Uncovering the dynamics and consequences of RNA isoform changes during neuronal differentiation.

Static gene expression programs have been extensively characterized in stem cells and mature human cells. However, the dynamics of RNA isoform changes upon cell-state-transitions during cell differentiation, the determinants and functional consequences have largely remained unclear. Here, we established an improved model for human neurogenesis in vitro that is amenable for systems-wide analyses of gene expression. Our multi-omics analysis reveals that the pronounced alterations in cell morphology correlate strongly with widespread changes in RNA isoform expression. Our approach identifies thousands of new RNA isoforms that are expressed at distinct differentiation stages. RNA isoforms mainly arise from exon skipping and the alternative usage of transcription start and polyadenylation sites during human neurogenesis. The transcript isoform changes can remodel the identity and functions of protein isoforms. Finally, our study identifies a set of RNA binding proteins as a potential determinant of differentiation stage-specific global isoform changes. This work supports the view of regulated isoform changes that underlie state-transitions during neurogenesis.

Circulating metabolomic markers linking diabetic kidney disease and incident cardiovascular disease in type 2 diabetes: analyses from the Hong Kong Diabetes Biobank.

AIMS/HYPOTHESIS: The aim of this study was to describe the metabolome in diabetic kidney disease (DKD) and its association with incident CVD in type 2 diabetes, and identify prognostic biomarkers. METHODS: From a prospective cohort of individuals with type 2 diabetes, baseline sera (N=1991) were quantified for 170 metabolites using NMR spectroscopy with median 5.2 years of follow-up. Associations of chronic kidney disease (CKD, eGFR<60 ml/min per 1.73 m2) or severely increased albuminuria with each metabolite were examined using linear regression, adjusted for confounders and multiplicity. Associations between DKD (CKD or severely increased albuminuria)-related metabolites and incident CVD were examined using Cox regressions. Metabolomic biomarkers were identified and assessed for CVD prediction and replicated in two independent cohorts. RESULTS: At false discovery rate (FDR)<0.05, 156 metabolites were associated with DKD (151 for CKD and 128 for severely increased albuminuria), including apolipoprotein B-containing lipoproteins, HDL, fatty acids, phenylalanine, tyrosine, albumin and glycoprotein acetyls. Over 5.2 years of follow-up, 75 metabolites were associated with incident CVD at FDR<0.05. A model comprising age, sex and three metabolites (albumin, triglycerides in large HDL and phospholipids in small LDL) performed comparably to conventional risk factors (C statistic 0.765 vs 0.762, p=0.893) and adding the three metabolites further improved CVD prediction (C statistic from 0.762 to 0.797, p=0.014) and improved discrimination and reclassification. The 3-metabolite score was validated in independent Chinese and Dutch cohorts. CONCLUSIONS/INTERPRETATION: Altered metabolomic signatures in DKD are associated with incident CVD and improve CVD risk stratification.

Establishing targets for goal-directed anesthesia in renal transplantation: A cohort analysis of high-saliency surgical time courses.

Delayed graft function (DGF) increases morbidity and mortality in kidney transplant recipients. Operative parameters, including hemodynamic manipulation through vasopressors and fluids, can impact perfusion to the newly transplanted kidney and influence DGF incidence. We analyzed intraoperative time-series data in 5-minute intervals from kidney transplant recipient operations (N = 545) in conjunction with pretransplant characteristics and postsurgical outcomes, including DGF incidence, 60-day creatinine, and graft survival. Of the operations, 127 DGF events were captured in our cohort from a single academic transplant center (57/278 donations after brainstem death [DBDs], 65/150 donations after circulatory/cardiac death [DCDs], 5/117 live donations). In multiple regression, postanastomosis hypotension defined as mean arterial pressure (MAP) <75 mmHg was a risk factor for DGF independent of conventional predictors of DGF in DCD and DBD kidneys. DCD recipients with DGF had lower average postanastomosis MAP (DGF: 80.1 ± 8.1 mmHg vs no DGF: 76.4 ± 6.7 mmHg, P = .004). Interaction analysis demonstrated above-average doses of vasopressors and crystalloids were associated with improved outcomes when used at MAPs ≤75 mmHg, but they were associated with increased DGF at MAPs >75 mmHg, suggesting that the incidence of DGF can be highly influenced by intraoperative hemodynamic controls. This analysis of surgical time courses has identified potential new strategies for goal-directed anesthesia in renal transplantation.

