Randomized, Placebo-Controlled Phase 2b Study to Evaluate the Safety and Efficacy of Recombinant Human Lecithin Cholesterol Acyltransferase in Acute ST-Segment-Elevation Myocardial Infarction: Results of REAL-TIMI 63B.

BACKGROUND: High-density lipoprotein plays a key role in reverse cholesterol transport. In addition, high-density lipoprotein particles may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin-cholesterol acyltransferase is a rate-limiting enzyme in reverse cholesterol transport. MEDI6012 is a recombinant human lecithin-cholesterol acyltransferase that increases high-density lipoprotein cholesterol. Administration of lecithin-cholesterol acyltransferase has the potential to reduce infarct size and regress coronary plaque in acute ST-segment-elevation myocardial infarction. METHODS: REAL-TIMI 63B (A Randomized, Placebo­controlled Phase 2b Study to Evaluate the Safety and Efficacy of MEDI6012 in Acute ST Elevation Myocardial Infarction) was a phase 2B multinational, placebo-controlled, randomized trial. Patients with ST-segment-elevation myocardial infarction within 6 hours of symptom onset and planned for percutaneous intervention were randomly assigned 2:1 to MEDI6012 (2- or 6-dose regimen) or placebo and followed for 12 weeks. The primary outcome was infarct size as a percentage of left ventricular mass by cardiac MRI at 10 to 12 weeks, with the primary analysis in patients with TIMI Flow Grade 0 to 1 before percutaneous intervention who received at least 2 doses of MEDI6012. The secondary outcome was change in noncalcified plaque volume on coronary computed tomographic angiography from baseline to 10 to 12 weeks with the primary analysis in patients who received all 6 doses of MEDI6012. RESULTS: A total of 593 patients were randomly assigned. Patients were a median of 62 years old, 77.9% male, and 95.8% statin naive. Median time from symptom onset to randomization was 146 (interquartile range [IQR], 103-221) minutes and from hospitalization to randomization was 12.7 (IQR, 6.6-24.0) minutes, and the first dose of drug was administered a median of 8 (IQR, 3-13) minutes before percutaneous intervention. The index myocardial infarction was anterior in 69.6% and TIMI Flow Grade 0 to 1 in 65.1% of patients. At 12 weeks, infarct size did not differ between treatment groups (MEDI6012: 9.71%, IQR 4.79-16.38; placebo: 10.48%, [IQR, 4.92-16.61], 1-sided P=0.79. There was also no difference in noncalcified plaque volume (geometric mean ratio, 0.96 [95% CI, NA-1.10], 1-sided P=0.30). There was no significant difference in treatment emergent serious adverse events. CONCLUSIONS: Administration of MEDI6012 in patients with acute ST-segment-elevation myocardial infarction did not result in a significant reduction in infarct size or noncalcified plaque volume at 12 weeks. MEDI6012 was well tolerated with no excess in overall serious adverse events. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03578809.

Update on Regulation of Regenerative Medicine in Taiwan.

Due to rapid development of biotechnology in recent years, the field of regenerative medicine has attracted considerable attention. Regenerative medicine-related regulations have been established in several countries to ensure the quality, safety, and efficacy of innovative treatments. Considering the diversity of regenerative medicine, the regulatory framework in Taiwan has been adjusted in response to global trend and local demand. Before 2010, cell and gene therapies were regarded as "new medical practice" under the "Medical Care Act." Along with the establishment of Taiwan Food and Drug Administration (TFDA) in 2010, regenerative medicine was regulated as "medicinal products" under the "Pharmaceutical Affairs Act." Then, the Ministry of Health and Welfare (MOHW) established a new dual-track regulatory pathway for regenerative medicine in 2016. The dual-track pathway divided regenerative medicine into medical practices and medicinal products, aiming to improve the accessibility of new treatments to patients and maintain the flexibility for clinical operations. In order to refine the regulation, the MOHW proposed two draft Acts for regenerative medicine in 2022. The two draft Acts are currently under legislative process. It is expected that the research and development of regenerative medicine can be further accelerated, thus providing early access to innovative therapies for patients in the future.

