Alternating Hot-Cold Water Immersion Facilitates Motor Function Recovery in the Paretic Upper Limb After Stroke: A Pilot Randomized Controlled Trial.

OBJECTIVE: To assess the effectiveness of alternating hot-cold water immersion (AHCWI) in patients with acute stroke. DESIGN: A single-blind pilot randomized controlled trial. SETTING: Department of Rehabilitation Medicine of a medical center. PARTICIPANTS: Early stroke survivors (N=24) with moderate-to-severe arm paresis. INTERVENTIONS: In addition to conventional rehabilitation, eligible patients were randomly assigned to an AHCWI group (n=12, for AHCWI) or a control group (n=12, for upper limb [UL] cycling exercises) 5 times per week for 6 weeks. MAIN OUTCOME MEASURES: The Fugl-Meyer Assessment motor-UL (FMA-UL) score, Motricity Index-UL (MI-UL) score, modified Motor Assessment Scale (MMAS; including its UL sections, MMAS-UL) score, Berg Balance Scale score, Barthel Index (BI), and modified Ashworth Scale score were assessed by the same uninvolved physical therapist at baseline and after 4 and 6 weeks of intervention. RESULTS: Compared with the control group, the AHCWI group performed better, with significant group effects (P<.05), and exhibited significant improvements in FMA-UL, MI-UL, and MMAS-UL scores at 4 and 6 weeks (P<.05). Although the remaining outcomes were not significantly different, they favored the AHCWI group. Notably, a significant difference was observed in the BI at 4 weeks (P=.032). Significant changes in the muscle tone or adverse effects were not observed in either group after the intervention. CONCLUSIONS: AHCWI with stroke rehabilitation is feasible and may facilitate motor function recovery of the paretic UL after a stroke.

Harnessing polyhydroxylated pyrrolidines as a stabilizer of acid alpha-glucosidase (GAA) to enhance the efficacy of enzyme replacement therapy in Pompe disease.

To discover small molecules as acid alpha-glucosidase (GAA) stabilizers for potential benefits of the exogenous enzyme treatment toward Pompe disease cells, we started from the initial screening of the unique chemical space, consisting of sixteen stereoisomers of 2-aminomethyl polyhydroxylated pyrrolidines (ADMDPs) to find out two primary stabilizers 17 and 18. Further external or internal structural modifications of 17 and 18 were performed to increase structural diversity, followed by the protein thermal shift study to evaluate the GAA stabilizing ability. Fortunately, pyrrolidine 21, possessing an l-arabino-typed configuration pattern, was identified as a specific potent rh-GAA stabilizer, enabling the suppression of rh-GAA protein denaturation. In a cell-based Pompe model, co-administration of 21 with rh-GAA protein significantly improved enzymatic activity (up to 5-fold) compared to administration of enzyme alone. Potentially, pyrrolidine 21 enables the direct increase of ERT (enzyme replacement therapy) efficacy in cellulo and in vivo.

[Reducing the Incidence of Feeding Intolerance in Premature Infants in the Neonatal Intensive Care Unit].

BACKGROUND ≥ PROBLEMS: Nutrition is very important for premature infants. Our recent research showed that the accuracy of recognition related to tube feeding was 74.8%, and the completeness of tube feeding was 74.3%. After analyzing this situation, the reasons found to be significantly associated with the low rates of tube-feeding recognition accuracy and completion included: inconsistent treatment of gastric residual by nurses in the neonatal intensive care unit (NICU), lack of sufficient assessment tools in the NICU, out-of-date specialist care guidelines, and lack of a regular inspection system. PURPOSE: Our aim was to improve tube-feeding-related recognition accuracy and completion to reduce the incidence of feeding intolerance. RESOLUTIONS: The intervention included developing a guideline manual for feeding procedures and making a gastric residual color card as a clinical-care reference. Holding on-the-job training and monitoring the quality of nursing care can reduce the incidence of feeding intolerance in preterm. RESULTS: The accuracy of tube-feeding recognition increased from 74.8% to 93.7%. The completion of tube feeding increased from 74.3% to 95.5%. The incidence of feeding intolerance in premature infants decreased from 71.8% to 39.0%. CONCLUSIONS: The results and process of this project provides a reference for improving the clinical care model for preterm infants in the NICU and for improving the enteral nutrition of preterm infants. The implementation of this project may improve the quality of nursing care and enable preterm infants to receive safer and more-complete care.

