Optimal glycaemic control and the reduced risk of colorectal adenoma and cancer in patients with diabetes: a population-based cohort study.

OBJECTIVE: Whether varying degrees of glycaemic control impact colonic neoplasm risk in patients with diabetes mellitus (DM) remains uncertain. DESIGN: Patients with newly diagnosed DM were retrieved from 2005 to 2013. Optimal glycaemic control at baseline was defined as mean haemoglobin A1c (HbA1c)<7%. Outcomes of interest included colorectal cancer (CRC) and colonic adenoma development. We used propensity score (PS) matching with competing risk models to estimate subdistribution HRs (SHRs). We further analysed the combined effect of baseline and postbaseline glycaemic control based on time-weighted mean HbA1c during follow-up. RESULTS: Of 88 468 PS-matched patients with DM (mean (SD) age: 61.5 (±11.7) years; male: 47 127 (53.3%)), 1229 (1.4%) patients developed CRC during a median follow-up of 7.2 (IQR: 5.5-9.4) years. Optimal glycaemic control was associated with lower CRC risk (SHR 0.72; 95% CI 0.65 to 0.81). The beneficial effect was limited to left-sided colon (SHR 0.71; 95% CI 0.59 to 0.85) and rectum (SHR 0.71; 95% CI 0.57 to 0.89), but not right-sided colon (SHR 0.86; 95% CI 0.67 to 1.10). Setting suboptimal glycaemic control at baseline/postbaseline as a reference, a decreased CRC risk was found in optimal control at postbaseline (SHR 0.79), baseline (SHR 0.71) and both time periods (SHR 0.61). Similar associations were demonstrated using glycaemic control as a time-varying covariate (HR 0.75). A stepwise greater risk of CRC was found (Ptrend<0.001) with increasing HbA1c (SHRs 1.34, 1.30, 1.44, 1.58 for HbA1c 7.0% to <7.5%, 7.5% to <8.0%, 8.0% to <8.5% and ≥8.5%, respectively). Optimal glycaemic control was associated with a lower risk of any, non-advanced and advanced colonic adenoma (SHRs 0.73-0.87). CONCLUSION: Glycaemic control in patients with DM was independently associated with the risk of colonic adenoma and CRC development with a biological gradient.

Multicenter evaluation of the safety and efficacy of selective internal radiation therapy with yttrium-90 resin microspheres in Taiwan: data from the RESIN registry.

BACKGROUND AND AIM: The REgistry of Selective Internal radiation therapy in AsiaNs (RESIN) was a multicenter, single-arm, prospective, observational study of 90Y resin microspheres in patients with hepatocellular carcinoma (HCC) or metastatic colorectal cancer (mCRC) from Taiwan. RESIN is the first real-life clinical study of this therapy in an Asian cohort. Study objectives were to evaluate the safety and efficacy of 90Y resin microspheres. METHODS: Adults with HCC or mCRC scheduled to receive SIRT with 90Y resin microspheres were included. Primary endpoints were best overall response rate (ORR), adverse events, and changes from baseline in liver function. Secondary efficacy endpoints included overall survival (OS). RESULTS: Of 107 enrolled patients, 83 had HCC, and 24 had mCRC. ORR was 55.41% (HCC) and 33.33% (mCRC). Of 58 HCC patients with 6-month post-SIRT data, 13.79% (n = 8) had resection, transplantation, transarterial chemoembolization, or radiofrequency ablation as the result of down-staging or down-sizing of their lesions. One hundred and ten treatment emergent adverse events (TEAEs) were reported in 51 patients, and five serious adverse events (SAEs) were reported in five patients. The most frequent TEAEs were abdominal pain, nausea and decreased appetite (HCC), and abdominal pain, decreased appetite, fatigue, and vomiting (mCRC). Two deaths due to SAEs (probably related to SIRT) were reported, both in patients with extensive HCC, active hepatitis infection, and other comorbidities. Median OS was 24.07 (HCC) and 12.66 (mCRC) months. CONCLUSIONS: Safety and efficacy outcomes with the routine use of SIRT with 90Y resin microspheres in Taiwan are consistent with published data.

Poleward migration of tropical corals inhibited by future trends of seawater temperature and calcium carbonate (CaCO3) saturation.