Efficacy and safety of cotadutide, a dual glucagon-like peptide-1 and glucagon receptor agonist, in a randomized phase 2a study of patients with type 2 diabetes and chronic kidney disease.

AIM: To assess the efficacy, safety and tolerability of cotadutide in patients with type 2 diabetes mellitus and chronic kidney disease. MATERIALS AND METHODS: In this phase 2a study (NCT03550378), patients with body mass index 25-45 kg/m2 , estimated glomerular filtration rate 30-59 ml/min/1.73 m2 and type 2 diabetes [glycated haemoglobin 6.5-10.5% (48-91 mmol/mol)] controlled with insulin and/or oral therapy combination, were randomized 1:1 to once-daily subcutaneous cotadutide (50-300 µg) or placebo for 32 days. The primary endpoint was plasma glucose concentration assessed using a mixed-meal tolerance test. RESULTS: Participants receiving cotadutide (n = 21) had significant reductions in the mixed-meal tolerance test area under the glucose concentration-time curve (-26.71% vs. +3.68%, p < .001), more time in target glucose range on continuous glucose monitoring (+14.79% vs. -21.23%, p = .001) and significant reductions in absolute bodyweight (-3.41 kg vs. -0.13 kg, p < .001) versus placebo (n = 20). In patients with baseline micro- or macroalbuminuria (n = 18), urinary albumin-to-creatinine ratios decreased by 51% at day 32 with cotadutide versus placebo (p = .0504). No statistically significant difference was observed in mean change in estimated glomerular filtration rate between treatments. Mild/moderate adverse events occurred in 71.4% of participants receiving cotadutide and 35.0% receiving placebo. CONCLUSIONS: We established the efficacy of cotadutide in this patient population, with significantly improved postprandial glucose control and reduced bodyweight versus placebo. Reductions in urinary albumin-to-creatinine ratios suggest potential benefits of cotadutide on kidney function, supporting further evaluation in larger, longer-term clinical trials.

The impacts of maternal childhood adversity, stress, and mental health on child development at 6 months in Taiwan: A follow-up study.

Exposure to adverse childhood experiences (ACEs) is not only associated with one's adverse health outcomes in adulthood but also increases the risk of child developmental problems in offspring. However, the mechanisms involved in the transmission of the effects of maternal ACEs to the offspring largely remain unexplored. This study sought to identify possible psychosocial pathways of intergenerational effects of maternal ACEs on child development at 6 months. Data from a longitudinal study on maternal childhood adversity and maternal psychosocial risk during pregnancy as well as maternal mental health problems and child development at 6 months postnatal were used. Structural equation modeling with bootstrapping was used to estimate the indirect effects of maternal ACEs on child development at 6 months. The model showed that maternal ACEs indirectly influenced offspring's development via maternal stressful events during pregnancy and pre- and postnatal mental health problems. This finding highlights the possible interventions at the prenatal and postnatal periods. Early identification of women who have ACEs or who are at psychosocial risk during pre- and postnatal periods is critical to provide interventions to buffer those negative effects on offspring's development. Future studies are needed to longitudinally assess the effects of maternal ACEs on child development over time.

Incidence and characteristics of paediatric abusive head trauma in Taiwan, 2006-2015: a nationwide population-based study.