What is loneliness? A reflection on my Imperial College London Patient Project.

Loneliness has emerged as a significant public health concern, with profound implications for health outcomes, which can manifest in physical, psychological, and social affliction. Working alongside Fulham Medical Centre, I sought out to create a range of both offline and online resources (YouTube video, ten-episode Spotify podcast, online website, GP practice brochure and poster) designed to provide base learning, practical strategies, community connections and a sense of support to those grappling with loneliness. These resources were well-received by the practice and were implemented on a practice basis, to provide support to the local community. Reflection on this project, highlights the need for student projects, and emphasises the tangible impact that we can have on community support and care for individuals tackling feelings of loneliness.

Relative leucocyte telomere length is associated with incident end-stage kidney disease and rapid decline of kidney function in type 2 diabetes: analysis from the Hong Kong Diabetes Register.

AIMS/HYPOTHESIS: Few large-scale prospective studies have investigated associations between relative leucocyte telomere length (rLTL) and kidney dysfunction in individuals with type 2 diabetes. We examined relationships between rLTL and incident end-stage kidney disease (ESKD) and the slope of eGFR decline in Chinese individuals with type 2 diabetes. METHODS: We studied 4085 Chinese individuals with type 2 diabetes observed between 1995 and 2007 in the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data. rLTL was measured using quantitative PCR. ESKD was diagnosed based on the ICD-9 code and eGFR. RESULTS: In this cohort (mean ± SD age 54.3 ± 12.6 years) followed up for 14.1 ± 5.3 years, 564 individuals developed incident ESKD and had shorter rLTL at baseline (4.2 ± 1.2 vs 4.7 ± 1.2, p < 0.001) than the non-progressors (n = 3521). On Cox regression analysis, each ∆∆Ct decrease in rLTL was associated with an increased risk of incident ESKD (HR 1.21 [95% CI 1.13, 1.30], p < 0.001); the association remained significant after adjusting for baseline age, sex, HbA1c, lipids, renal function and other risk factors (HR 1.11 [95% CI 1.03, 1.19], p = 0.007). Shorter rLTL at baseline was associated with rapid decline in eGFR (>4% per year) during follow-up (unadjusted OR 1.22 [95% CI 1.15, 1.30], p < 0.001; adjusted OR 1.09 [95% CI 1.01, 1.17], p = 0.024). CONCLUSIONS/INTERPRETATION: rLTL is independently associated with incident ESKD and rapid eGFR loss in individuals with type 2 diabetes. Telomere length may be a useful biomarker for the progression of kidney function and ESKD in type 2 diabetes.

High-density lipoprotein subclasses and cardiovascular disease and mortality in type 2 diabetes: analysis from the Hong Kong Diabetes Biobank.

OBJECTIVE: High-density lipoproteins (HDL) comprise particles of different size, density and composition and their vasoprotective functions may differ. Diabetes modifies the composition and function of HDL. We assessed associations of HDL size-based subclasses with incident cardiovascular disease (CVD) and mortality and their prognostic utility. RESEARCH DESIGN AND METHODS: HDL subclasses by nuclear magnetic resonance spectroscopy were determined in sera from 1991 fasted adults with type 2 diabetes (T2D) consecutively recruited from March 2014 to February 2015 in Hong Kong. HDL was divided into small, medium, large and very large subclasses. Associations (per SD increment) with outcomes were evaluated using multivariate Cox proportional hazards models. C-statistic, integrated discrimination index (IDI), and categorial and continuous net reclassification improvement (NRI) were used to assess predictive value. RESULTS: Over median (IQR) 5.2 (5.0-5.4) years, 125 participants developed incident CVD and 90 participants died. Small HDL particles (HDL-P) were inversely associated with incident CVD [hazard ratio (HR) 0.65 (95% CI 0.52, 0.81)] and all-cause mortality [0.47 (0.38, 0.59)] (false discovery rate < 0.05). Very large HDL-P were positively associated with all-cause mortality [1.75 (1.19, 2.58)]. Small HDL-P improved prediction of mortality [C-statistic 0.034 (0.013, 0.055), IDI 0.052 (0.014, 0.103), categorical NRI 0.156 (0.006, 0.252), and continuous NRI 0.571 (0.246, 0.851)] and CVD [IDI 0.017 (0.003, 0.038) and continuous NRI 0.282 (0.088, 0.486)] over the RECODe model. CONCLUSION: Small HDL-P were inversely associated with incident CVD and all-cause mortality and improved risk stratification for adverse outcomes in people with T2D. HDL-P may be used as markers for residual risk in people with T2D.