Neuropeptide S-initiated sequential cascade mediated by OX1, NK1, mGlu5 and CB1 receptors: a pivotal role in stress-induced analgesia.

BACKGROUND: Stress-induced analgesia (SIA) is an evolutionarily conserved phenomenon during stress. Neuropeptide S (NPS), orexins, substance P, glutamate and endocannabinoids are known to be involved in stress and/or SIA, however their causal links remain unclear. Here, we reveal an unprecedented sequential cascade involving these mediators in the lateral hypothalamus (LH) and ventrolateral periaqueductal gray (vlPAG) using a restraint stress-induced SIA model. METHODS: Male C57BL/6 mice of 8-12 week-old were subjected to intra-cerebroventricular (i.c.v.) and/or intra-vlPAG (i.pag.) microinjection of NPS, orexin-A or substance P alone or in combination with selective antagonists of NPS receptors (NPSRs), OX1 receptors (OX1Rs), NK1 receptors (NK1Rs), mGlu5 receptors (mGlu5Rs) and CB1 receptors (CB1Rs), respectively. Antinociceptive effects of these mediators were evaluated via the hot-plate test. SIA in mice was induced by a 30-min restraint stress. NPS levels in the LH and substance P levels in vlPAG homogenates were compared in restrained and unrestrained mice. RESULTS: NPS (i.c.v., but not i.pag.) induced antinociception. This effect was prevented by i.c.v. blockade of NPSRs. Substance P (i.pag.) and orexin-A (i.pag.) also induced antinociception. Substance P (i.pag.)-induced antinociception was prevented by i.pag. Blockade of NK1Rs, mGlu5Rs or CB1Rs. Orexin-A (i.pag.)-induced antinociception has been shown previously to be prevented by i.pag. blockade of OX1Rs or CB1Rs, and here was prevented by NK1R or mGlu5R antagonist (i.pag.). NPS (i.c.v.)-induced antinociception was prevented by i.pag. blockade of OX1Rs, NK1Rs, mGlu5Rs or CB1Rs. SIA has been previously shown to be prevented by i.pag. blockade of OX1Rs or CB1Rs. Here, we found that SIA was also prevented by i.c.v. blockade of NPSRs or i.pag. blockade of NK1Rs or mGlu5Rs. Restrained mice had higher levels of NPS in the LH and substance P in the vlPAG than unrestrained mice. CONCLUSIONS: These results suggest that, during stress, NPS is released and activates LH orexin neurons via NPSRs, releasing orexins in the vlPAG. Orexins then activate OX1Rs on substance P-containing neurons in the vlPAG to release substance P that subsequently. Activates NK1Rs on glutamatergic neurons to release glutamate. Glutamate then activates perisynaptic mGlu5Rs to initiate the endocannabinoid retrograde inhibition of GABAergic transmission in the vlPAG, leading to analgesia.

N-Cadherin Regulates Cell Migration Through a Rab5-Dependent Temporal Control of Macropinocytosis.

Macropinocytosis is a clathrin-independent endocytic pathway implicated in fluid uptake, pathogen invasion and cell migration. During collective cell migration, macropinocytosis occurs primarily at membrane ruffles arising from the leading edges of migrating cells. We report here that N-cadherin (Ncad) regulates the tempo of macropinocytosis and thereby influences wound-induced collective cell migration. Using live-cell and super-resolution imaging techniques, we observed that Ncad formed clusters at the membrane ruffles and macropinosomes. De-clustering of Ncad by an interfering antibody impaired the recruitment of Rab5-an early endosomal marker-to the macropinosomes. Moreover, we demonstrated that Ncad interacts with Rab5, and laser ablation of Ncad caused Rab5 to dissociate from the macropinosomes. Although Rab5 detached from macropinosomes upon the de-clustering of Ncad, the recruitment of late endosomal marker Rab7 occurred earlier. Consequently, both centripetal trafficking of macropinosomes and collective migration were accelerated due to de-clustering of Ncad. Thus, our results suggest that Ncad is involved in the maturation of macropinocytosis through Rab5 recruitment, linking macropinocytosis and cell migration through a novel function of Ncad.