OBJECTIVES: To examine the incidence rate and characteristics of paediatric abusive head trauma (PAHT) among children under age 5 years in Taiwan. METHODS: The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) was used to identify broad and narrow definitions of children aged under 5 years with PAHT from 2006 to 2015 in Taiwan using a representative national insurance research database. Medical resource utilisation was also analysed. Incidence rates per 100 000 person-years were calculated and presented with 95% CI. Joinpoint regression analysis was used to detect the changes in trends and calculate the annual percentage change in PAHT incidence over time. RESULTS: From 2006 to 2015, 479 (narrow definition) and 538 (broad definition) PAHT cases were identified. Incidence rates of PAHT by narrow and broad definitions among children under 1 year of age (18.7/100 000 and 20.0/100 000) were nearly 10-fold or 20-fold higher than for children aged 1-2 (1.7/100 000 and 2.1/100 000) and 3-5 (0.9/100 000 and 1.2/100 000) years. The PAHT incidence significantly increased since 2012, with trends varying by age and gender. Our results suggest that over 40% of the children with PAHT experienced serious injury and nearly 13% were fatal cases. For 87% (n=57) of fatal cases, this was their first ever hospitalisation. The number of fatal cases among infants was fourfold higher than that of children aged 1-5 years. CONCLUSIONS: This study provides a robust national estimate of PAHT and identifies infants as the most vulnerable group for PAHT in Taiwan. Education to enhance healthcare profession's sensitivity and competence for the early identification and diagnosis of PAHT is critical.

External light activates hair follicle stem cells through eyes via an ipRGC-SCN-sympathetic neural pathway.

Changes in external light patterns can alter cell activities in peripheral tissues through slow entrainment of the central clock in suprachiasmatic nucleus (SCN). It remains unclear whether cells in otherwise photo-insensitive tissues can achieve rapid responses to changes in external light. Here we show that light stimulation of animals' eyes results in rapid activation of hair follicle stem cells with prominent hair regeneration. Mechanistically, light signals are interpreted by M1-type intrinsically photosensitive retinal ganglion cells (ipRGCs), which signal to the SCN via melanopsin. Subsequently, efferent sympathetic nerves are immediately activated. Increased norepinephrine release in skin promotes hedgehog signaling to activate hair follicle stem cells. Thus, external light can directly regulate tissue stem cells via an ipRGC-SCN autonomic nervous system circuit. Since activation of sympathetic nerves is not limited to skin, this circuit can also facilitate rapid adaptive responses to external light in other homeostatic tissues.

Recipient vessel selection for multiple free flap transfers in head and neck reconstruction at different periods.

BACKGROUND: Treatment decisions can be challenging in patients undergoing multiple oropharyngeal microsurgical reconstructions at different periods by various causes. We, retrospectively, reviewed patients with at least three consecutive free flap reconstructions to determine the optimal strategy for selecting recipient vessels. METHODS: Then, 36 patients (33 men and 3 women) who underwent at least 3 microsurgical reconstructions with a total of 51 free flap transfers for head and neck defects were included in this report. The most common reason for multiple microsurgical reconstructions was recurrent disease. For reconstructions, recipient vessel candidates on the same side of the head and neck were prioritized; if ipsilateral vessels were unavailable, contralateral recipient vessels, which might necessitate vein grafts, were used. RESULTS: The most common reconstructions were anterolateral thigh flaps (19 cases). The most commonly used contralateral recipient vessels were the superior thyroid artery, facial artery, and external jugular vein. All vessel anastomoses were performed using the end-to-end method. Postoperative complications occurred at the sites of 26 free flap reconstructions. The overall flap reconstruction success rate in patients with at least three surgeries was 90.2%. The median follow-up duration was 25.8 months. During follow-up, 26 patients survived until the end of follow-up. CONCLUSIONS: In patients undergoing multiple free flap reconstructions, recipient vessels on the ipsilateral side that have not been subjected to radiation should be selected first. Recipient vessels contralateral to the reconstruction side can then be selected; however, they may require vein grafts. Finally, distant healthy recipient vessels can be selected through vein grafting.

A potential probiotic Chromobacterium aquaticum with bacteriocin-like activity enhances the expression of indicator genes associated with nutrient metabolism, growth performance and innate immunity against pathogen infections in zebrafish (Danio rerio).