Enabling large-scale genome editing at repetitive elements by reducing DNA nicking.

To extend the frontier of genome editing and enable editing of repetitive elements of mammalian genomes, we made use of a set of dead-Cas9 base editor (dBE) variants that allow editing at tens of thousands of loci per cell by overcoming the cell death associated with DNA double-strand breaks and single-strand breaks. We used a set of gRNAs targeting repetitive elements-ranging in target copy number from about 32 to 161 000 per cell. dBEs enabled survival after large-scale base editing, allowing targeted mutations at up to ∼13 200 and ∼12 200 loci in 293T and human induced pluripotent stem cells (hiPSCs), respectively, three orders of magnitude greater than previously recorded. These dBEs can overcome current on-target mutation and toxicity barriers that prevent cell survival after large-scale genome engineering.

Large lateral tibial slope and lateral-to-medial slope difference are risk factors for poorer clinical outcomes after posterolateral meniscus root tear repair in anterior cruciate ligament reconstruction.

BACKGROUND: Meniscus root tear is an uncommon but detrimental injury of the knee. Hoop stress is lost during meniscus root tear, which can lead to excessive tibiofemoral contact pressure and early development of osteoarthritis. Posterolateral meniscus root tears (PLRT) are more commonly associated with anterior cruciate ligament (ACL) tears. As the lateral compartment is less congruent than the medial compartment, it is more susceptible to a shearing force, which is increased in the ACL-deficient knee. In accordance with the compressive axial load, the increase in the tibial slope would generate a greater shearing force. The additional lateral compartment mobility caused by ACL tear should be reduced after ACL reconstruction (ACLR). However, there is a lack of evidence to conclude that ACLR can sufficiently limit the effect of large tibial slope (LTS) on the healing after PLRT repair. This study aimed to evaluate whether a steep LTS would be a risk factor for poorer clinical outcomes after PLRT repair concomitant with ACLR. METHODS: In this retrospective study, a chart review was conducted to identify patients with concomitant unilateral primary ACLR and PLRT repair. Patients with a partial tear or healed tear were excluded. Postoperative MRI and clinical assessments were performed at a mean follow up of 35 months. MRI data was used to measure the LTS, medial tibial slope (MTS), coronal tibial slope (CTS), the lateral-to-medial slope difference (LTS-MTS) and meniscus healing and extrusion. Functional outcomes were evaluated by patient-reported outcomes (International Knee Documentation Committee [IKDC], Lysholm and Tegner scores) and KT-1000 arthrometer assessment. Interobserver reproducibility was assessed by two reviewers. RESULTS: Twenty-five patients were identified for the analysis. Patients with larger LTS and larger LTS-MTS differences were shown to be correlated with poorer IKDC scores after surgery (R = -0.472, p = 0.017 and R = -0.429, p = 0.032, respectively). Herein, patients with LTS ≥ 6° or LTS-MTS ≥ 3° demonstrated poorer IKDC scores. CONCLUSION: A large LTS (≥ 6°) and a large difference of LTS-MTS (≥ 3°) were shown to be risk factors for poorer functional and radiological outcomes for PLRT repair in patients after ACLR. Clinically, closer monitoring and a more stringent rehabilitation plan for patients with LTS ≥ 6° or LTS-MTS ≥ 3° would be recommended.

MRI of the Carpal Tunnel 3 and 12 Months After Endoscopic Carpal Tunnel Release.

