 subjects who received systematic DR screening in Hong Kong between 2010 and 2016 were included to develop and validate the risk algorithm using a parametric survival model. The risk algorithm can be used to predict the individual risk of STDR within a specific time interval, or the time to reach a specific risk margin and thus to allocate a screening interval. The calibration performance was assessed by comparing the cumulative STDR events versus predicted risk over 2 years, and discrimination by using receiver operative characteristics (ROC) curve. Results: Duration of diabetes, glycosylated hemoglobin, systolic blood pressure, presence of chronic kidney disease, diabetes medication, and age were included in the risk algorithm. The validation of prediction performance showed that there was no significant difference between predicted and observed STDR risks in males (5.6% vs. 5.1%, P=0.724) or females (4.8% vs. 4.6%, P=0.099). The area under the receiver operating characteristic curve was 0.80 (95% confidence interval [CI], 0.78 to 0.81) for males and 0.81 (95% CI, 0.79 to 0.83) for females. Conclusion The risk algorithm has good prediction performance for referable STDR. Using a risk-based screening interval allows us to allocate screening visits disproportionally more to those at higher risk, while reducing the frequency of screening of lower risk people.

Background: The optimal screening interval for diabetic retinopathy (DR) remains controversial. This study aimed to develop a risk algorithm to predict the individual risk of referable sight-threatening diabetic retinopathy (STDR) in a mainly Chinese population and to provide evidence for risk-based screening intervals. Methods: The retrospective cohort data from 117,418 subjects who received systematic DR screening in Hong Kong between 2010 and 2016 were included to develop and validate the risk algorithm using a parametric survival model. The risk algorithm can be used to predict the individual risk of STDR within a specific time interval, or the time to reach a specific risk margin and thus to allocate a screening interval. The calibration performance was assessed by comparing the cumulative STDR events versus predicted risk over 2 years, and discrimination by using receiver operative characteristics (ROC) curve. Results: Duration of diabetes, glycosylated hemoglobin, systolic blood pressure, presence of chronic kidney disease, diabetes medication, and age were included in the risk algorithm. The validation of prediction performance showed that there was no significant difference between predicted and observed STDR risks in males (5.6% vs. 5.1%, P=0.724) or females (4.8% vs. 4.6%, P=0.099). The area under the receiver operating characteristic curve was 0.80 (95% confidence interval [CI], 0.78 to 0.81) for males and 0.81 (95% CI, 0.79 to 0.83) for females. Conclusion The risk algorithm has good prediction performance for referable STDR. Using a risk-based screening interval allows us to allocate screening visits disproportionally more to those at higher risk, while reducing the frequency of screening of lower risk people.

Community-acquired respiratory infection is the commonest cause of sepsis presenting to emergency departments. Yet current experimental animal models simulate peritoneal sepsis with intraperitoneal (I.P.) injection of lipopolysaccharide (LPS) as the predominant route. We aimed to compare the progression of organ injury between I.P. LPS and intranasal (I.N.) LPS in order to establish a better endotoxemia murine model of respiratory sepsis. Eight weeks old male BALB/c mice received LPS-Escherichia coli doses at 0.15, 1, 10, 20, 40 and 100 mg per kg body weight (e.g. LPS-10 is a dose of 10 mg/kg body weight). Disease severity was monitored by a modified Mouse Clinical Assessment Score for Sepsis (M-CASS; range 0–21). A M-CASS score ≥ 10 or a weight reduction of ≥ 20%, was used as a criterion for euthanasia. The primary outcome was the survival rate (either no death or no need for euthanasia). The progression of disease was specified as M-CASS, body weight, blood glucose, histopathological changes to lung, liver, spleen, kidney, brain and heart tissues. Survival rate in I.P. LPS-20 mice was 0% (2/3 died; 1/3 euthanized with M-CASS > 10) at 24 h. Survival rate in all doses of I.N. LPS was 100% (20/20; 3–4 per group) at 96 h. 24 h mean M-CASS post-I.P. LPS-10 was 6.4/21 significantly higher than I.N. LPS-10 of 1.7/21 (Unpaired t test, P < 0.05). Organ injury was present at 96 h in the I.P. LPS-10 group: lung (3/3; 100%), spleen (3/3; 100%) and liver (1/3; 33%). At 24 h in the I.P. LPS-20 group, kidney injury was observed in the euthanized mouse. At 96 h in the post-I.N. LPS-20 group, only lung injury was observed in 2/3 (67%) mice (Kruskal-Wallis test with Dunn’s, P < 0.01). At 24 h in the post-I.N. LPS-100 group all (4/4) mice had evidence of lung injury. Variable doses of I.N. LPS in mice produced lung injury but did not produce sepsis. Higher doses of I.P. LPS induced multi-organ injury but not respiratory sepsis. Lethal models of respiratory virus, e.g., influenza A, might provide alternative avenues that can be explored in future research.