The use of probiotics as alternatives to antibiotics for disease control is a relatively eco-friendly approach in aquaculture; hence, studies isolating and assessing the benefit of potential probiotics to fish farming are common. The zebrafish is an excellent model system for validating beneficial functions of potential probiotics before their practical application in aquaculture. Here, a potentially probiotic Chromobacterium aquaticum was isolated from lake water samples and characterized by biochemical analysis and 16S rDNA sequencing. The probiotic produced extracellular enzymes (protease and xylanase) and a bacteriocin-like substance, which exhibited tolerance to extreme pH and high-temperature conditions and broad-spectrum bactericidal activity against diverse pathogens, including aquatic, foodborne, clinical and plant pathogens. The effects of C. aquaticum on zebrafish nutrient metabolism, growth performance and innate immunity were evaluated by measuring the expression of indicator genes after C. aquaticum feeding for 8 weeks. Fish administered the probiotic exhibited significantly increased hepatic mRNA expression of carbohydrate metabolism-related genes, including glucokinase (GK), hexokinase (HK), glucose-6-phosphatase (G6Pase), and pyruvate kinase (PK-L), and growth-related genes, including the growth hormone receptor (GHR) and insulin-like growth factor-1 (IGF-1). Innate immune-related genes (IL-1ß, IL-6, TNF-α, IL-10, IL-21, NF-κb, lysozyme and complement C3b) were induced in fish with probiotic supplementation. Probiotic-treated fish exhibited a higher survival rate than control fish after challenge with Aeromonas hydrophila and Streptococcus iniae. Together, these data suggest that C. aquaticum, as a probiotic feed supplement, could enhance nutrient metabolism and growth performance and could modulate innate immunity against A. hydrophila and S. iniae in zebrafish.

Approval of modified-release products by FDA without clinical efficacy/safety studies: A retrospective survey from 2008 to 2017.

In principle, approval of a modified-release (MR) drug product is based on evidence from pharmacokinetic (PK) and/or pharmacodynamic studies and clinical efficacy/safety studies. The purpose of this survey is (i) to explore the number of new drug applications (NDAs) of MR drug products, approved by the FDA, employ the PK study as a bridge to already-approved immediate-release drug products without conducting their own clinical efficacy/safety studies; and (ii) to understand the type of PK studies are required for such NDAs. To this end, we surveyed the approved records of MR drug products from 2008 to 2017 from the Drug@FDA website, and filtered pertinent information from FDA's assessment reports. A total of five out of 79 products were found. A single dose PK study was conducted to investigate the underlying drug release mechanisms in four of these products. For these products, the applicants also performed multiple dose PK equivalence studies, but the PK parameters used to support the equivalence were different among studies. Information regarding the exposure-response relationship was available for all selected products, which is fundamental for such cases. Although the difference in PK curve shapes is recognized as being critical for the clinical effectiveness, this evaluation was not performed in all selected cases, as indicated in FDA's assessment reports.

Architecture of retinal projections to the central circadian pacemaker.

The suprachiasmatic nucleus (SCN) receives direct retinal input from the intrinsically photosensitive retinal ganglion cells (ipRGCs) for circadian photoentrainment. Interestingly, the SCN is the only brain region that receives equal inputs from the left and right eyes. Despite morphological assessments showing that axonal fibers originating from ipRGCs cover the entire SCN, physiological evidence suggests that only vasoactive intestinal polypeptide (VIP)/gastrin-releasing peptide (GRP) cells located ventrally in the SCN receive retinal input. It is still unclear, therefore, which subpopulation of SCN neurons receives synaptic input from the retina and how the SCN receives equal inputs from both eyes. Here, using single ipRGC axonal tracing and a confocal microscopic analysis in mice, we show that ipRGCs have elaborate innervation patterns throughout the entire SCN. Unlike conventional retinal ganglion cells (RGCs) that innervate visual targets either ipsilaterally or contralaterally, a single ipRGC can bilaterally innervate the SCN. ipRGCs form synaptic contacts with major peptidergic cells of the SCN, including VIP, GRP, and arginine vasopressin (AVP) neurons, with each ipRGC innervating specific subdomains of the SCN. Furthermore, a single SCN-projecting ipRGC can send collateral inputs to many other brain regions. However, the size and complexity of the axonal arborizations in non-SCN regions are less elaborate than those in the SCN. Our results provide a better understanding of how retinal neurons connect to the central circadian pacemaker to synchronize endogenous circadian clocks with the solar day.