OBJECTIVE. The purpose of this study was to study changes in the median nerve, retinaculum, and carpal tunnel on MRI after successful endoscopic carpal tunnel release (ECTR). SUBJECTS AND METHODS. In this prospective study, 35 wrists in 32 patients (five men, 27 women; mean age, 56.7 ± 6.8 [SD] years) with nerve conduction test-confirmed primary carpal tunnel syndrome were evaluated from May 2013 to September 2016. Clinical scores ranging from 0 to 4 (no improvement to symptoms completely resolved) and MRI morphologic features of median nerve and carpal tunnel were evaluated at baseline and 3 and 12 months after ECTR. The paired t test was used to compare MRI parameters before and after ECTR and their relationships to clinical improvement scores. RESULTS. All patients' conditions improved after ECTR with mean clinical improvement scores of 2.94 ± 1.0 at 3 months and 3.49 ± 0.56 at 12 months. Although median nerve swelling did decrease proximally, the nerve remained swollen (> 15 mm2) and flattened in all areas, even 12 months after ECTR. Additional changes occurred in median nerve caliber-change ratio, relative signal intensity, and carpal tunnel cross-sectional area. A retinacular gap was present in 33 (94%) wrists 3 months and six (17%) wrists 12 months after ECTR, and increased retinacular bowing persisted. CONCLUSION. After ECTR, undue swelling and flattening of the median nerve persist as long as 12 months after surgery, even in patients with a good surgical outcome. One should be wary of using these MRI findings as signs of persistent neural compression. The retinaculum reforms in most patients within 12 months of surgery but with a more bowed configuration.

Repeatability of pupil size measurements with NIDEK OPD-Scan III in myopic children.

OBJECTIVE: To investigate the repeatability of pupil size measurements, determined from the NIDEK OPD-Scan III, of myopic eyes in children wearing single-vision spectacles (SVS), undergoing orthokeratology (OK) and receiving combined treatment of 0.01% atropine and orthokeratology (AOK). METHODS: A single examiner took two sets of mesopic pupil size measurements from the right eyes of 80 children (SVS:16, OK: 34, AOK: 30) (mesopic 1 and mesopic 2) and two sets of photopic (photopic 1 and photopic 2) pupil size measurements (internal light source) using the NIDEK OPD-Scan III. Each set was taken at a single visit, 15 min apart. Subjects in the OK and AOK groups had undergone treatment for at least 6 months, and the SVS subjects had no previous myopia treatment other than wearing spectacles. Repeatability of measurements was analysed using intraclass correlation coefficient (ICC), Bland-Altman (BA) plot, and coefficient of repeatability (CoR). RESULTS: Mesopic 1 and 2 values were not significantly different among the three groups (p = 0.56, 0.77), hence the data were pooled for each set of measurements (mean [±S.D.] values were 7.09 ± 0.61 and 7.12 ± 0.61 mm, respectively) for further analyses. ICC for repeated mesopic pupil size measurements was 0.98 (95% CI, 0.98-0.99). No significant correlation was found between the means of the mesopic 1 and 2 measurements and their differences (Pearson's r = -0.02, p = 0.83). A BA plot also demonstrated narrow 95% limits of agreement, with a CoR of 0.28 mm. Mean photopic 1 and 2 measurements for the AOK group (3.74 ± 0.46; 3.73 ± 0.43 mm, respectively) were significantly larger (p = 0.01; 0.009) than those of the SVS and OK groups, but no significant difference was found between the latter two groups (p > 0.05). Hence, photopic 1 and 2 measurements for the SVS and OK groups were pooled (SVS-OK) for further analyses. ICC for repeatability of the photopic measurements was 0.98 (95% CI, 0.96 to 0.99) for the SVS-OK and AOK groups. The differences between photopic 1 and 2 measurements were not significantly correlated with their means, either in the AOK group (Pearson's r = -0.25, p = 0.19), or in the pooled SVS-OK group (Pearson's r = -0.04, p = 0.78). BA plots also showed narrow 95% limits of agreement, and CoR was 0.25 mm and 0.23 mm in the AOK and pooled SVS-OK groups, respectively. CONCLUSION: Mesopic and photopic pupil size measurement using the NIDEK OPD-Scan III was highly repeatable and suitable for use on children.

Circulating branched-chain amino acids and incident heart failure in type 2 diabetes: The Hong Kong Diabetes Register.