Risk factors for contralateral inguinal hernia repair after unilateral inguinal hernia repair in male adult patients: analysis from a nationwide population based cohort study.

BACKGROUND: To identify the rate of and risk factors for contralateral inguinal hernia (CIH) after unilateral inguinal hernia repair in adult male patients. METHODS: This retrospective cohort study identified from the Taiwan National Health Insurance Research Database (NHIRD). Information on all adult patients who underwent primary unilateral inguinal hernia repair without any other operation was collected using ICD-9 diagnostic and procedure codes. The exclusion criteria were laparoscopic hernia repair, non-primary repair, complicated hernia, other combined procedures, female and undetermined gender. RESULTS: A total of 170,492 adult male patients were included, with a median follow-up of 87 months. The overall CIH rate was 10.5%, with a median time of 48 months to a subsequent hernia operation. The 1-year, 2-year, 3-year and 5-year-recurrent rate was 2.6, 3, 4.3, and 6.7% respectively. Further, 3.7% patients who underwent CIH repair had a complicated inguinal hernia. Multivariate analysis demonstrated that age > 45 y, direct hernia, cirrhosis (HR = 1.564), severe liver disease (HR = 1.663), prostate disease (HR = 1.178), congestive heart failure (HR = 1.138), and history of malignancy (HR = 1.116) had a significantly higher risk of CIH repair. CONCLUSIONS: Among adult male patients undergoing long-term follow-up, we identified several significant risk factors for CIH repair. If these risk factors are presented, the surgeon should inform the following risk of CIH repair to patients so that it can be repaired as soon as possible.

Carboxypeptidase E is a prediction marker for tumor recurrence in early-stage hepatocellular carcinoma.

Tumor recurrence and metastasis are the major causes of death for hepatocellular carcinoma (HCC) patients who are able to receive curative resection. Identifying the predicting biomarkers for tumor recurrence would improve their survival. RNA extracted from fresh frozen tumors and adjacent non-tumor liver tissues of 120 HCC patients were obtained from Taiwan Liver Cancer Network (TLCN) in year 2010 for determination of the carboxypeptidase E (CPE) expression level (including its splicing mutant CPE-ΔN) in the tumor tissue (T) and paired non-tumor liver tissue (N) by real-time quantitative polymerase chain reaction. All patients were male, had chronic hepatitis B virus infection, were in the early pathology stage, and received curative resection. The T/N ratio of the CPE expression level was correlated with the updated survival data from TLCN in 2015. The CPE expression level in the 120 HCC patients was divided into three groups according to the T/N ratio: <1, ≥1 and ≤2, and >2, respectively. By multivariate analyses, the recurrence-free survival (RFS) was only significantly associated with the pathology stage and the CPE expression level. For overall survival (OS), only the CPE expression level was the significant prognostic factor. The CPE expression level was also significantly correlated with the tumor recurrence for both stage I (p = 0.0106) and stage II patients (p = 0.0006). The CPE mRNA expression level in HCC can be a useful biomarker for predicting tumor recurrence in HCC patients who are in the early pathology stage and able to receive curative resection.

Can student self-ratings be compared with peer ratings? A study of measurement invariance of multisource feedback.