Poleward range expansion of marine organisms is commonly attributed to anthropogenic ocean warming. However, the extent to which a single species can migrate poleward remains unclear. In this study, we used molecular data to examine the current distribution of the Pocillopora damicornis species complex in Taiwan waters and applied niche modeling to predict its potential range through the end of the 21st Century. The P. damicornis species complex is widespread across shallow, tropical and subtropical waters of the Indo-Pacific regions. Our results revealed that populations from subtropical nonreefal coral communities are P. damicornis, whose native geographical ranges are approximately between 23°N and 35°N. In contrast, those from tropical reefs are P. acuta. Our analysis of 50 environmental data layers demonstrated that the concentrations of CaCO3 polymorphs had the greatest contributions to the distributions of the two species. Future projections under intermediate shared socioeconomic pathways (SSP) 2-4.5 and very high (SSP5-8.5) scenarios of greenhouse gas emissions showed that while sea surface temperature (SST) isotherms would shift northwards, saturation isolines of two CaCO3 polymorphs, calcite (Ωcal) and aragonite (Ωarag), would shift southwards by 2100. Subsequent predictions of future suitable habitats under those conditions indicated that distinct delimitation of geographical ranges for the two species would persist, and neither would extend beyond its native geographical zones, indicating that tropical Taiwan waters are the northern limit for P. acuta. In contrast, subtropical waters are the southern limit for P. damicornis. We concluded that the decline in CaCO3 saturation would make high latitudes less inhabitable, which could be one of the boundary elements that limit poleward range expansion driven by rising SSTs and preserve the latitudinal diversity gradient (LDG) on Earth. Consequently, poleward migration of tropical reef corals to cope with warming oceans should be reevaluated.

Automated liver volumetry and hepatic steatosis quantification with magnetic resonance imaging proton density fat fraction.

BACKGROUND: Preoperative imaging evaluation of liver volume and hepatic steatosis for the donor affects transplantation outcomes. However, computed tomography (CT) for liver volumetry and magnetic resonance spectroscopy (MRS) for hepatic steatosis are time consuming. Therefore, we investigated the correlation of automated 3D-multi-echo-Dixon sequence magnetic resonance imaging (ME-Dixon MRI) and its derived proton density fat fraction (MRI-PDFF) with CT liver volumetry and MRS hepatic steatosis measurements in living liver donors. METHODS: This retrospective cross-sectional study was conducted from December 2017 to November 2022. We enrolled donors who received a dynamic CT scan and an MRI exam within 2 days. First, the CT volumetry was processed semiautomatically using commercial software, and ME-Dixon MRI volumetry was automatically measured using an embedded sequence. Next, the signal intensity of MRI-PDFF volumetric data was correlated with MRS as the gold standard. RESULTS: We included the 165 living donors. The total liver volume of ME-Dixon MRI was significantly correlated with CT (r = 0.913, p < 0.001). The fat percentage measured using MRI-PDFF revealed a strong correlation between automatic segmental volume and MRS (r = 0.705, p < 0.001). Furthermore, the hepatic steatosis group (MRS ≥5%) had a strong correlation than the non-hepatic steatosis group (MRS <5%) in both volumetric (r = 0.906 vs. r = 0.887) and fat fraction analysis (r = 0.779 vs. r = 0.338). CONCLUSION: Automated ME-Dixon MRI liver volumetry and MRI-PDFF were strongly correlated with CT liver volumetry and MRS hepatic steatosis measurements, especially in donors with hepatic steatosis.

Age-related differences in the impact of resilience on mental health outcomes during the COVID-19 pandemic in Hong Kong.

