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Background: Necrotizing soft tissue infections (NSTI) are rapidly progressing and life-threatening conditions that require prompt diagnosis. However, differentiating NSTI from other non-necrotizing skin and soft tissue infections (SSTIs) remains challenging. We aimed to evaluate the diagnostic value of the biochemical analysis of soft tissue infectious fluid in distinguishing NSTIs from non-necrotizing SSTIs., Methods: This cohort study prospectively enrolled adult patients between May 2023 and April 2024, and retrospectively included patients from April 2019 to April 2023. Patients with a clinical suspicion of NSTI in the limbs who underwent successful ultrasound-guided aspiration to obtain soft tissue infectious fluid for biochemical analysis were evaluated and classified into the NSTI and non-necrotizing SSTI groups based on their final discharge diagnosis. Common extravascular body fluid (EBF) criteria were applied., Results: Of the 72 patients who met the inclusion criteria, 10 patients with abscesses identified via ultrasound-guided aspiration were excluded. Based on discharge diagnoses, 39 and 23 patients were classified into the NSTI and non-necrotizing SSTI groups, respectively. Biochemical analysis revealed significantly higher albumin, lactate, lactate dehydrogenase (LDH), and total protein levels in the NSTI group than in the non-necrotizing SSTI group, and the NSTI group had significantly lower glucose levels and pH in soft tissue fluids. In the biochemical analysis, LDH demonstrated outstanding discrimination (area under the curve (AUC) = 0.955; p < 0.001) among the biochemical markers. Albumin (AUC = 0.884; p < 0.001), lactate (AUC = 0.891; p < 0.001), and total protein (AUC = 0.883; p < 0.001) levels also showed excellent discrimination. Glucose level (AUC = 0.774; p < 0.001) and pH (AUC = 0.780; p < 0.001) showed acceptable discrimination. When the EBF criteria were evaluated, the total scores of Light's criteria (AUC = 0.925; p < 0.001), fluid-to-serum LDH ratio (AUC = 0.929; p < 0.001), and fluid-to-serum total protein ratio (AUC = 0.927; p < 0.001) demonstrated outstanding discrimination., Conclusion: Biochemical analysis and EBF criteria demonstrated diagnostic performances ranging from acceptable to outstanding for NSTI when analyzing soft tissue infectious fluid. These findings provide valuable diagnostic insights into the recognition of NSTI. Further research is required to validate these findings., (© 2024. The Author(s).)

Pulse arrival time (PAT), Pulse transit time (PTT), and Pulse Wave Velocity (PWV) have all been used as metrics for assessing a number of cardiovascular applications, including arterial stiffness and cuffless blood pressure monitoring. These have been measured using various sensing methods, including electrocardiogram (ECG) with photoplethysmogram (PPG), two PPG sensors, or two Bioimpedance (BioZ) sensors. Our study addresses the mathematical inaccuracies of previous bioimpedance approaches and incorporates PTT weights for the peak-peak (PTTpp), middle-middle (PTTmm), and foot-foot (PTTff) segments of the sensing signal into a single neuron model to determine a more accurate and stable PWV. In addition, we developed a tetherless bioimpedance device and compared our PTT estimation approaches, which yielded PWV across six subjects and two different arteries. Specifically, using our model, we found that the most reliable combination of weights corresponding to PTTpp, PTTmm, and PTTff was (0.260, 0.704, 0.036) for the brachial artery and (0.104, 0.858, 0.038) for radial artery. This model consistently yielded stable values across repetitions, with PWV values of 5.2 m/s, 5.3 m/s, and 5.9 m/s for the brachial artery and values of 5.8 m/s, 6.6 m/s, and 6.5 m/s for the radial artery. This system and model offer the possibility of obtaining higher reliability PTT and PWV values yielding better monitoring of cardiovascular health measures such as blood pressure and arterial stiffness., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The emergence of SARS-CoV-2 in late 2019 sparked the global COVID-19 pandemic, leading to varied vaccine policies worldwide. The evolving patterns of respiratory pathogens, aside from SARS-CoV-2, during the pandemic have had a significant impact on the development of vaccine strategies., Methods: This study explores the landscape of respiratory pathogens, encompassing SARS-CoV-2, respiratory syncytial virus (RSV), and influenza viruses, through a retrospective analysis of data obtained from the BioFire Respiratory Panel 2.1 (RP 2.1) at China Medical University Hospital (Taichung, Taiwan) spanning from January 2020 to November 2023., Results: Among the 7950 respiratory samples studied, pediatric cases exhibited higher positivity (64.9%, 2488/3835) and mixed detection rates (43.8%, 1090/2488) than adults. Annual mixed detection rates increased (27.9-48%). Prevalence analysis revealed diverse patterns across age groups, with higher rates in pediatrics. Notably, human rhinovirus/enterovirus predominated (48.1%). Mixed detection illustrated viral co-detections, notably with parainfluenza viruses and adenovirus. Government policies and pandemic dynamics influenced infection patterns, with RSV resurgence after May 2022. Age-specific RSV detection demonstrated a shift, influencing vaccine considerations. Amid global vaccine initiatives, RSV's increasing trend in adults warrants attention., Conclusions: This comprehensive analysis emphasizes the importance of multiplex PCR testing in shaping targeted vaccination strategies during evolving respiratory pathogen landscapes., Competing Interests: Declaration of competing interests All authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