Measurement invariance is a prerequisite for comparing measurement scores from different groups. In medical education, multi-source feedback (MSF) is utilized to assess core competencies, including the professionalism. However, little attention has been paid to the measurement invariance of assessment instruments; that is, whether an instrument holds the same meaning across different rater groups. To examine the measurement invariance of the National Taiwan University professionalism MSF (NTU P-MSF) in order to determine whether medical students' self-rating can be compared to their peers' rating. An eight-factor model was specified for confirmatory factor analysis to examine the construct validity of the NTU P-MSF. Cronbach's alpha was computed for the items of each domain to evaluate internal consistent reliability. The same eight-factor model was used for multi-group confirmatory factor analyses. Four hierarchical models were specified to test configural (i.e., identical factor-item relationship), metric (i.e., identical factor loadings), scalar (i.e., identical intercepts), and error variance across self-rating and peer rating groups. One hundred and twenty second-year medical students from weekly discussion groups conducted as part of a medical professionalism course agreed to use the NTU P-MSF to assess themselves or their discussion group peers. NTU P-MSF assessment scores were a good fit for the eight-factor model among self group and peer group. The Cronbach's alpha coefficients of students' NTU P-MSF scores and peers' scores ranged from 0.76 to 0.89 and 0.84 to 0.91, respectively indicating that the NTU P-MSF scores also have good internal consistent reliability between both groups. In addition, same factor structure and similar factor loadings and intercepts of NTU P-MSF scores between both groups indicate that NTU P-MSF scores had configural, metric, and scalar invariance. Thus, students' self-assessments and peer assessments can be compared in terms of the constructs of NTU P-MSF scores, change in NTU P-MSF scores, and its factor scores. This study demonstrates how to investigate the measurement invariance of a professionalism MSF and contributes to the discussion on self- and peer assessment in medical education.

Rating dental arch relationships and palatal morphology with the EUROCRAN index on three different formats of dental casts in children with unilateral cleft lip and palate.

BACKGROUND: The EUROCRAN index has been used in inter-center studies to assess dental arch relationship (DAR) and palatal morphology (PM) in children with unilateral cleft lip and palate (UCLP). For this type of inter-center research, a scoring method that could be performed over the internet would be the most effective. Therefore, the aim of this study was to investigate the reliability of application of the EUROCRAN index on 3D digital models or photographs of plaster models instead of using plaster models. METHODS: The EUROCRAN reference models were presented in three formats: plaster models, 2D photographs of plaster models, and 3D digital models. Plaster models of children with UCLP (n = 45) were rated. Of each case, all three formats were rated by six calibrated observers in random order. The strength of agreement of the ratings was assessed with kappa statistics. Concordance among observers was evaluated with the intra-class correlation coefficient (ICC). RESULTS: The ICC showed a good inter-observer agreement for the DAR and poor inter-observer agreement for the PM. Intra-observer agreement for the DAR was moderate to very good, yet for the PM poor to moderate. Comparison between the three formats per observer for the DAR was good or very good and for the PM moderate to poor. CONCLUSIONS: The overall results show that the EUROCRAN index is an acceptable and reliable scoring method for the DAR on plaster models, 2D photographs of plaster models, and 3D digital models. However, due to the small range of deviations in palatal morphology between the cases in our study, the PM component of the index was difficult to assess. CLINICAL RELEVANCE: In clinical audits and inter-center studies, plaster models can be substituted by 2D photographs of plaster casts or 3D digital models when grading treatment outcome with the EUROCRAN index.

Does powdering of the dentition increase the accuracy of fusing 3D stereophotographs and digital dental casts.

OBJECTIVES: The shiny vestibular surfaces of teeth make it difficult to match digital dental casts to 3D stereophotogrammetric images of patient teeth. This study tested whether reducing this shininess by coating the teeth with titanium-oxide powder might improve the accuracy of the matching procedure. METHODS: Twenty patients participated in the study. For each patient, 3D stereophotogrammetric images were taken without and with a powder coating. Separately, digital dental casts were created. Next, the digital dental casts were fused with the 3D stereophotogrammetric images of either non-powdered or powdered dentition. Distance maps were created to evaluate the inter-surface distance between the digital dental cast and the 3D images. The matching accuracy was compared for dentition with and without powdering. RESULTS: Of all recorded distances between corresponding points, 95% was smaller than 0.84mm for the powdered dentition and smaller than 0.90mm for the non-powdered dentition. Although powdered dentition showed significantly better matching than non-powdered dentition, the difference was less than 0.1mm. Intra-observer statistics showed that five out of 24 repetitions gave significantly different results, but only for dentition that was not powdered. LIMITATIONS: The patients did not have any major malocclusions. Severe malocclusions might cause greater difficulty in matching the dentition without powder. Only one type of powder was used, but it effectively reduced shininess. CONCLUSION: Powdering the dentition had a small, but significant, positive effect on matching. However, this effect was of minor clinical importance. Therefore, we do not recommend powdering the dentition for 3D stereophotogrammetric images used for matching procedures.