AIM: Levels of branched-chain amino acids (BCAAs, namely, isoleucine, leucine, and valine) are modulated by dietary intake and metabolic/genetic factors. BCAAs are associated with insulin resistance and increased risk of type 2 diabetes (T2D). Although insulin resistance predicts heart failure (HF), the relationship between BCAAs and HF in T2D remains unknown. METHODS: In this prospective observational study, we measured BCAAs in fasting serum samples collected at inception from 2139 T2D patients free of cardiovascular-renal diseases. The study outcome was the first hospitalization for HF. RESULTS: During 29 103 person-years of follow-up, 115 primary events occurred (age: 54.8 ± 11.2 years, 48.2% men, median [interquartile range] diabetes duration: 5 years [1-10]). Patients with incident HF had 5.6% higher serum BCAAs than those without HF (median 639.3 [561.3-756.3] vs 605.2 [524.8-708.7] µmol/L; P = .01). Serum BCAAs had a positive linear association with incident HF (per-SD increase in logarithmically transformed BCAAs: hazard ratio [HR] 1.22 [95% CI 1.07-1.39]), adjusting for age, sex, and diabetes duration. The HR remained significant after sequential adjustment of risk factors including incident coronary heart disease (1.24, 1.09-1.41); blood pressure, low-density lipoprotein cholesterol, and baseline use of related medications (1.31, 1.14-1.50); HbA1c , waist circumference, triglyceride, and baseline use of related medications (1.28, 1.11-1.48); albuminuria and estimated glomerular filtration rate (1.28, 1.11-1.48). The competing risk of death analyses showed similar results. CONCLUSIONS: Circulating levels of BCAAs are independently associated with incident HF in patients with T2D. Prospective cohort analysis and randomized trials are needed to evaluate the long-term safety and efficacy of using different interventions to optimize BCAAs levels in these patients.

Accuracy of ultrasound in the characterisation of deep soft tissue masses: a prospective study.

PURPOSE: To investigate the accuracy of ultrasound in characterising the type of mass and likelihood of malignancy in deep soft tissue masses. METHODS: Five hundred seventy-nine deep soft tissue masses were prospectively studied by ultrasound. Masses (n = 137) with prior MRI or CT were not included. Following ultrasound examination, the likely nature of the mass as well as the confidence of the reporting radiologist ('fully confident' versus 'not fully confident') about the ultrasound diagnosis was recorded. Clinical and ultrasound diagnoses were compared with the histological diagnosis which was available in 134 (23%) of the 579 masses. RESULTS: Compared with histology, clinical and ultrasound accuracy for characterising the type of mass were 47% and 88% respectively when all differential diagnoses were considered. The radiologist was fully confident regarding the type of 436 (75%) of 579 masses and, in this setting, for those cases that could be compared with histology, diagnostic accuracy was 96%. For the remaining masses, where the radiologist was not fully confident, accuracy compared with histology was 58% for the first differential diagnosis and 80% for all differential diagnoses. For identifying malignancy, sensitivity, specificity, and positive and negative predictive value of ultrasound were 97%, 58%, 67%, and 99% respectively. Ultrasound alone was considered sufficient for diagnostic workup in over half of all deep soft tissue masses. CONCLUSION: Ultrasound is useful at characterising and recognising malignancy in deep soft tissue masses. Provided local practice patterns are favourable, ultrasound may be considered a first-line investigation in the diagnostic workup of deep soft tissue masses. KEY POINTS: • In three-quarters of cases, one can be fully confident about characterising the nature of deep soft tissue masses on ultrasound and, for those fully confident cases that could be compared with histology, the diagnostic accuracy of ultrasound was 96%. • Ultrasound can correctly recognise nearly all malignant deep soft tissue masses but some benign masses will also be considered possibly malignant. • Ultrasound alone was considered sufficient for imaging workup in over half of deep soft tissue masses.

Sociodemographic, behavioral, and medical risk factors associated with visual impairment among older adults: a community-based pilot survey in Southern District of Hong Kong.

BACKGROUND: The last visual survey of older adults in Hong Kong was a district-level study in 2002, with no assessment of behavioral and medical risk factors for visual impairment (VI). Our objectives were to determine the latest VI prevalence among older adults, significance of any spatial and temporal differences on the prevalence, and any associations of sociodemographic, behavioral and medical risk factors with VI from a multi-perspective analysis. METHODS: Community-based pilot survey of residents from a suburb of Hong Kong, aged ≥50, using a standardized questionnaire, was conducted in 2016. RESULTS: Of the 222 subjects, crude rates of bilateral and unilateral VI were 9.46 and 32.88%, respectively, or corresponding age-and-gender-adjusted rates of 6.89 and 30.5%. Older age and lower educational were associated with higher risk for unilateral VI, while older age, temporary housing, obesity and hyperlipidemia were associated with higher risk for bilateral VI. Smoking and alcohol-drinking status were not associated with unilateral or bilateral VI. Relative changes in ORs of hypertension or educational level on unilateral or bilateral VI were >  10% after adjusting for age. Interaction term between hyperlipidemia and gender or obesity was significant for unilateral VI. Gender, hypertension and cataract were not associated with unilateral or bilateral VI in general population of pooled analysis but were identified as risk factors in specific subgroups of stratified analysis. Refractive error (myopia or hyperopia) was significantly associated with VI in the eye-level analysis after adjusting the inter-eye correlation. CONCLUSIONS: Sociodemographic and medical risk factors contributed to VI, but behavioral risk factors did not. Sociodemographic disparities of visual health existed. Age was the confounders of the VI-hypertension or VI-educational level relationships. Gender and obesity were more likely to have multiplicative effect on unilateral VI when combined with hyperlipidemia. Stratified analysis should be conducted to provide further insight into the risk factors for VI in specific populations. Uncorrected refractive error remains a significant cause of impaired vision. The spatial and temporal differences in bilateral VI prevalence from the previous local study indicates a territory-wide survey is needed to assess regional differences and overall prevalence of VI in Hong Kong.