OBJECTIVE: This study investigated changes in mental health in Hong Kong over two years and examined the role of resilience and age in mitigating the negative effects of public health emergencies, particularly the COVID-19 pandemic. METHODS: Complete data of interest from two telephone surveys conducted in 2020 (n = 1182) and 2021 (n = 1108) were analysed. Participants self-reported depressive and anxiety symptoms using the Patient Health Questionnaire 4-item version (PHQ), psychotic-like experiences (PLEs) using three items from the Prodromal Questionnaire Brief (PQB), and resilience using the Connor-Davidson Resilience Scale 2-item version (CD-RISC-2). RESULTS: We observed an increase in the percentage of participants with high depressive and anxiety symptoms and PLEs from 1.6% to 6.5% between 2020 and 2021. The likelihood of having high depressive and anxiety symptoms or PLEs depended on resilience and age, with no significant between-year differences. Resilience and age interaction effects were significant when comparing the high PHQ-high PQB group to the low PHQ-low PQB group only in 2021 but not in 2020. CONCLUSIONS: This study provides valuable insights into the impact of the COVID-19 pandemic on mental health in Hong Kong, emphasising the age-dependent nature of resilience in mitigating negative effects. Future research should explore the mechanisms by which resilience promotes mental health and well-being and identify ways to enhance resilience among older individuals during public health crises.

Lower baseline testosterone level is related to earlier development of castration resistance in metastatic prostate cancer: a multi-center cohort study.

Purpose: In the era of concurrent combination therapy in metastatic hormone sensitive prostate cancer, the impact of the testosterone level before initiating androgen deprivation therapy on treatment outcome is still uncertain. We aimed to investigate its effect on time-to-castration-resistance in a metastatic hormone sensitive prostate cancer cohort. Methods: This is a multi-center retrospective study of 5 databases from China, Japan, Austria and Spain including 258 metastatic hormone sensitive prostate cancer patients with androgen deprivation therapy initiated between 2002 and 2021. Baseline testosterone was divided into high and low groups using 12 nmol/L as cutoff level. Primary outcome was time-to-castration-resistance. Secondary outcomes were survival functions. Kaplan-Meier method was employed to evaluate the correlation between baseline testosterone and time-to-castration-resistance. Subgroup analysis was performed to elucidate the effect of upfront combination-therapy and metastatic volume. Results: Median age was 72 years. Median follow-up time was 31 months. Median pre-treatment prostate-specific-antigen level was 161 ng/mL. Majority of case were graded as International-Society-of-Urological-Pathology grade 5 (63.6%). 57.8% patients had high volume disease and 69.0% received upfront combination treatment. 44.6% of the cohort developed castration-resistance. The low testosterone group demonstrated shorter mean-time-to-castration-resistance (19.0 vs 22.4 months, p=0.031). The variance was more significant in patients without combination therapy (13.2 vs 26.3 months, p=0.015). Cancer-specific and overall survival were inferior in the low baseline testosterone level group without receiving combination therapy (p=0.001). Conclusions: Lower pre-treatment testosterone level is correlated to shorter time-to-castration resistance and worse survival in metastatic prostate cancer patients without upfront combination therapy. Those with low baseline testosterone should be encouraged to adopt combination therapy to delay progression.

Access Site Complication Rates Following Peripheral Artery Revascularization in patients With End-Stage Renal Disease: A Comparison of Vascular Closure Devices and Manual Compression.

OBJECTIVES: Manual compression (MC) or vascular closure devices (VCDs) are used to achieve hemostasis after percutaneous transluminal angioplasty (PTA). However, limited data on the comparative safety and effectiveness of VCDs vs MC in patients with end-stage renal disease (ESRD) undergoing PTA are available. Accordingly, this study compared the safety and effectiveness of VCD and MC in patients with ESRD undergoing PTA. METHODS: This single-center retrospective cohort study included the data of patients with ESRD undergoing peripheral intervention at Chang Gung Memorial Hospital, Taiwan, from January 1, 2019, to June 30, 2022. The patients were divided into VCD and MC groups. The primary endpoint was a composite of puncture site complications, including acute limb ischemia, marked hematoma, pseudoaneurysm, and puncture site bleeding requiring blood transfusion. RESULTS: We included 264 patients with ESRD undergoing PTA, of whom 60 received a VCD and 204 received MC. The incidence of puncture site complications was 3.3% in the VCD group and 4.4% in the MC group (hazard ratio: .75; 95% confidence interval: .16-3.56 L P = 1.000), indicating no significant between-group difference. CONCLUSION: VCDs and MC had comparable safety and effectiveness for hemostasis in patients with ESRD undergoing peripheral intervention.

Molecular mechanisms involved in alcohol craving, IRF3, and endoplasmic reticulum stress: a multi-omics study.