Equal, global, local: discourses in Taiwan's international medical graduate debate.

CONTEXT: With the globalisation of medicine, the role of international medical graduates (IMGs) has expanded. Nonetheless, the experiences of native-born IMGs remain under-researched. In Taiwan, public controversy has unfolded around IMGs educated in Poland, calling into question the meaning(s) of equality in policy and medicine. In focusing on the return of IMGs to their countries of origin, this study adds to the growing literature concerning equality and globalisation in medical education. OBJECTIVES: The primary research aim was to analyse how stakeholders in the IMG debate use equality in their arguments. The authors set out to frame the dispute within the recent history of Taiwanese medical governance. An overarching objective was to contribute a critical, historical view of how discourses of globalisation and equality construct different policy approaches to international medical education. METHODS: The authors performed a critical discourse analysis of a public policy dispute in Taiwan, assembling an archive from online interactions, government reports and news articles. Coding focused on stakeholders' uses of equality to generate broader discourses. RESULTS: International and domestic Taiwanese students conceived of equality differently, referencing both 'equality of opportunity' and 'equality of outcome' within localisation and globalisation frameworks, respectively. The dominance of localisation discourse is reflected in hostile online rhetoric towards Poland-educated IMGs. CONCLUSIONS: Rhetorical disagreements over equality in medical education trace shifting state policies, from earlier attempts to remove barriers for IMGs to the present-day push to regulate IMGs for acculturation and quality assurance. The global Internet had a double-sided influence, facilitating both democratic political mobilization and the spread of hate speech. The policy debate in Taiwan mirrors discourses in Canada, where IMGs are likewise conceived either as globally competent physicians or as lacking in merit and technical competence. Future research could investigate the discursive formation and evidential basis of policies regulating international medical education.

Epidemiology, Patient Characteristics, and Treatment Patterns of Myasthenia Gravis in Taiwan: A Population-Based Study.

INTRODUCTION: Myasthenia gravis (MG) is a chronic neuromuscular disease leading to significant disease burden. This study aimed to investigate the epidemiology of MG in Taiwan. METHODS: A retrospective study was conducted using the Taiwan National Health Insurance Research Database. Prevalent patients with MG diagnosis (either ocular or generalized MG) from 2013 to 2019 were identified, and 2813 patients with initial MG diagnosis from 2014 to 2019 were further defined as the incident cohort. Patient characteristics, treatment patterns, and the occurrence of MG-related events were analyzed. RESULTS: The number of prevalent patients with MG increased from 4476 in 2013 to 5752 in 2019, with the prevalence rate increasing from 19 to 24 per 100,000 population. The incidence rate also slightly increased from 1.9 to 2.3 per 100,000 population during the study period. Almost all incident patients (99%, n = 2791) received MG-related treatment during the follow-up period. Among 1876 patients who received monotherapy as their initial treatment in the outpatient setting, the mean time from the index date to initial treatment was 48.8 (standard deviation 164.3) days, and most patients received acetylcholinesterase inhibitors (88.5%, n = 1661) as their initial treatment. During the first year after the index date, 133 (4.7%) incident patients experienced their first myasthenic crisis, and 96.2% of these events occurred within 3 months. CONCLUSION: The prevalence of MG increased steadily in Taiwan, and the treatment of patients with MG was consistent with guidelines. Despite a high treatment rate, patients still experienced MG-related events, highlighting the limitation of current treatments and emphasizing the need for early intervention and novel treatment approaches.

Demands for medical imaging and workforce Size: A nationwide population-based Study, 2000-2020.