One-year results of 0.01% atropine with orthokeratology (AOK) study: a randomised clinical trial.

PURPOSE: To report the 1-year results of an investigation into whether there is an additive effect between 0.01% atropine and orthokeratology (ortho-k), in a single-masked, two-arm, randomised controlled trial: Combined Atropine with Orthokeratology (AOK) for myopia control study (ClinicalTrials.gov number: NCT02955927). METHODS: Chinese children aged between 6 and 11 years with 1.00-4.00 D of myopia, astigmatism <2.50 D, and no more than 1.00 D anisometropia, were randomly assigned either to an AOK group or ortho-k only (OK) group at a 1:1 ratio. Subjects in the AOK group instilled one drop of 0.01% atropine into each eye, 10 min before nightly wear of ortho-k lenses. The primary outcome, axial elongation, was examined at 6-monthly intervals, along with secondary outcomes including best-corrected visual acuity (BCVA), manifest refraction, accommodation, pupil size, and corneal topography. RESULTS: 29 AOK and 30 OK subjects completed the 1-year visit. The overall axial elongation rate was significantly slower in the AOK group than in the OK group (mean (S.D.), 0.07 (0.16) mm vs 0.16 (0.15) mm, respectively; p = 0.03). A significant between-group difference in axial elongation was observed over the first 6-month period only (p < 0.001), but not over the second period (p = 0.818). At the 1-year visit, increases in mean (S.D.) mesopic and photopic pupil sizes in the AOK group were 0.64 (0.48) mm and 0.36 (0.34) mm, respectively, which were significantly higher than 0.10 (0.50) mm and 0.02 (0.28) mm in the OK group (p < 0.001). At the 6-month visit, a significant moderate negative correlation was found between axial elongation and the increase in photopic pupil size (r = -0.42, p = 0.02) in the AOK group. CONCLUSIONS: There is an additive effect between 0.01% atropine and ortho-k over one year, with mean axial elongation in the AOK group 0.09 mm slower than that in the OK group. It appears that the additive effect was only during the first six months; a second-year investigation is warranted to determine whether the effect is sustained over time.

Higher order aberrations and axial elongation in combined 0.01% atropine with orthokeratology for myopia control.

PURPOSE: To compare the changes in higher order aberrations (HOA's) for photopic and mesopic pupil diameters in children undergoing orthokeratology treatment (OK) or combined 0.01% atropine with orthokeratology treatment (AOK), and their association with axial elongation. METHODS: Children aged 6 to <11 years with 1.00-4.00 D of myopia were randomly assigned to each treatment group. Photopic and mesopic pupil diameters were quantified using automated pupillometry and HOA's were measured with a Hartmann-Shack aberrometer and Badal system to control for accommodation. HOA's were rescaled to photopic and mesopic pupil diameters and fitted with a 6th order Zernike polynomial expansion. Axial length was measured using an optical biometer under cycloplegia. RESULTS: Baseline and six-month data from 25 AOK and 28 OK participants were analysed. At the six-month visit, pupil diameter was larger in the AOK group under photopic conditions (3.70 ± 0.42 vs 3.12 ± 0.33 mm, p < 0.001), along with a range of HOA metrics [3rd to 6th order and higher order root mean square error values (HO RMS), all p ≤ 0.003] and individual Zernike terms (primary spherical aberration, and oblique quadrafoil, both p ≤ 0.03). Axial elongation was greater in the OK treatment group (0.05 ± 0.08 vs -0.01 ± 0.12 mm, p = 0.02). In the AOK group, axial elongation was correlated with the increase in photopic pupil diameter (r = -0.45, p = 0.02) and with several HOA metrics; however, these associations were not observed in the OK group. CONCLUSION: AOK treatment resulted in increased photopic pupil size and HOA's, and significantly less axial elongation over a six-month period compared to OK treatment alone. The improved myopia control observed with combination 0.01% atropine and orthokeratology may be a result of an enhanced optical effect due to a larger photopic pupil size.