Rule-based modulation of a sensorimotor transformation across cortical areas.

Flexible responses to sensory stimuli based on changing rules are critical for adapting to a dynamic environment. However, it remains unclear how the brain encodes rule information and uses this information to guide behavioral responses to sensory stimuli. Here, we made single-unit recordings while head-fixed mice performed a cross-modal sensory selection task in which they switched between two rules in different blocks of trials: licking in response to tactile stimuli applied to a whisker while rejecting visual stimuli, or licking to visual stimuli while rejecting the tactile stimuli. Along a cortical sensorimotor processing stream including the primary (S1) and secondary (S2) somatosensory areas, and the medial (MM) and anterolateral (ALM) motor areas, the single-trial activity of individual neurons distinguished between the two rules both prior to and in response to the tactile stimulus. Variable rule-dependent responses to identical stimuli could in principle occur via appropriate configuration of pre-stimulus preparatory states of a neural population, which would shape the subsequent response. We hypothesized that neural populations in S1, S2, MM and ALM would show preparatory activity states that were set in a rule-dependent manner to cause processing of sensory information according to the current rule. This hypothesis was supported for the motor cortical areas by findings that (1) the current task rule could be decoded from pre-stimulus population activity in ALM and MM; (2) neural subspaces containing the population activity differed between the two rules; and (3) optogenetic disruption of pre-stimulus states within ALM and MM impaired task performance. Our findings indicate that flexible selection of an appropriate action in response to a sensory input can occur via configuration of preparatory states in the motor cortex.

Rule-based modulation of a sensorimotor transformation across cortical areas.

Flexible responses to sensory stimuli based on changing rules are critical for adapting to a dynamic environment. However, it remains unclear how the brain encodes and uses rule information to guide behavior. Here, we made single-unit recordings while head-fixed mice performed a cross-modal sensory selection task where they switched between two rules: licking in response to tactile stimuli while rejecting visual stimuli, or vice versa. Along a cortical sensorimotor processing stream including the primary (S1) and secondary (S2) somatosensory areas, and the medial (MM) and anterolateral (ALM) motor areas, single-neuron activity distinguished between the two rules both prior to and in response to the tactile stimulus. We hypothesized that neural populations in these areas would show rule-dependent preparatory states, which would shape the subsequent sensory processing and behavior. This hypothesis was supported for the motor cortical areas (MM and ALM) by findings that (1) the current task rule could be decoded from pre-stimulus population activity; (2) neural subspaces containing the population activity differed between the two rules; and (3) optogenetic disruption of pre-stimulus states impaired task performance. Our findings indicate that flexible action selection in response to sensory input can occur via configuration of preparatory states in the motor cortex.

Erector spinae plane block reduces opioid consumption and improves incentive spirometry volume after cardiac surgery: A retrospective cohort study.