PURPOSE: The aim of this study was to investigate associations between workforce and workload among radiologists in Taiwan. MATERIALS AND METHODS: Data for the period 2000-2020 describing the demand for imaging services and radiologists have been obtained from databases and statistical reports of the Ministry of Health and Welfare. The future demand for radiologists was based on Taiwanese people aged 40 and over. RESULTS: The workforce of Taiwan's radiologists has increased by 6 % annually over the past 20 years (from 450 to 993), performing 2125, 3202 and 3620 monthly examinations (mainly conventional radiography and CT) in medical centers, regional hospitals and district hospitals. Between 2000 and 2020, the use of CT and MRI increased by more than 3.5 times. Demand for interventional radiology also increased by 1.77 times, 2.25 times, and 5 times, respectively. To maintain this volume of services in 2040, at least 1168 radiologists are needed, about 1.18 times more in 2020. CONCLUSION: Taiwan has 2.4 to 2.9 times fewer radiologists than the United States and 3 times fewer than Europe, while the annual workload is approximately 2 to 3.4 times greater than that of the United States and 1.4 to 2.5 times greater than that of the United Kingdom. This report may serve as a reference for policy makers who address the challenges of the growing workload among radiologists in countries of similar situations.

Mechanistic Insights into Dibasic Iminosugars as pH-Selective Pharmacological Chaperones to Stabilize Human α-Galactosidase.

The use of pharmacological chaperones (PCs) to stabilize specific enzymes and impart a therapeutic benefit is an emerging strategy in drug discovery. However, designing molecules that can bind optimally to their targets at physiological pH remains a major challenge. Our previous study found that dibasic polyhydroxylated pyrrolidine 5 exhibited superior pH-selective inhibitory activity and chaperoning activity for human α-galactosidase A (α-Gal A) compared with its monobasic parent molecule, 4. To further investigate the role of different C-2 moieties on the pH-selectivity and protecting effects of these compounds, we designed and synthesized a library of monobasic and dibasic iminosugars, screened them for α-Gal A-stabilizing activity using thermal shift and heat-induced denaturation assays, and characterized the mechanistic basis for this stabilization using X-ray crystallography and binding assays. We noted that the dibasic iminosugars 5 and 20 protect α-Gal A from denaturation and inactivation at lower concentrations than monobasic or other N-substituted derivatives; a finding attributed to the nitrogen on the C-2 methylene of 5 and 20, which forms the bifurcated salt bridges (BSBs) with two carboxyl residues, E203 and D231. Additionally, the formation of BSBs at pH 7.0 and the electrostatic repulsion between the vicinal ammonium cations of dibasic iminosugars at pH 4.5 are responsible for their pH-selective binding to α-Gal A. Moreover, compounds 5 and 20 demonstrated promising results in improving enzyme replacement therapy and exhibited significant chaperoning effects in Fabry cells. These findings suggest amino-iminosugars 5 and 20 as useful models to demonstrate how an additional exocyclic amino group can improve their pH-selectivity and protecting effects, providing new insights for the design of pH-selective PCs.

A practical synthesis of nitrone-derived C5a-functionalized isofagomines as protein stabilizers to treat Gaucher disease.

Isofagomine (IFG) and its analogues possess promising glycosidase inhibitory activities. However, a flexible synthetic strategy toward both C5a-functionalized IFGs remains to be explored. Here we show a practical synthesis of C5a-S and R aminomethyl IFG-based derivatives via the diastereoselective addition of cyanide to cyclic nitrone 1. Nitrone 1 was conveniently prepared on a gram scale and in high yield from inexpensive (-)-diethyl D-tartrate via a straightforward method, with a stereoselective Michael addition of a nitroolefin and a Nef reaction as key steps. A 268-membered library (134 × 2) of the C5a-functionalized derivatives was submitted to enzyme- or cell-based bio-evaluations, which resulted in the identification of a promising ß-glucocerebrosidase (GCase) stabilizer demonstrating a 2.7-fold enhancement at 25 nM in p.Asn370Ser GCase activity and a 13-fold increase at 1 µM in recombinant human GCase activity in Gaucher cell lines.