Objective: TFG mutations have previously been implicated in autosomal recessive hereditary spastic paraplegia (HSP), also known as SPG57. This study aimed to investigate the clinical and molecular features of TFG mutations in a Taiwanese HSP cohort., Methods: Genetic analysis of TFG was conducted in 242 unrelated Taiwanese HSP patients using a targeted resequencing panel covering the entire coding regions of TFG. Functional assays were performed using an in vitro cell model to assess the impact of TFG variants on protein function. Additionally, other representative TFG mutant proteins were examined to understand the broader implications of TFG mutations in HSP., Results: The study identified a novel homozygous TFG c.177A>C (p.(Lys59Asn)) variant in a family with adolescent-onset, pure form HSP. Functional analysis revealed that the Lys59Asn TFG variant, similar to other HSP-associated TFG mutants, exhibited a low affinity between TFG monomers and abnormal assembly of TFG homo-oligomers. These structural alterations led to aberrant intracellular distribution, compromising TFG's protein secretion function and resulting in decreased cellular viability., Interpretation: These findings confirm that the homozygous TFG c.177A>C (p.(Lys59Asn)) variant is a novel cause of SPG57. The study expands our understanding of the clinical and mutational spectrum of TFG-associated diseases, highlighting the functional defects associated with this specific TFG variant. Overall, this research contributes to the broader comprehension of the genetic and molecular mechanisms underlying HSP., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

PAR3/INSC/LGN form an evolutionarily conserved complex required for asymmetric cell division in the developing brain, but its post-developmental function and disease relevance in the peripheral nervous system (PNS) remains unknown. We mapped a new locus for axonal Charcot-Marie-Tooth disease (CMT2) and identified a missense mutation c.209 T > G (p.Met70Arg) in the INSC gene. Modeling the INSC M70R variant in Drosophila, we showed that it caused proprioceptive defects in adult flies, leading to gait defects resembling those in CMT2 patients. Cellularly, PAR3/INSC/LGN dysfunction caused tubulin aggregation and necrotic neurodegeneration, with microtubule-stabilizing agents rescuing both morphological and functional defects of the INSC M70R mutation in the PNS. Our findings underscore the critical role of the PAR3/INSC/LGN machinery in the adult PNS and highlight a potential therapeutic target for INSC-associated CMT2., (© 2024. The Author(s).)

The factors related to conflicts in emergency departments (EDs) have been studied for decades. The post-pandemic digital era may transform the medical landscape in EDs, potentially changing the patterns of conflict between healthcare professionals. This study used focus group interviews to explore conflicts in EDs. Four groups, each with 4-6 participants, took part in this study. Semi-structured interviews were conducted using six research questions. Summative content analysis was used to analyze the data. The participant's average age was 37.82 years, and the average number of working years was 12.12. The following five themes emerged: multiple patterns of internal conflict; external conflicts arising from cross-departmental coordination; conflicts due to unclear job boundaries; adapting to conflicts in diverse ways; and seeking hospital arbitration. The results of this study suggest extending interdisciplinary collaborative practice from emergency departments to all coordinating departments. An inclusive environment for equality between professions and open communication should be promoted by hospitals.

Despite aggressive antibiotic therapy and surgical debridement, Aeromonas necrotizing fasciitis (NF) can lead to high amputation and mortality rates. Our study compares the different antibiotic minimum inhibitory concentrations (MICs) via Epsilometer tests (E-tests) between non-survivors and survivors of Aeromonas NF of limbs. A prospective review of 16 patients with Aeromonas NF was conducted for 3.5 years in a tertiary coastal hospital. E-tests were conducted for 15 antimicrobial agents to determine the MIC value for Aeromonas species. These patients were divided into non-survival and survival groups. The clinical outcomes, demographics, comorbidities, presenting signs and symptoms, laboratory findings, and microbiological results between the two periods were compared. A total of four patients died, whereas 12 survived, resulting in a 25% mortality rate. A higher proportion of bloodstream infections (100% vs. 41.7%; p = 0.042), monomicrobial infections (100% vs. 33.3%; p = 0.021), shock (100% vs. 33.3%; p = 0.021), serous bullae (50% vs. 0%; p = 0.009), liver cirrhosis (100% vs. 25%; p = 0.009), chronic kidney disease (100% vs. 33.3%; p = 0.021), lower susceptibility to cefuroxime (25% vs. 83.3%; p = 0.028), and ineffective antibiotic prescriptions (75% vs. 16.7%; p = 0.029) was observed in non-survivors. Aeromonas NF is an extremely rare skin and soft-tissue infection that is associated with high mortality, bacteremia, antibiotic resistance, and polymicrobial infection. Therefore, antibiotic regimen selection is rendered very challenging. To improve clinical outcomes and irrational antimicrobial usage, experienced microbiologists can help physicians identify specific pathogens and test MIC.