BACKGROUND: Effective postoperative pain management is vital in cardiac surgery to prevent opioid dependency and respiratory complications. Previous studies on the erector spinae plane (ESP) block have focused on single-shot applications or immediate postoperative outcomes. This study evaluates the efficacy of continuous ESP block vs conventional care in reducing opioid consumption and enhancing respiratory function recovery postcardiac surgery over 72 hours. METHODS: A retrospective study at a tertiary hospital (January 2021-July 2022) included 262 elective cardiac surgery patients. Fifty-three received a preoperative ESP block, matched 1:1 with a control group (n = 53). The ESP group received 0.5% ropivacaine intraoperatively and 0.16% ropivacaine every 4 hours postoperatively. Outcomes measured were cumulative oral morphine equivalent (OME) dose within 72 hours postextubation, daily maximum numerical rating scale (NRS) ≥3, incentive spirometry volume, and %baseline performance, stratified by surgery type (sternotomy or thoracotomy). RESULTS: Significant OME reduction was observed in the ESP group (sternotomy: median decrease of 113 mg, 95% CI: 60-157.5 mg, p < 0.001; thoracotomy: 172.5 mg, 95% CI: 45-285 mg, p = 0.010). The ESP group also had a lower risk of daily maximum NRS ≥3 (adjusted OR sternotomy: 0.22, p < 0.001; thoracotomy: 0.07, p < 0.001), a higher incentive spirometry volumes (sternotomy: mean increase of 149 mL, p = 0.019; thoracotomy: 521 mL, p = 0.017), and enhanced spirometry %baseline (sternotomy: mean increase of 11.5%, p = 0.014; thoracotomy: 26.5%, p < 0.001). CONCLUSION: Continuous ESP block was associated with a reduction of postoperative opioid requirements, lower instances of pain scores ≥3, and improve incentive spirometry performance following cardiac surgery. These benefits appear particularly prominent in thoracotomy patients. Further prospective studies with larger sample size are required to validate these findings.

Tactile processing in mouse cortex depends on action context.

The brain receives constant tactile input, but only a subset guides ongoing behavior. Actions associated with tactile stimuli thus endow them with behavioral relevance. It remains unclear how the relevance of tactile stimuli affects processing in the somatosensory (S1) cortex. We developed a cross-modal selection task in which head-fixed mice switched between responding to tactile stimuli in the presence of visual distractors or to visual stimuli in the presence of tactile distractors using licking movements to the left or right side in different blocks of trials. S1 spiking encoded tactile stimuli, licking actions, and direction of licking in response to tactile but not visual stimuli. Bidirectional optogenetic manipulations showed that sensory-motor activity in S1 guided behavior when touch but not vision was relevant. Our results show that S1 activity and its impact on behavior depend on the actions associated with a tactile stimulus.

Case report: Malignant transformation of ovarian endometrioma during long term use of dienogest in a young lady.

Endometriosis is a benign disease, which is also regarded as a precursor to ovarian malignancy. Dienogest is a progestin treatment for endometriosis with efficacy and tolerability. A 35-year-old Taiwanese lady with ovarian endometrioma had taken dienogest for the last 5 years. During sonographic follow-up, surgery was suggested owing to suspicious of malignant transformation of ovarian endometrioma. While she hesitated and turned to receive two cycles of oocyte retrieval because of nulliparity. Meanwhile, more papillary growth in the ovarian endometrioma with intratumor flow was found during follow-up. Laparoscopic enucleation was performed later, and pathology revealed clear cell carcinoma with peritoneal involvement, at least FIGO stage IIB. She then underwent debulking surgery to grossly no residual tumor and received adjuvant chemotherapy with no tumor recurrence in post-operative 17-months follow-up. Considering fertility preservation, conservative treatment of ovarian endometrioma is typically indicated for those women who have not yet completed childbearing. However, malignant transformation may still occur despite long-term progestin treatment. Therefore, careful image follow-up is still indispensable.

The Effectiveness of Parenting Programs in Preventing Abusive Head Trauma: A Systematic Review and Meta-Analysis.