Bacterial coinfections in hospitalized children with COVID-19 during the SARS-CoV-2 Omicron BA.2 variant pandemic in Taiwan.

Background: Bacterial coinfections have been widely recognized in adults with coronavirus disease 2019 (COVID-19). However, bacterial coinfections in hospitalized children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have not been sufficiently researched. This study aimed to determine the clinical presentations and risk factors for bacterial coinfections of pediatric inpatients during the SARS-CoV-2 Omicron BA.2 variant pandemic. Methods: This retrospective, observational study included patients younger than 18 years of age who were hospitalized for COVID-19 confirmed by polymerase chain reaction (PCR) or antigen rapid tests during the SARS-CoV-2 Omicron BA.2 variant pandemic. Data and outcomes of these patients with or without bacterial coinfections were compared. Results: During this study period, 161 children with confirmed COVID-19 were hospitalized. Twenty-four had bacterial coinfections. The most frequently reported concurrent diagnosis was bacterial enteritis, followed by lower respiratory tract infections. Children with bacterial coinfections had higher white blood cell (WBC) counts and PCR cycle threshold values. The bacterial coinfection group comprised a relatively greater proportion of patients who required high-flow nasal cannula oxygen and remdesivir. The length of stay in the hospital and that in the intensive care unit were longer for children with COVID-19 with bacterial coinfections. Mortality was not observed in either group. Abdominal pain, diarrhea, and comorbidity with neurologic illnesses were risk factors for bacterial coinfections with COVID-19. Conclusion: This study provides clinicians with reference points for the detection of COVID-19 in children and its possible association with bacterial infections. Children with COVID-19 and neurologic diseases who present with abdominal pain or diarrhea are at risk of bacterial coinfections. Prolonged fever duration and higher PCR test cycle threshold values, WBC levels, and high-sensitivity C-reactive protein (hsCRP) levels may indicate bacterial coinfections in children with COVID-19.

Comparing Three Profoundly Influential Prognostic Scores in Cirrhotic Patients with Acute-on-Chronic-Liver Failure Admitted to the ICU: Prediction of One-Month Mortality-A Retrospective Cohort Study.

BACKGROUND: Acute-on-chronic-liver failure (ACLF) demonstrates high short-term mortality rates and usually requires intensive care unit (ICU) admission. Accurate prognostication of these patients is pivotal for timely referral for liver transplantation. The superiority of CLIF-C ACLF, CLIF-C ACLF lactate, and NACSELD-ACLF scores in Asian patients with ACLF admitted to an ICU remains inconclusive. AIMS: To compare the predictive performance of CLIF-C ACLF, CLIF-C ACLF lactate, and NACSELD-ACLF scores for one-month mortality. METHODS: 276 consecutive cirrhotic patients with ACLF admitted to ICU were enrolled. The prognostic values for one-month mortality were assessed by AUROC analysis. RESULTS: The primary cause of cirrhosis in this cohort was alcohol abuse (56.5%). AUROC analysis (95% confidence intervals) demonstrated that CLIF-C ACLF lactate [0.802 (0.747-0.856)] outperformed both CLIF-C ACLF [0.791 (0.733-0.848)] and NACSELD-ACLF [0.673 (0.606-0.740)] in predicting one-month mortality. However, no statistically significant difference was observed between the predictive abilities of CLIF-C ACLF and CLIF-C ACLF lactate. CONCLUSIONS: In critically ill cirrhotic patients with ACLF admitted to the hepatology ICU, CLIF ACLF-lactate outperformed CLIF-C ACLF and NACSELD-ACLF in predicting one-month mortality. Nevertheless, no statistically significant difference was observed between CLIF-C ACLF and CLIF-C ACLF lactate. Larger-scale multi-center prospective studies are warranted to validate these results.

Synthesis, evaluation, and mechanism of 1-(4-(arylethylenylcarbonyl)phenyl)-4-carboxy-2-pyrrolidinones as potent reversible SARS-CoV-2 entry inhibitors.