Alcohol use disorder (AUD) is the most prevalent substance use disorder worldwide. Acamprosate and naltrexone are anti-craving drugs used in AUD pharmacotherapy. However, molecular mechanisms underlying their anti-craving effect remain unclear. This study utilized a patient-derived induced pluripotent stem cell (iPSC)-based model system and anti-craving drugs that are used to treat AUD as "molecular probes" to identify possible mechanisms associated with alcohol craving. We examined the pathophysiology of craving and anti-craving drugs by performing functional genomics studies using iPSC-derived astrocytes and next-generation sequencing. Specifically, RNA sequencing performed using peripheral blood mononuclear cells from AUD patients with extreme values for alcohol craving intensity prior to treatment showed that inflammation-related pathways were highly associated with alcohol cravings. We then performed a genome-wide assessment of chromatin accessibility and gene expression profiles of induced iPSC-derived astrocytes in response to ethanol or anti-craving drugs. Those experiments identified drug-dependent epigenomic signatures, with IRF3 as the most significantly enriched motif in chromatin accessible regions. Furthermore, the activation of IRF3 was associated with ethanol-induced endoplasmic reticulum (ER) stress which could be attenuated by anti-craving drugs, suggesting that ER stress attenuation might be a target for anti-craving agents. In conclusion, we found that craving intensity was associated with alcohol consumption and treatment outcomes. Our functional genomic studies suggest possible relationships among craving, ER stress, IRF3 and the actions of anti-craving drugs.

Risk factors, patterns, and outcome predictors of late recurrence in patients with hepatocellular carcinoma after curative resection: A large cohort study with long-term follow-up results.

BACKGROUND: Late recurrence of hepatocellular carcinoma after curative resection significantly influences long-term patient survival outcomes, and yet it remains understudied. This study aims to explore the risk factors and patterns of late recurrence and predictors of subsequent outcome. METHODS: This single-center retrospective study analyzed 1,701 consecutive patients who achieved a disease-free survival period exceeding 2 years after curative resection for hepatocellular carcinoma between 2001 and 2018. Univariate and multivariate analyses of factors associated with late recurrence and death after recurrence were conducted using Cox's models. RESULTS: The mean age of patients was 60.2 years, with 76.8% being male. During a median follow-up of 8.1 years, 653 patients (38.4%) experienced late recurrence, with median time to recurrence being 4.0 years (interquartile range, 2.7-6.0). Factors such as age >60, chronic hepatitis C, cirrhosis, high albumin-bilirubin grade, absence of family history, multiple tumors, satellite nodules, alpha-fetoprotein levels <400 ng/mL, and minor hepatic resection were identified as risk factors for late recurrence. Among patients with late recurrence, 131 (20.1%) underwent surgical treatment, 272 (41.7%) received radiofrequency ablation, and 27 (4.1%) exhibited extrahepatic lesions. A higher-high albumin-bilirubin grade, recurrent tumor >3 cm, and nonsurgical treatment emerged as predictors of death after late recurrence. CONCLUSION: Over one-third of patients who remain disease-free for more than 2 years postresection will experience late recurrence during subsequent follow-up. For 2-year disease-free survivors, risk factors for late recurrence differ from early recurrence. Treating underlying hepatitis is of paramount importance, given its association with both the risk of late recurrence and survival outcomes post-recurrence.

Prophylactic anti-reflux procedure for children undergoing laparoscopic gastrostomy: Rethinking of the routine practice.