Parenting programs are the most common intervention for preventing the lethal form of child maltreatment, abusive head trauma (AHT). However, certain results of the effects of these programs have not yet been compared across studies. A systematic review with meta-analysis is warranted to quantitively synthesize the available evidence to identify effective elements and strategies of the programs for preventing AHT. This review aims to estimate AHT preventive parenting programs' pooled effect on the reduction of AHT incidence, the improvement of parental knowledge, and the increased use of safe strategies in response to infants' inconsolable crying. Studies published in English and Mandarin were searched and retained if they were randomized control trials (RCTs) or with a quasi-experimental design, included an AHT preventive parenting program, and provided data that quantified targeted outcomes. Eighteen studies were included in this review. AHT preventive parenting programs had a pooled effect on improving parents' knowledge and increasing the use of safe coping strategies in response to inconsolable crying but not on the incidence of AHT and parents' emotional self-regulation. Subgroup analyses showed that the intervention effects were mostly present across study designs or measurements and emerged in the reduction of AHT incidence compared with historical controls. The findings suggest that AHT preventive parenting programs enhance parenting knowledge and skills to provide safe care for infants. Further efforts to evaluate AHT parenting programs on the reduction of AHT incidence are necessary for decision-making on allocating and disseminating interventions.

Systematic review of effectiveness of situated e-learning on medical and nursing education.

OBJECTIVES: Because of the complexity of clinical situations, traditional didactic education is limited in providing opportunity for student-patient interaction. Situated e-learning can enhance learners' knowledge and associated abilities through a variety of activities. Healthcare providers who interact with virtual patients in designed situations may avoid unnecessary risks and encounters with real patients. However, the effectiveness of situated e-learning is inconsistent. The purpose of this study is to determine the effectiveness of situated e-learning in prelicensure and postlicensure medical and nursing education. METHODS: Literature databases of PubMed, Medline, CINAHL, ERIC, and Cochrane Library were searched. The study eligibility criteria included articles published in English, which examined the effectiveness of situated e-learning on the outcomes of knowledge and performance for clinicians or students in medicine and nursing. Effect sizes were calculated with 95% confidence intervals. RESULTS: Fourteen articles were included for meta-analysis. Situated e-learning could effectively enhance learners' knowledge and performance when the control group received no training. Compared to traditional learning, the effectiveness of situated e-learning on performance diminished but still remained significant whereas the effect become insignificant on knowledge. The subgroup analyses indicate the situated e-learning program significantly improved students' clinical performance but not for clinicians. CONCLUSIONS: Situated e-learning is an effective method to improve novice learners' performance. The effect of situated e-learning on the improvement of cognitive ability is limited when compared to traditional learning. Situated e-learning is a useful adjunct to traditional learning for medical and nursing students.

Kernel-wise difference minimization for convolutional neural network compression in metaverse.

Convolutional neural networks have achieved remarkable success in computer vision research. However, to further improve their performance, network models have become increasingly complex and require more memory and computational resources. As a result, model compression has become an essential area of research in recent years. In this study, we focus on the best-case scenario for Huffman coding, which involves data with lower entropy. Building on this concept, we formulate a compression with a filter-wise difference minimization problem and propose a novel algorithm to solve it. Our approach involves filter-level pruning, followed by minimizing the difference between filters. Additionally, we perform filter permutation to further enhance compression. Our proposed algorithm achieves a compression rate of 94× on Lenet-5 and 50× on VGG16. The results demonstrate the effectiveness of our method in significantly reducing the size of deep neural networks while maintaining a high level of accuracy. We believe that our approach holds great promise in advancing the field of model compression and can benefit various applications that require efficient neural network models. Overall, this study provides important insights and contributions toward addressing the challenges of model compression in deep neural networks.

Gut microbiota of Pacific white shrimp (Litopenaeus vannamei) exhibits distinct responses to pathogenic and non-pathogenic Vibrio parahaemolyticus.

