Explore the vast range of titles available.

Some patients treated with nirmatrelvir-ritonavir have experienced rebound of COVID-19 infections and symptoms; however, data are scarce on whether viral rebound also occurs in patients with COVID-19 receiving or not receiving molnupiravir. To examine the incidence of viral rebound in patients with COVID-19 who were treated with the oral antiviral agents nirmatrelvir-ritonavir and molnupiravir. This cohort study identified 41 255 patients with COVID-19 who were hospitalized from January 1, 2022, to March 31, 2022, in Hong Kong and assessed 12 629 patients with serial cycle threshold (Ct) values measured. Patients were followed up until the occurrence of the clinical end point of interest, death, date of data retrieval (July 31, 2022), or up to 30 days of follow-up, whichever came first. Molnupiravir or nirmatrelvir-ritonavir treatment. Viral rebound, defined as a Ct value greater than 40 that decreased to 40 or less. Of 12 629 patients (mean [SD] age, 65.4 [20.9] years; 6624 [52.5%] male), 11 688 (92.5%) were oral antiviral nonusers, 746 (5.9%) were molnupiravir users, and 195 (1.5%) were nirmatrelvir-ritonavir users. Compared with nonusers, oral antiviral users were older, had more comorbidities, and had lower complete vaccination rates. The mean (SD) baseline Ct value was slightly higher in nirmatrelvir-ritonavir users (22.2 [6.0]) than nonusers (21.0 [5.4]) and molnupiravir users (20.9 [5.4]) (P = .04). Viral rebound occurred in 68 nonusers (0.6%), 2 nirmatrelvir-ritonavir users (1.0%), and 6 molnupiravir users (0.8%). Among 76 patients with viral rebound, 12 of 68 nonusers, 1 of 6 molnupiravir users, and neither of the nirmatrelvir-ritonavir users died of COVID-19. In this cohort study, viral rebound was uncommon in patients taking molnupiravir or nirmatrelvir-ritonavir and was not associated with increased risk of mortality. Given these findings, novel oral antivirals should be considered as a treatment for more patients with COVID-19 in the early phase of the infection.

Background Bacterial infections are not prevalent among patients hospitalized with COVID-19, while unnecessary prescription of antibiotics was commonly observed. This study aimed to determine the impact of procalcitonin testing on antibiotics prescription in the real-world setting. Methods We performed a territory-wide retrospective cohort study involving all laboratory-confirmed patients hospitalized in public hospitals in Hong Kong in 2020 with COVID-19. We determined the prevalence of bacterial co-infections (documented infections within 72 h of admission) and secondary bacterial infections (infections after 72 h of admission) and antibiotics consumption, and the correlation between procalcitonin testing and antibiotics prescription. Results The cohort included 8666 patients, with mean age 45.3 ± 19.9 years, 48.5% male, and comorbidities in 26.9%. Among 2688 patients with bacterial cultures performed, 147 (5.5%) had bacterial co-infections, and 222 (8.3%) had secondary bacterial infections. Antibiotics were prescribed for 2773 (32.0%) patients during the hospital admission. Procalcitonin tests were performed for 2543 (29.3%) patients. More patients with procalcitonin testing received antibiotics (65.9% vs. 17.9%, p < 0.001). Procalcitonin testing was associated with 5-fold increased risk of antibiotics prescription after adjusting for confounding variables. At hospital level, procalcitonin testing correlated with antibiotics prescription. Patients with procalcitonin level < 0.5 ng/mL had a lower probability of antibiotics initiation and shorter duration of antibiotics therapy. Conclusions Procalcitonin testing was not associated with lower prescription of antibiotics. Patients with low procalcitonin level had lower antibiotics exposure, supporting the use of procalcitonin to exclude bacterial infections aiding early stopping of antibiotics among patients hospitalized with COVID-19.

The ability to modulate the efficacy of synaptic communication between neurons constitutes an essential property critical for normal brain function. Animal models have proved invaluable in revealing a wealth of diverse cellular mechanisms underlying varied plasticity modes. However, to what extent these processes are mirrored in humans is largely uncharted thus questioning their relevance in human circuit function. In this study, we focus on neurogliaform cells, that possess specialized physiological features enabling them to impart a widespread inhibitory influence on neural activity. We demonstrate that this prominent neuronal subtype, embedded in both mouse and human neural circuits, undergo remarkably similar activity-dependent modulation manifesting as epochs of enhanced intrinsic excitability. In principle, these evolutionary conserved plasticity routes likely tune the extent of neurogliaform cell mediated inhibition thus constituting canonical circuit mechanisms underlying human cognitive processing and behavior.