A class of 1-(4-(arylethylenylcarbonyl)phenyl)-4-carboxy-2-pyrrolidinones were designed and synthesized via Michael addition, cyclization, aldol condensation, and deprotonation to inhibit the human transmembrane protease serine 2 (TMPRSS2) and Furin, which are involved in priming the SARS-CoV-2 Spike for virus entry. The most potent inhibitor 2f (81) was found to efficiently inhibit the replication of various SARS-CoV-2 delta and omicron variants in VeroE6 and Calu-3 cells, with EC50 range of 0.001-0.026 µM by pre-incubation with the virus to avoid the virus entry. The more potent antiviral activities than the proteases inhibitory activities led to discovery that the synthesized compounds also inhibited Spike's receptor binding domain (RBD):angiotensin converting enzyme 2 (ACE2) interaction as a main target, and their antiviral activities were enhanced by inhibiting TMPRSS2 and/or Furin. To further confirm the blocking effect of 2f (81) on virus entry, SARS-CoV-2 Spike pseudovirus was used in the entry assay and the results showed that the compound inhibited the pseudovirus entry in a ACE2-dependent pathway, via mainly inhibiting RBD:ACE2 interaction and TMPRSS2 activity in Calu-3 cells. Finally, in the in vivo animal model of SARS-CoV-2 infection, the oral administration of 25 mg/kg 2f (81) in hamsters resulted in reduced bodyweight loss and 5-fold lower viral RNA levels in nasal turbinate three days post-infection. Our findings demonstrated the potential of the lead compound for further preclinical investigation as a potential treatment for SARS-CoV-2.

A cross-cultural study of students' approaches to professional dilemmas: sticks or ripples.

CONTEXT: Medical educators internationally are faced with the challenge of teaching and assessing professionalism in their students. Some studies have drawn attention to contextual factors that influence students' responses to professional dilemmas. Although culture is a significant contextual factor, no research has examined student responses to professional dilemmas across different cultures. METHODS: Semi-structured interviews inquiring into reactions towards, and reasoning about, five video clips depicting students facing professional dilemmas were conducted with 24 final-year medical students in Taiwan. The interviews were transcribed and analysed according to the theoretical framework used in prior Canadian studies using the same videos and interview questions. RESULTS: The framework from previous Canadian research, including the components of principles, affect and implications, was generally applicable to the decision making of Taiwanese students, with some distinctions. Taiwanese students cited a few more avowed principles. Taiwanese students emphasised an additional unavowed principle that pertained to following the advice of more senior trainees. In addition to implications for patients, team members or themselves, Taiwanese students considered the impact of their responses on multiple relationships, including those with patients' families and alumni residents. Cultural norms were also cited by Taiwanese students. CONCLUSIONS: Medical educators must acknowledge students' reasoning in professionally challenging situations and guide students to balance considerations of principles, implications, affects and cultural norms. The prominence of Confucian relationalism in this study, exhibited by students' considerations of the rippling effects of their behaviours on all their social relationships, calls for further cross-cultural studies on medical professionalism to move the field beyond a Western individualist focus.

Is cleft severity related to maxillary growth in patients with unilateral cleft lip and palate?

OBJECTIVE: To study the relationship of cleft severity and maxillary growth in patients with unilateral cleft lip and palate. DESIGN: A systematic literature review. METHODS: A literature survey from the PubMed database from January 1966 to December 2008 used the Medical Subject Headings terms facial growth, unilateral cleft lip palate, cephalometry, and cleft severity or cleft width. The Cleft Palate-Craniofacial Journal from 1964 to November 2008 was hand searched. Studies published as full-length articles reporting quantitative data on the relationship of cleft severity and written in English were selected. Two reviewers selected and extracted the data independently and also assessed the quality of the studies. RESULTS: Four studies met the selection criteria and were included in the review. All were retrospective and longitudinal. Quality analysis revealed medium to low level of the included studies. Heterogeneity of the studies prevented major conclusions about the relationship of a severe cleft and unfavorable maxillary forward growth. CONCLUSIONS: The review has highlighted the importance of further research. Further well-designed controlled studies and long-term studies are needed, and researchers have to consider combined assessment of cleft size and palate size. Further studies should also focus on the cleft severity at birth and at the time of palate repair.