Acute hepatopancreatic necrosis disease (AHPND), a high-mortality-rate shrimp disease, is caused by specific Vibrio parahaemolyticus (Vp) strains with a plasmid encoding the PirABVp toxins. As a bacterial pathogen, the invasion of AHPND-causing Vp might impose pressure on commensal microbiota in the shrimp gut, while the relationship between the pathogenesis of AHPND and the dysbiosis of gut bacterial communities remains unclear. Here we explored the temporal changes of shrimp gut microbiota in response to AHPND-causing and non-AHPND-causing Vp strains, with the non-infected controls as a baseline of the shrimp gut microbiota. The diversity and composition of bacterial communities from 168 gut samples (covering three treatments at seven time points with eight individuals per set) were investigated using 16S rRNA gene metabarcoding with high-throughput sequencing. The results showed that (i) species diversity of gut bacterial communities declined in Vp-infected shrimp, independent of the strain pathogenicity; (ii) taxonomic compositions of gut bacterial communities were significantly different between shrimp infected by AHPND-causing and non-AHPND-causing Vp strains; (iii) short-term (within 6 hours) compositional shifts in the gut microbiota were found only in AHPND-causing Vp-infected shrimp; (iv) the gut microbiota of AHPND-causing Vp-infected shrimp was enriched with genera Photobacterium and Vibrio, with a decline in Candidatus Bacilliplasma; and (v) functional predictions suggested the loss of normal metabolism due to compositional shifts in the gut microbiota. Our work reveals distinct features of community dynamics in shrimp gut microbiota, associated with pathogenic versus non-pathogenic Vibrio infections, providing a new perspective of the pathogenesis of AHPND. IMPORTANCE Shrimp production is continually threatened by newly emerging diseases, such as AHPND, which is caused by specific Vp strains. Previous studies on the pathogenesis of AHPND have mainly focused on the histopathology and immune responses of the host. However, more attention needs to be paid to the gut microbiota, which acts as the first barrier to pathogen colonization. In this study, we revealed that shrimp gut microbiota responded differently to pathogenic and non-pathogenic Vp strains, with bacterial genera Photobacterium and Vibrio enriched in pathogenic Vp-infected shrimp, and Candidatus Bacilliplasma enriched in non-pathogenic Vp-infected shrimp. Moreover, functional predictions suggested that changes in taxonomic compositions would further affect normal metabolic functions, emphasizing the importance of sustaining an equilibrium in the gut microbiota. Several biomarkers associated with specific microbial taxa and functional pathways were identified in our data sets, which help predict the incidence of disease outcomes.

Cotadutide promotes glycogenolysis in people with overweight or obesity diagnosed with type 2 diabetes.

Cotadutide is a dual glucagon-like peptide 1 and glucagon receptor agonist under development for the treatment of non-alcoholic steatohepatitis and type 2 diabetes mellitus (T2DM) and chronic kidney disease. Non-alcoholic steatohepatitis is a complex disease with no approved pharmacotherapies, arising from an underlying state of systemic metabolic dysfunction in association with T2DM and obesity. Cotadutide has been shown to improve glycaemic control, body weight, lipids, liver fat, inflammation and fibrosis. We conducted a two-part, randomized phase 2a trial in men and women with overweight or obesity diagnosed with T2DM to evaluate the efficacy and safety of cotadutide compared with placebo and liraglutide. The primary endpoints were change from baseline to day 28 of treatment in postprandial hepatic glycogen (part A) and to day 35 of treatment in fasting hepatic glycogen (part B) with cotadutide versus placebo. Secondary endpoints in part B were changes in fasting hepatic glycogen with cotadutide versus the mono glucagon-like peptide 1 receptor agonist, liraglutide, and change in hepatic fat fraction. The trial met its primary endpoint. We showed that cotadutide promotes greater reductions in liver glycogen and fat compared with placebo and liraglutide. Safety and tolerability findings with cotadutide were comparable to those of previous reports. Thus, this work provides evidence of additional benefits of cotadutide that could be attributed to glucagon receptor engagement. Our results suggest that cotadutide acts on the glucagon receptor in the human liver to promote glycogenolysis and improve the metabolic health of the liver. ClinicalTrials.gov registration: NCT03555994 .