In violation of Dale’s principle several neuronal subtypes utilize more than one classical neurotransmitter. Molecular identification of vesicular glutamate transporter three and cholecystokinin expressing cortical interneurons (CCK+VGluT3+INTs) has prompted speculation of GABA/glutamate corelease from these cells for almost two decades despite a lack of direct evidence. We unequivocally demonstrate CCK+VGluT3+INT-mediated GABA/glutamate cotransmission onto principal cells in adult mice using paired recording and optogenetic approaches. Although under normal conditions, GABAergic inhibition dominates CCK+VGluT3+INT signaling, glutamatergic signaling becomes predominant when glutamate decarboxylase (GAD) function is compromised. CCK+VGluT3+INTs exhibit surprising anatomical diversity comprising subsets of all known dendrite targeting CCK+ interneurons in addition to the expected basket cells, and their extensive circuit innervation profoundly dampens circuit excitability under normal conditions. However, in contexts where the glutamatergic phenotype of CCK+VGluT3+INTs is amplified, they promote paradoxical network hyperexcitability which may be relevant to disorders involving GAD dysfunction such as schizophrenia or vitamin B6 deficiency.

Projections from auditory cortex to the amygdala are thought to contribute to the induction of auditory fear learning. In addition, fear conditioning has been found to enhance cortical responses to conditioned tones, suggesting that cortical plasticity contributes to fear learning. However, the functional role of auditory cortex in the retrieval of fear memories is unclear and how fear learning regulates cortical sensory representations is not well understood. To address these questions, we use acute optogenetic silencing and chronic two-photon calcium imaging in mouse auditory cortex during fear learning. Longitudinal imaging of neuronal ensemble activity reveals that discriminative fear learning modulates cortical sensory representations via the suppression of cortical habituation.

This article reviews state-of-the-art microfluidic biosensors of nucleic acids and proteins for point-of-care (POC) diagnostics. Microfluidics is capable of analyzing small sample volumes (10 −9 –10 −18  l) and minimizing costly reagent consumption as well as automating sample preparation and reducing processing time. The merger of microfluidics and advanced biosensor technologies offers new promises for POC diagnostics, including high-throughput analysis, portability and disposability. However, this merger also imposes technological challenges on biosensors, such as high sensitivity and selectivity requirements with sample volumes orders of magnitude smaller than those of conventional practices, false response errors due to non-specific adsorption, and integrability with other necessary modules. There have been many prior review articles on microfluidic-based biosensors, and this review focuses on the recent progress in last 5 years. Herein, we review general technologies of DNA and protein biosensors. Then, recent advances on the coupling of the biosensors to microfluidics are highlighted. Finally, we discuss the key challenges and potential solutions for transforming microfluidic biosensors into POC diagnostic applications.

BackgroundTo develop innovative risk models for predicting liver-related events including hepatic decompensation and hepatocellular carcinoma in patients with metabolic dysfunction-associated steatotic liver disease (MASLD).MethodsThe training cohort included adult patients with MASLD from a territory-wide database in Hong Kong between January 2000 and July 2021. Five modern domain adaptation (DA) methods on fully connected neural networks were evaluated using the area under the time-dependent receiver operating characteristic curves (AUROCs) and compared with the FIB-4 index, NAFLD outcomes score (NOS), and a Fine-Gray model. The validation cohort comprised adult patients with type 2 diabetes (T2D) and probable MASLD, identified using previously developed NAFLD ridge score. We excluded patients with liver-related events before MASLD diagnosis or follow-up <6 months. This study was supported by the Health and Medical Research Fund (Reference number: 19202141).ResultsAmong 25,166 patients with MASLD in the training cohort (mean age 56.9 years, 54.3% females, 0.7% cirrhosis), 272 (1.1%) developed liver-related events during 133,816 person-years (PYs). During 4,386,544 PYs among 411,395 patients in the validation cohort (mean age 61.8 years, 49.3% females, 0.4% cirrhosis), 5,984 (1.5%) developed liver-related events. Among the five DA methods, maximum classifier discrepancy (MCD) (AUROC [95% CI] 0.822 [0.814-0.829]) and confidence regularised self-training (CRST) (0.825 [0.817-0.832]) performed best in validation (IDDF2024-ABS-0124 Figure 1). The AUROC of the Fine-Gray model decreased from 0.804 in training to 0.681 in validation, demonstrating the advantage of DA in preserving model accuracy in a less definite MASLD population. Similarly, the AUROC of NOS and FIB-4 dropped to 0.649 and 0.645 in validation. Among the 19 factors, including common laboratory tests, comorbidities, and demographics in MCD and CRST, the eight leading factors were cirrhosis, diabetes, platelets, aspartate aminotransferase, gamma-glutamyl transferase, international normalised ratio, dyslipidaemia, and albumin. MCD labelled 78.6% of patients with T2D and MASLD as low risk, achieving a 99.2% negative predictive value for excluding liver-related events in 15 years.Abstract IDDF2024-ABS-0124 Figure 1ConclusionsOur novel models, integrating common clinical parameters, effectively identify low-risk individuals for liver-related events among patients with MASLD and patients with T2D and probable MASLD.