AIM: Laparoscopic gastrostomy is a frequently performed procedure in children requiring long-term enteral nutrition. The role of prophylactic anti-reflux surgery during gastrostomy placements is controversial. The current study aims to evaluate the role of prophylactic anti-reflux procedures during gastrostomy placement. METHODS: A retrospective single-center analysis of all children without reflux receiving laparoscopic gastrostomy from January 2005 through December 2021 was performed. Demographics and clinical outcomes were compared between patients receiving gastrostomy placement alone and patients receiving gastrostomy with prophylactic anti-reflux surgery. RESULTS: A total of 79 patients had a confirmed absence of reflux by a 24-h pH/impedance study before operation. Thirty-six of these patients underwent prophylactic anti-reflux surgery (PAR) while 43 received gastrostomy (PG) alone. The operative time and conversion rate were significantly higher in the PAR group (140.5 ± 67.5 vs. 80.2 ± 66.8 min, p = 0.0001 and 8.3% vs. 0%, p = 0.04). There were no major complications in either group. De novo reflux was detected in five patients (11.6%) in the PG group. None of these patients progressed to require anti-reflux surgery. CONCLUSION: The occurrence of de novo reflux after laparoscopic gastrostomy was low and could be managed without anti-reflux surgery. A routine pre-operative pH study is helpful for appropriate patient selection to avoid unnecessary anti-reflux surgery, which lengthens operative time and increases the conversion rate.

Patient preference on once-daily oral versus injectable androgen deprivation therapy for Asian patients with advanced prostate cancer.

PURPOSE: The study aimed at investigating prostate cancer patients' choice of androgen deprivation treatment (ADT) and possible factors that would affect their preferences of ADT. METHODS: This was a single-centre cross-sectional study investigating the usage and preferences of ADT. Consecutives prostate cancer patients who were receiving injectable luteinizing hormone-releasing hormone (LHRH) agonist or antagonist were recruited from the prostate cancer clinic in a tertiary academic hospital. Patients who received bilateral orchidectomy or those who could not consent to the study were excluded. Disease characteristics, treatment information and patient background were documented. The survey collected information related to their change in ADT regimen, preferences on drug usage (routes and frequency of administration) and their reasons. A hypothetical set of three drug formularies was designed. Questions regarding patient preference and the contributing reasons raised in the format of questionnaire. RESULTS: 100 patients completed the survey. Most patients started with more frequent injections (3-monthly, 54%; 1-monthly, 38%) and switched to 6-monthly injections (89%) at the time of the survey. Primary reasons for the change were healthcare opinion (72%) and less frequent treatment (51%). Three options of ADT (oral daily, 1-monthly and 6-monthly injection) with the same efficacies and side effect profile were offered: 61% preferred 6-monthly injection, 1% preferred 1-monthly injection and 38% preferred oral regimen. When patients were informed of lower cardiovascular side effects in 1-monthly injection or daily oral drug, patients' preference was 56% (6-monthly), 6% (1-monthly), and 39% (oral). Patients with polypharmacy (more than 5 regular medications) were more inclined to choose injections (p = 0.025). Patient age, educational background, employment status, marriage status and disease status were not found to be statistically significant contributing factors to patient preference. CONCLUSION: 6-monthly ADT injection was the preferred ADT despite greater cardiovascular risks. Among 1-monthly or daily oral LHRH antagonist, more patients prefer oral option. Convenience factor was highly valued.

Model-Based Virtual PK/PD Exploration and Machine Learning Approach to Define PK Drivers in Early Drug Discovery.

While poor translatability of preclinical efficacy models can be responsible for clinical phase II failures, misdefinition of the optimal PK properties required to achieve therapeutic efficacy can also be a contributing factor. In the present work, the pharmacological dependency of PK end points in driving efficacy is demonstrated for six common pharmacological processes via model-based analysis. The analysis shows that the response is driven by multiple pharmacology-specific PK end points that change with how the response is defined. Moreover, the results demonstrate that the most important chemical structural features influencing response are specific to both target and downstream pharmacology, meaning the design and screening criteria must be defined uniquely for each target and corresponding pharmacology. The model-based virtual exploration of PK/PD relationships presented in this work offers one approach to identify target pharmacology-specific PK drivers and the associated potency-ADME space early in discovery to increase the probability of success and, ultimately, clinical attrition.

HBV DNA Integration into Telomerase or MLL4 Genes and TERT Promoter Point Mutation as Three Independent Signatures in Subgrouping HBV-Related HCC with Distinct Features.