Using prostate-specific antigen (PSA) for prostate cancer (PCa) screening led to overinvestigation and overdiagnosis of indolent PCa. We aimed to investigate the value of prostate health index (PHI) and magnetic resonance imaging (MRI) prostate in an Asian PCa screening program. Men aged 50-75 years were prospectively recruited from a community-based PSA screening program. Men with PSA 4.0-10.0 ng ml -1 had PHI result analyzed. MRI prostate was offered to men with PSA 4.0-50.0 ng ml -1 . A systematic prostate biopsy was offered to men with PSA 4.0-9.9 ng ml -1 and PHI ≥35, or PSA 10.0-50.0 ng ml -1 . Additional targeted prostate biopsy was offered if they had PI-RADS score ≥3. Clinically significant PCa (csPCa) was defined as the International Society of Urological Pathology (ISUP) grade group (GG) ≥2 or ISUP GG 1 with involvement of ≥30% of total systematic cores. In total, 12.8% (196/1536) men had PSA ≥4.0 ng ml -1 . Among 194 men with PSA 4.0-50.0 ng ml -1 , 187 (96.4%) received MRI prostate. Among them, 28.3% (53/187) had PI-RADS ≥3 lesions. Moreover, 7.0% (107/1536) men were indicated for biopsy and 94.4% (101/107) men received biopsy. Among the men received biopsy, PCa, ISUP GG ≥2 PCa, and csPCa was diagnosed in 42 (41.6%), 24 (23.8%), and 34 (33.7%) men, respectively. Compared with PSA/PHI pathway in men with PSA 4.0-50.0 ng ml -1 , additional MRI increased diagnoses of PCa, ISUP GG ≥2 PCa, and csPCa by 21.2% (from 33 to 40), 22.2% (from 18 to 22), and 18.5% (from 27 to 32), respectively. The benefit of additional MRI was only observed in PSA 4.0-10.0 ng ml -1 , and the number of MRI needed to diagnose one additional ISUP GG ≥2 PCa was 20 in PHI ≥35 and 94 in PHI <35. Among them, 45.4% (89/196) men with PSA ≥4.0 ng ml -1 avoided unnecessary biopsy with the use of PHI and MRI. A screening algorithm with PSA, PHI, and MRI could effectively diagnose csPCa while reducing unnecessary biopsies. The benefit of MRI prostate was mainly observed in PSA 4.0-9.9 ng ml -1 and PHI ≥35 group. PHI was an important risk stratification step for PCa screening.
Humans ; Male ; Early Detection of Cancer/methods* ; East Asian People ; Image-Guided Biopsy/methods* ; Magnetic Resonance Imaging/methods* ; Prostate/pathology* ; Prostate-Specific Antigen ; Prostatic Neoplasms/pathology* ; Retrospective Studies ; Middle Aged ; Aged

Drug metabolism and pharmacokinetics (DMPK) is an important branch of pharmaceutical sciences. The nature of ADME (absorption, distribution, metabolism, excretion) and PK (pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems. Tremendous progress has been made in the past decade, not only in the characterization of physiochemical properties of drugs that influence their ADME, target organ exposure, and toxicity, but also in the identification of design principles that can minimize drug-drug interaction (DDI) potentials and reduce the attritions. The importance of membrane transporters in drug disposition, efficacy, and safety, as well as the interplay with metabolic processes, has been increasingly recognized. Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs, such as peptides, oligonucleotides, and antibody-drug conjugates, necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties. In this review, we highlight some of the most notable advances in the last decade, and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.

Purpose: The aim of this study was to investigate the feasibility and preliminary efficacy of a modified mindfulness-based stress reduction (MBSR) program and mindfulness-based cognitive therapy (MBCT) program for reducing the stress, depressive symptoms, and subjective burden of family caregivers of people with dementia (PWD). Methods: A prospective, parallel-group, randomized controlled trial design was adopted. Fifty-seven participants were recruited from the community and randomized into either the modified MBSR group (n = 27) or modified MBCT group (n = 26), receiving seven face-to-face intervention sessions for more than 16 weeks. Various psychological outcomes were measured at baseline (T0), immediately after intervention (T1), and at the 3-month follow-up (T2). Results: Both interventions were found to be feasible in view of the high attendance (more than 70.0%) and low attrition (3.8%) rates. The mixed analysis of variance (ANOVA) results showed positive within-group effects on perceived stress (p = .030, Cohen's d = 0.54), depressive symptoms (p = .002, Cohen's d = 0.77), and subjective caregiver burden (p < .001, Cohen's d = 1.12) in both interventions across the time points, whereas the modified MBCT had a larger effect on stress reduction, compared with the modified MBSR (p = .019). Conclusion Both the modified MBSR and MBCT are acceptable to family caregivers of PWD. Their preliminary effects were improvements in stress, depressive symptoms, and subjective burden. The modified MBCT may be more suitable for caregivers of PWD than the MBSR. A future clinical trial is needed to confirm their effectiveness in improving the psychological well-being of caregivers of PWD.

Purpose: The aim of this study was to investigate the feasibility and preliminary efficacy of a modified mindfulness-based stress reduction (MBSR) program and mindfulness-based cognitive therapy (MBCT) program for reducing the stress, depressive symptoms, and subjective burden of family caregivers of people with dementia (PWD). Methods: A prospective, parallel-group, randomized controlled trial design was adopted. Fifty-seven participants were recruited from the community and randomized into either the modified MBSR group (n = 27) or modified MBCT group (n = 26), receiving seven face-to-face intervention sessions for more than 16 weeks. Various psychological outcomes were measured at baseline (T0), immediately after intervention (T1), and at the 3-month follow-up (T2). Results: Both interventions were found to be feasible in view of the high attendance (more than 70.0%) and low attrition (3.8%) rates. The mixed analysis of variance (ANOVA) results showed positive within-group effects on perceived stress (p = .030, Cohen's d = 0.54), depressive symptoms (p = .002, Cohen's d = 0.77), and subjective caregiver burden (p < .001, Cohen's d = 1.12) in both interventions across the time points, whereas the modified MBCT had a larger effect on stress reduction, compared with the modified MBSR (p = .019). Conclusion Both the modified MBSR and MBCT are acceptable to family caregivers of PWD. Their preliminary effects were improvements in stress, depressive symptoms, and subjective burden. The modified MBCT may be more suitable for caregivers of PWD than the MBSR. A future clinical trial is needed to confirm their effectiveness in improving the psychological well-being of caregivers of PWD.