BackgroundWe aimed to develop a risk score to predict hepatic complications including hepatic decompensation and hepatocellular carcinoma in patients with non-alcoholic fatty liver disease (NAFLD).MethodsThe training cohort included adult NAFLD patients identified using a territory-wide electronic database in Hong Kong between January 2000 and July 2021. A risk score was developed using the Fine-Gray model, assessed by area under the time-dependent receiver operating characteristic curves (AUROCs) with competing risk of non-liver-related death, and compared to FIB-4 index and aspartate aminotransferase to platelet ratio index (APRI). The validation cohort comprised adult patients with type 2 diabetes (T2D) from 2000-2016 who likely had NAFLD detected by a published score. T2D was defined by antidiabetic drug uses, haemoglobin A1c ≥6.5%, fasting glucose ≥7mmol/L, and/or diagnosis codes; patients with diagnosis codes of type 1 diabetes were excluded. Patients with hepatic complications before baseline or follow-upResultsOf 26,993 NAFLD patients in the training cohort (mean age 56.3±13.5 years, 46.1% males, 0.6% cirrhosis, 44.1% diabetes), 282 (1.0%) developed hepatic complications during 148,007 person-years of follow-up. In the validation cohort of 411,395 patients (mean age 61.8±12.4 years, 50.7% males, 0.4% cirrhosis), 5,984 (1.5%) developed hepatic complications during 4,386,580 person-years of follow-up. Age, cirrhosis, diabetes with and without optimal glycaemic control, hypertension, gamma-glutamyl transferase, albumin, total bilirubin, international normalised ratio, and platelet were independently associated with hepatic complications; the risk score with these factors achieved an AUROC (95%CI) of 0.81 (0.77-0.85) at 5 years and around 0.8 over 15 years (IDDF2023-ABS-0051 Figure 1. The AUROC of NAFLD risk score FIB-4 index and APRI over 15 years in the training and validation cohorts, IDDF2023-ABS-0051 Figure 2. The AUROC of NAFLD risk score FIB-4 index and APRI at 5 years in the training and validation cohorts). In validation, the risk score achieved an AUROC of 0.73-0.78 in the first 5 years, and 0.73 (95%CI: 0.71-0.74) at year 5 (IDDF2023-ABS-0051 Figure 1. The AUROC of NAFLD risk score FIB-4 index and APRI over 15 years in the training and validation cohorts, IDDF2023-ABS-0051 Figure 2. The AUROC of NAFLD risk score FIB-4 index and APRI at 5 years in the training and validation cohorts). In both the training and validation cohorts, the risk score outperformed the FIB-4 index and APRI (IDDF2023-ABS-0051 Figure 1. The AUROC of NAFLD risk score FIB-4 index and APRI over 15 years in the training and validation cohorts, IDDF2023-ABS-0051 Figure 2. The AUROC of NAFLD risk score FIB-4 index and APRI at 5 years in the training and validation cohorts); its low cut-off achieved a 99.4% negative predictive value (IDDF2023-ABS-0051 Figure 3. Cumulative incidence of hepatic complications by gray-s method in patients with low medium and high risk of developing hepatic complications based on NAFLD risk score).ConclusionsWe developed a risk score using common clinical and laboratory parameters to predict hepatic complications in NAFLD patients.Abstract IDDF2023-ABS-0051 Figure 1The AUROC of NAFLD risk score FIB-4 index and APRI over 15 years in the training and validation cohortAbstract IDDF2023-ABS-0051 Figure 2The AUROC of NAFLD risk score FIB-4 index and APRI at 5 years in the training and validation cohortsAbstract IDDF2023-ABS-0051 Figure 3Cumulative incidence of hepatic complications by gray-s method in patients with low medium and high risk of developing hepatic complications based on NAFLD risk score