Introduction: A set of genetic mutations to classify hepatocellular carcinoma (HCC) useful to clinical studies is an unmet need. Hepatitis B virus-related HCC (HBV-HCC) harbors a unique genetic mutation, namely, the HBV integration, among other somatic endogenous gene mutations. We explored a combination of HBV DNA integrations and common somatic mutations to classify HBV-HCC by using a capture-sequencing platform. Methods: A total of 153 HBV-HCCs after surgical resection were subjected to capture sequencing to identify HBV integrations and three common somatic mutations in genomes. Three mutually exclusive mutations, HBV DNA integration into the TERT promoter, HBV DNA integration into MLL4, or TERT promoter point mutation, were identified in HBV-HCC. Results: They were used to classify HBV-HCCs into four groups: G1 with HBV-TERT integration (25.5%); G2 with HBV-MLL4 integration (10.5%); G3 with TERT promoter mutation (30.1%); and G4 without these three mutations (34.0%). Clinically, G3 has the highest male-to-female ratio, cirrhosis rate, and associated with higher early recurrence and mortality after resection, but G4 has the best outcome. Transcriptomic analysis revealed a grouping different from the published ones and G2 with an active immune profile related to immune checkpoint inhibitor response. Analysis of integrated HBV DNA provided clues for HBV genotype and variants in carcinogenesis of different HCC subgroup. This new classification was also validated in another independent cohort. Conclusion: A simple and robust genetic classification was developed to aid in understanding HBV-HCC and in harmonizing clinical studies.

FastEval Parkinsonism: an instant deep learning-assisted video-based online system for Parkinsonian motor symptom evaluation.

The Motor Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is designed to assess bradykinesia, the cardinal symptoms of Parkinson's disease (PD). However, it cannot capture the all-day variability of bradykinesia outside the clinical environment. Here, we introduce FastEval Parkinsonism ( https://fastevalp.cmdm.tw/ ), a deep learning-driven video-based system, providing users to capture keypoints, estimate the severity, and summarize in a report. Leveraging 840 finger-tapping videos from 186 individuals (103 patients with Parkinson's disease (PD), 24 participants with atypical parkinsonism (APD), 12 elderly with mild parkinsonism signs (MPS), and 47 healthy controls (HCs)), we employ a dilated convolution neural network with two data augmentation techniques. Our model achieves acceptable accuracies (AAC) of 88.0% and 81.5%. The frequency-intensity (FI) value of thumb-index finger distance was indicated as a pivotal hand parameter to quantify the performance. Our model also shows the usability for multi-angle videos, tested in an external database enrolling over 300 PD patients.

Parameter-Free and Electron Counting Satisfied Material Representation for Machine Learning Potential Energy and Force Fields.

We proposed a parameter-free volume element representation that satisfies the electron counting model and obtains accurate machine learning potential energy and direct force fitting of randomly perturbed hexagonal BN. Our method preserves permutational, translational, and rotational invariance and can be extended to three-dimensional systems, verified by a system of bulk Si. As a result, we obtained 0.57 meV/atom potential energy root mean squared error (RMSE) and 59 meV/Å force RMSE for perturbed bulk BN systems and 0.43 meV/atom potential energy RMSE and 36 meV/Å force RMSE for perturbed Si systems. In addition, an unbiased perturbation-based data set construction scheme is introduced and a continuous population distribution is obtained with a training data set of 4500, which is about 1 order of magnitude smaller than standard methods based on first-principles molecular dynamics simulations and saves a large amount of computing resources. General validity of our model is verified by structure optimization, molecular dynamics simulations, and extrapolations.

Human liver afferent and efferent nerves revealed by 3-D/Airyscan super-resolution imaging.