Accuracy of ultrasound in the characterization of superficial soft tissue tumors: a prospective study.

OBJECTIVE: To prospectively evaluate the accuracy of ultrasound in defining the specific nature of superficial soft tissue masses as well as determining malignancy. MATERIALS AND METHOD: Eight hundred twenty-three superficial soft tissue masses were prospectively evaluated with ultrasound by one of five experienced musculoskeletal radiologists. The radiologist at the time of examination provided one to three specific differential diagnoses and the perceived level of confidence with regard to each diagnosis. Clinical and ultrasound diagnoses were compared with the histological diagnosis to determine accuracy. Tumor malignancy was determined by histology or clinical/imaging follow-up. RESULTS: Histological correlation was present for 219 (26.6%) of the 823 masses. Compared with histology, the accuracy of clinical and ultrasound examination for determining specific tumor type was 25.6% and 81.2% respectively considering all differential diagnoses provided. Radiologists were "fully confident" with the ultrasound diagnosis in 585 (71.1%) of 823 masses overall. In this setting, when compared with histology, the diagnostic accuracy of ultrasound was 95.5%. When the radiologist was "not fully confident," accuracy was 41.3% for the first differential diagnosis and 60.9% for all differential diagnoses. Diagnostic accuracy improved with increasing radiologist experience. Sensitivity, specificity, positive predictive value, and negative predictive value of ultrasound for identifying malignant tumor were 93.3%, 97.9%, 45.2%, and 99.9% respectively. CONCLUSIONS: One can be "fully confident" at characterizing over two-thirds of superficial soft tissue masses based on ultrasound appearances and, in this setting, diagnostic accuracy is very high. Ultrasound examination is also highly accurate at discriminating benign from malignant superficial soft tissue masses.

MRI criteria for diagnosis and predicting severity of carpal tunnel syndrome.

OBJECTIVE: To study MRI criteria for diagnosing and predicting severity of carpal tunnel syndrome (CTS). METHODS: Sixty-nine wrists in 41 symptomatic CTS patients and 32 wrists in 28 asymptomatic subjects were evaluated by MRI. Circumferential surface area (CSA), flattening ratio, relative median nerve signal intensity, and retinacular bowing were measured. CTS severity was classified as mild, moderate, or severe. Parameters for patients with and without CTS and for the three severity groups were compared. ROC curves were plotted to assess accuracy for CTS diagnosis and severity prediction. RESULTS: Significant differences were found between CTS and control wrists for median nerve CSA, flattening ratio at inlet, relative median nerve signal intensity, and retinacular bowing. ROC curve analysis revealed a sensitivity, specificity, and accuracy of median nerve CSA > 15 mm2 proximal to the tunnel (CSAp) of 85.5, 100, and 90.1%. Using either CSAp or CSAd > 15 mm2 as a diagnostic criterion, MRI could achieve a sensitivity of 100% and specificity of 94% for diagnosis of CTS while overall accuracy was 98%. Significant differences were found among the three severity groups. Sensitivity, specificity, and accuracy of prediction of severe CTS using for CSAp > 19 mm2 were 75.0, 65.9, and 69.6%, respectively. CONCLUSIONS: MRI is highly accurate at diagnosing CTS and moderately accurate at determining CTS severity. We recommend using CSA > 15 mm2 either proximal to or distal to the tunnel as a diagnostic criterion for CTS and CSA > 19 mm2 proximal to the tunnel as a marker for severe CTS.

A Review on Evidence-Based Treatments for Meibomian Gland Dysfunction.