BackgroundTo evaluate the long-term risk of hepatocellular carcinoma (HCC) and hepatic decompensation in chronic hepatitis B (CHB) patients who cleared hepatitis B surface antigen (HBsAg).MethodsAll adult CHB monoinfected patients who achieved HBsAg seroclearance between January 2000 and June 2021 were identified using a territory-wide electronic healthcare database managed by Hospital Authority, Hong Kong. Patients with liver transplantation and/or HCC before HBsAg loss or follow-up less than 6 months were excluded. Hepatic decompensation included ascites, variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, spontaneous bacterial peritonitis, liver transplantation, and liver-related mortality. The comparison of patients before and after year 7 of HBsAg loss was handled by clustered data in the Fine-Gray model.Results9,769 CHB patients who cleared HBsAg at a mean age of 57 years (60.0% male, 5.7% cirrhosis) were identified; most patients had compensated liver function at HBsAg seroclearance. At a mean follow-up of 5.4 ± 3.7 years, 106 (1.1%) patients developed HCC. Patients who developed HCC were older, more likely to be male and cirrhotic, and had higher alanine aminotransferase, and lower platelets than patients without HCC development. The cumulative incidence of HCC remained steady in 0–7 and 8–12 years after HBsAg loss (P=0.898) (crude annual incidence reduction: -0.04%, 95% CI -0.13%–0.04%, P=0.265) (IDDF2022-ABS-0226 Figures 1A. Cumulative incidence of hepatocellular carcinoma, IDDF2022-ABS-0226 Figure 1B. Crude annual incidence of hepatocellular carcinoma). Meanwhile, 124/9,640 (1.3%) patients without prior hepatic decompensation developed hepatic decompensation. The cumulative incidence of hepatic decompensation decelerated in 8–12 years after the first 7 years of HBsAg seroclearance (P=0.009) (crude annual incidence reduction: -0.23%, 95% CI -0.40% – -0.06%, P=0.012) (IDDF2022-ABS-0226 Figures 1C. Cumulative incidence of hepatic decompensation in chronic hepatitis B patients who achieved hepatitis B surface antigen (HSbAg) loss, IDDF2022-ABS-0226 Figure 1D. Crude annual incidence of hepatic decompensation in chronic hepatitis B patients who achieved hepatitis B surface antigen (HSbAg) loss). HBsAg loss for over 7 years was found to be associated with a reduced risk of hepatic decompensation (adjusted subdistribution hazard ratio [aSHR] 0.53, 95% CI 0.30–0.94, P=0.029) but not HCC (aSHR 1.38, 95% CI 0.85–2.23, P=0.193) after adjusting for age, gender, presence of cirrhosis and diabetes, platelet, and liver biochemistry.Abstract IDDF2022-ABS-0226 Figure 1A-DConclusionsThe risk of HCC persists up to 12 years in patients after HBsAg loss, whereas the risk of hepatic decompensation reduces after 7 years.

In violation of Dale's principle several neuronal subtypes utilize more than one classical neurotransmitter. Molecular identification of vesicular glutamate transporter three and cholecystokinin expressing cortical interneurons (CCK.sup.+VGluT3.sup.+INTs) has prompted speculation of GABA/glutamate corelease from these cells for almost two decades despite a lack of direct evidence. We unequivocally demonstrate CCK.sup.+VGluT3.sup.+INT-mediated GABA/glutamate cotransmission onto principal cells in adult mice using paired recording and optogenetic approaches. Although under normal conditions, GABAergic inhibition dominates CCK.sup.+VGluT3.sup.+INT signaling, glutamatergic signaling becomes predominant when glutamate decarboxylase (GAD) function is compromised. CCK.sup.+VGluT3.sup.+INTs exhibit surprising anatomical diversity comprising subsets of all known dendrite targeting CCK.sup.+ interneurons in addition to the expected basket cells, and their extensive circuit innervation profoundly dampens circuit excitability under normal conditions. However, in contexts where the glutamatergic phenotype of CCK.sup.+VGluT3.sup.+INTs is amplified, they promote paradoxical network hyperexcitability which may be relevant to disorders involving GAD dysfunction such as schizophrenia or vitamin B6 deficiency.