Neural regulation of hepatic metabolism has long been recognized. However, the detailed afferent and efferent innervation of the human liver has not been systematically characterized. This is largely due to the liver's high lipid and pigment contents, causing false-negative (light scattering and absorption) and false-positive (autofluorescence) results in in-depth fluorescence imaging. Here, to avoid the artifacts in three-dimensional (3-D) liver neurohistology, we embed the bleached human liver in the high-refractive-index polymer for tissue clearing and antifade 3-D/Airyscan super-resolution imaging. Importantly, using the paired substance P (SP, sensory marker) and PGP9.5 (pan-neuronal marker) labeling, we detect the sensory nerves in the portal space, featuring the SP+ varicosities in the PGP9.5+ nerve bundles/fibers, confirming the afferent liver innervation. Also, using the tyrosine hydroxylase (TH, sympathetic marker) labeling, we identify 1) condensed TH+ sympathetic nerves in the portal space, 2) extension of sympathetic nerves from the portal to the intralobular space, in which the TH+ nerve density is 2.6 ± 0.7-fold higher than that of the intralobular space in the human pancreas, and 3) the TH+ nerve fibers and varicosities contacting the ballooning cells, implicating potential sympathetic influence on hepatocytes with macrovesicular fatty change. Finally, using the vesicular acetylcholine transporter (VAChT, parasympathetic marker), PGP9.5, and CK19 (epithelial marker) labeling with panoramic-to-Airyscan super-resolution imaging, we detect and confirm the parasympathetic innervation of the septal bile duct. Overall, our labeling and 3-D/Airyscan imaging approach reveal the hepatic sensory (afferent) and sympathetic and parasympathetic (efferent) innervation, establishing a clinically related setting for high-resolution 3-D liver neurohistology.NEW & NOTEWORTHY We embed the human liver (vs. pancreas, positive control) in the high-refractive-index polymer for tissue clearing and antifade 3-D/Airyscan super-resolution neurohistology. The pancreas-liver comparison reveals: 1) sensory nerves in the hepatoportal space; 2) intralobular sympathetic innervation, including the nerve fibers and varicosities contacting the ballooning hepatocytes; and 3) parasympathetic innervation of the septal bile duct. Our results highlight the sensitivity and resolving power of 3-D/Airyscan super-resolution imaging in human liver neurohistology.

Role of overnight oximetry in assessing the severity of obstructive sleep apnoea in typically developing children: a multicentre study.

BACKGROUND AND OBJECTIVE: Cardiorespiratory polygraphy (CRP) is the predominant technology used to diagnose obstructive sleep apnoea (OSA) in tertiary centres in the UK. Nocturnal pulse oximetry (NPO) is, however, cheaper and more accessible. This study evaluated the ability of NPO indices to predict OSA in typically developing (TD) children. METHODS: Indices from simultaneous NPO and CRP recordings were compared in TD children (aged 1-16 years) referred to evaluate OSA in three tertiary centres. OSA was defined as an obstructive apnoea-hypopnoea index (OAHI) ≥1 event/hour. Receiver operating characteristic curves assessed the diagnostic accuracy of NPO indices including ODI3 (3% Oxygen Desaturation Index, ODI4 (4% Oxygen Desaturation Index), delta 12 s index and minimum oxygen saturation. Two-by-two tables were generated to determine the sensitivities and specificities of whole number cut-off values for predicting OAHIs ≥1, 5 and 10 events/hour. RESULTS: Recordings from 322 TD children, 197 male (61.2%), median age 4.9 years (range 1.1-15.6), were reviewed. OAHI was ≥1/hour in 144 (44.7%), ≥5/hour in 61 (18.9%) and ≥10/hour in 28 (8.7%) cases. ODI3 and ODI4 had the best diagnostic accuracy. ODI3 ≥7/hour and ODI4 ≥4/hour predicted OSA in TD children with sensitivities/specificities of 57.6%/85.4% and 46.2%/91.6%, respectively. ODI3 ≥8/hour was the best predictor of OAHI ≥5/hour (sensitivity 82.0%, specificity 84.3%). CONCLUSION: Raised ODI3 and ODI4 predict OSA in TD children with high specificity but variable sensitivity. NPO may be an alternative to diagnose moderate-severe OSA if access to CRP is limited. Low sensitivities to detect mild OSA mean that confirmatory CRP is needed if NPO is normal.

Development of an individualized risk calculator of treatment resistance in patients with first-episode psychosis (TRipCal) using automated machine learning: a 12-year follow-up study with clozapine prescription as a proxy indicator.