OBJECTIVES: To evaluate recent studies on available therapies for meibomian gland dysfunction (MGD). METHODS: A literature search on recent publications, within the last five years, concerning treatment options for MGD was performed. RESULTS: A total of 35 articles were reviewed after curation by the authors for relevance. In general, all modalities of treatments were shown to have clinical efficacy in alleviating dry eye signs and symptoms, although the extent of improvement and persistency of outcomes varied between the different treatments. Evidence from published studies demonstrate that thermal pulsation produces the longest lasting effect per treatment, but it also incurs the highest per-treatment cost. Reusable methods for warm compress with lipid/semi-fluorinated alkane-containing eye drops are recommended as first-line treatment for mild-to-moderate dry eye patients, because this option is most technically feasible and cost-effective in clinical practice. Intense pulsed light (IPL) therapy and thermal pulsation may be suitable as second line for patients unresponsive to warm compress therapy; however, their respective limitations need to be considered. For refractory MGD with features of periductal fibrosis or severe blepharitis, supplementary treatment with meibomian gland probing or oral antibiotics may be used. CONCLUSIONS: All eight forms of treatments, including self-applied eyelid warming, thermal pulsation, IPL, MG probing, antibiotics, lipid-containing eye drops, and perfluorohexyloctane, were effective against MGD, although with varying extent of clinical improvements. A better understanding on the mechanisms of actions may guide physicians to make better treatment decisions targeting the root causes.

A Survey of Context-Aware Access Control Mechanisms for Cloud and Fog Networks: Taxonomy and Open Research Issues.

Over the last few decades, the proliferation of the Internet of Things (IoT) has produced an overwhelming flow of data and services, which has shifted the access control paradigm from a fixed desktop environment to dynamic cloud environments. Fog computing is associated with a new access control paradigm to reduce the overhead costs by moving the execution of application logic from the centre of the cloud data sources to the periphery of the IoT-oriented sensor networks. Indeed, accessing information and data resources from a variety of IoT sources has been plagued with inherent problems such as data heterogeneity, privacy, security and computational overheads. This paper presents an extensive survey of security, privacy and access control research, while highlighting several specific concerns in a wide range of contextual conditions (e.g., spatial, temporal and environmental contexts) which are gaining a lot of momentum in the area of industrial sensor and cloud networks. We present different taxonomies, such as contextual conditions and authorization models, based on the key issues in this area and discuss the existing context-sensitive access control approaches to tackle the aforementioned issues. With the aim of reducing administrative and computational overheads in the IoT sensor networks, we propose a new generation of Fog-Based Context-Aware Access Control (FB-CAAC) framework, combining the benefits of the cloud, IoT and context-aware computing; and ensuring proper access control and security at the edge of the end-devices. Our goal is not only to control context-sensitive access to data resources in the cloud, but also to move the execution of an application logic from the cloud-level to an intermediary-level where necessary, through adding computational nodes at the edge of the IoT sensor network. A discussion of some open research issues pertaining to context-sensitive access control to data resources is provided, including several real-world case studies. We conclude the paper with an in-depth analysis of the research challenges that have not been adequately addressed in the literature and highlight directions for future work that has not been well aligned with currently available research.

Progression of diabetic kidney disease and trajectory of kidney function decline in Chinese patients with Type 2 diabetes.

Diabetes is a major cause of end stage renal disease (ESRD), yet the natural history of diabetic kidney disease is not well understood. We aimed to identify patterns of estimated GFR (eGFR) trajectory and to determine the clinical and genetic factors and their associations of these different patterns with all-cause mortality in patients with type 2 diabetes. Among 6330 patients with baseline eGFR >60 ml/min per 1.73 m2 in the Hong Kong Diabetes Register, a total of 456 patients (7.2%) developed Stage 5 chronic kidney disease or ESRD over a median follow-up of 13 years (incidence rate 5.6 per 1000 person-years). Joint latent class modeling was used to identify different patterns of eGFR trajectory. Four distinct and non-linear trajectories of eGFR were identified: slow decline (84.3% of patients), curvilinear decline (6.5%), progressive decline (6.1%) and accelerated decline (3.1%). Microalbuminuria and retinopathy were associated with accelerated eGFR decline, which was itself associated with all-cause mortality (odds ratio [OR] 6.9; 95% confidence interval [CI]: 5.6-8.4 for comparison with slow eGFR decline). Of 68 candidate genetic loci evaluated, the inclusion of five loci (rs11803049, rs911119, rs1933182, rs11123170, and rs889472) improved the prediction of eGFR trajectories (net reclassification improvement 0.232; 95% CI: 0.057--0.406). Our study highlights substantial heterogeneity in the patterns of eGFR decline among patients with diabetic kidney disease, and identifies associated clinical and genetic factors that may help to identify those who are more likely to experience an accelerated decline in kidney function.