About 15-40% of patients with schizophrenia are treatment resistance (TR) and require clozapine. Identifying individuals who have higher risk of development of TR early in the course of illness is important to provide personalized intervention. A total of 1400 patients with FEP enrolled in the early intervention for psychosis service or receiving the standard psychiatric service between July 1, 1998, and June 30, 2003, for the first time were included. Clozapine prescriptions until June 2015, as a proxy of TR, were obtained. Premorbid information, baseline characteristics, and monthly clinical information were retrieved systematically from the electronic clinical management system (CMS). Training and testing samples were established with random subsampling. An automated machine learning (autoML) approach was used to optimize the ML algorithm and hyperparameters selection to establish four probabilistic classification models (baseline, 12-month, 24-month, and 36-month information) of TR development. This study found 191 FEP patients (13.7%) who had ever been prescribed clozapine over the follow-up periods. The ML pipelines identified with autoML had an area under the receiver operating characteristic curve ranging from 0.676 (baseline information) to 0.774 (36-month information) in predicting future TR. Features of baseline information, including schizophrenia diagnosis and age of onset, and longitudinal clinical information including symptoms variability, relapse, and use of antipsychotics and anticholinergic medications were important predictors and were included in the risk calculator. The risk calculator for future TR development in FEP patients (TRipCal) developed in this study could support the continuous development of data-driven clinical tools to assist personalized interventions to prevent or postpone TR development in the early course of illness and reduce delay in clozapine initiation.

Left Atrial Strain Predicts Cardiovascular and All-Cause Mortality.

Background: Left atrial strain can usefully reflect left atrial function. The follow-up periods in previous studies assessing left atrial strain as a survival predictor have been relatively short, and few studies have examined the ability of left atrial strain to predict mortality in patients with borderline diastolic function. This study sought to investigate the survival predictive value of left atrial strain with a longer follow-up duration. In addition, we also evaluated the survival predictive value of left atrial strain in patients with borderline diastolic function. Methods: In total, 652 participants who received routine echocardiography underwent 2-D speckle tracking echocardiography to evaluate left atrial reservoir function by peak atrial longitudinal strain. The study endpoints were all-cause and cardiovascular mortality. Results: The mean left atrial strain was 27.6%, and the median follow-up duration was 92 months. During follow-up, 72 patients died of cardiovascular causes and 181 died of all causes. Univariable Cox regression analysis revealed that lower left atrial strain significantly predicted an increase in all-cause and cardiovascular mortality. After adjusting for common clinical and echocardiographic parameters, lower left atrial strain was still associated with a higher risk of all-cause mortality [hazard ratio (HR) = 0.942, p = 0.011] and cardiovascular mortality (HR = 0.915, p = 0.018) in multivariable Cox-regression analysis. In addition, 293 patients had borderline left ventricular diastolic function. Multivariable analysis still revealed that left atrial strain could predict cardiovascular mortality in this population. Conclusions: Our data showed that left atrial strain could predict all-cause and cardiovascular mortality, even after adjusting for general clinical and echocardiographic parameters.

Potential PCR amplification bias in identifying complex ecological patterns: Higher species compositional homogeneity revealed in smaller-size coral reef zooplankton by metatranscriptomics.

PCR-based high-throughput sequencing has permitted comprehensive resolution analyses of zooplankton diversity dynamics. However, significant methodological issues still surround analyses of complex bulk community samples, not least as in prevailing PCR-based approaches. Marine drifting animals-zooplankton-play essential ecological roles in the pelagic ecosystem, transferring energy and elements to higher trophic levels, such as fishes, cetaceans and others. In the present study, we collected 48 size-fractionated zooplankton samples in the vicinity of a coral reef island with environmental gradients. To investigate the spatiotemporal dynamics of zooplankton diversity patterns and the effect of PCR amplification biases across these complex communities, we first took metatranscriptomics approach. Comprehensive computational analyses revealed a clear pattern of higher/lower homogeneity in smaller/larger zooplankton compositions across samples respectively. Our study thus suggests changes in the role of dispersal across the sizes. Next, we applied in silico PCR to the metatranscriptomics datasets, in order to estimate the extent of PCR amplification bias. Irrespective of stringency criteria, we observed clear separations of size fraction sample clusters in both metatranscriptomics and in silico datasets. In contrast, the pattern-smaller-fractioned communities had higher compositional homogeneity than larger ones-was observed in the metatranscriptomics data but not in the in silico datasets. To investigate this discrepancy further, we analysed the mismatches of widely used mitochondrial CO1 primers and identified priming site mismatches likely driving PCR-based biases. Our results suggest the use of metatranscriptomics or, although less ideal, redesigning the CO1 primers is necessary to circumvent these issues.