Necrotizing fasciitis (NF) is a life-threatening infection. Skin necrosis is an important skin sign of NF. The purposes of this study was to investigate the initial skin conditions of Vibrio NF patients between emergency room (ER) to preoperative status, to compare the clinical and laboratory risk indicators of the skin necrosis group and non-skin necrosis group when they arrived at ER, and to evaluate whether initial cutaneous necrosis related to fulminant course and higher fatalities. From 2015 to 2019, seventy-two Vibrio NF patients with surgical confirmation were enrolled. We identified 25 patients for inclusion in the skin necrosis group and 47 patients for inclusion in the non-skin necrosis group due to the appearance of skin lesion at ER. Seven patients died, resulting in a mortality rate of 9.7%. Six patients of skin necrosis group and one patient of non-skin necrosis group died, which revealed the skin necrosis group had a significantly higher mortality rate than the non-skin necrosis group. All the patients in the skin necrosis group and 30 patients of non-skin necrosis group developed serous or hemorrhagic bullous lesions before operation (p = 0.0003). The skin necrosis group had a significantly higher incidence of APACHE score, postoperative intubation, Intensive care unit stay, septic shock, leukopenia, higher counts of banded leukocytes, elevated C-reactive protein (CRP), and lower serum albumin level. Vibrio NF patients presenting skin necrosis at ER were significantly associated with fulminant clinical courses and higher mortality. Physicians should alert the appearance of skin necrosis at ER to early suspect NF and treat aggressively by those clinical and laboratory risk indicators, such as elevated APACHE score, shock, leukopenia, higher banded leukocytes, elevated CRP, and hypoalbuminia., (© 2023. The Author(s).)

Livestock wastewater can contain high levels of phosphates and trace amounts of various ionic species harming the environment and human health. These ions can be successfully removed from livestock effluent and recovered in a non-toxic crystal form via crystallization. The fluidized bed homogeneous crystallization (FBHC) technology is a cutting-edge pretreatment method that removes phosphate and ammonium by crystallizing struvite. The findings demonstrated a 37% removal for ammonium solutions alone, 38% with copper, 35% with zinc, and 33% when copper and zinc were present, while the crystallization efficiency was achieved at 35%, 33% with copper, 28% with zinc, and 26% with copper and zinc. For phosphate-containing solutions, 95% was removed, 81% with copper, 96% with zinc, and 88% with copper and zinc. Similarly, crystallization efficiency was attained at 87%, 60% with copper, 94% with zinc, and 81% when copper and zinc were combined with phosphates. For ammonium solutions, copper and zinc reduced the removal and crystallization efficiency at constant pH and increased at increasing pH. For phosphate solutions, the removal and crystallization efficiencies increased at increasing pH. However, zinc ions resulted in the highest removal, and crystallization efficiency for phosphate solutions was attained. Based on SEM, EDS, XRD, and XPS analyses, the peaks revealed the presence of struvite in the form of magnesium ammonium phosphate., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Ming-Chun Lu reports financial support, administrative support, and equipment, drugs, or supplies were provided by National Council of Science and Technology, Taiwan. Ming-Chun Lu has a patent licensed to Intellectual Property Office, MOEA, TAIWAN., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The mitochondrial DNA m.3243A>G mutation can affect mitochondrial function and lead to a wide phenotypic spectrum, including mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, diabetes mellitus, hearing impairment, cardiac involvement, epilepsy, migraine, myopathy, and cerebellar ataxia. However, m.3243A>G has been rarely reported in patients with cerebellar ataxia as their predominant manifestation. The aim of this study is to investigate the prevalence and clinical features of m.3243A>G in a Taiwanese cohort of cerebellar ataxia with unknown genetic diagnosis., Methods: This retrospective cohort study conducted the mutation analysis of m.3243A>G by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) in 232 unrelated Han Chinese patients with genetically-undetermined cerebellar ataxia. The clinical presentation and neuroimaging features of patients with m.3243A>G mutation-related cerebellar ataxia were characterized., Results: We identified two patients harboring m.3243A>G mutation. These patients have suffered from apparently sporadic and slowly progressive cerebellar ataxia since age 52 and 35 years, respectively. Both patients had diabetes mellitus and/or hearing impairment. The neuroimaging studies revealed generalized brain atrophy with predominantly cerebellar involvement in both individuals and bilateral basal ganglia calcifications in one of the patients., Conclusion: Mitochondrial m.3243A>G mutation accounted for 0.9% (2/232) of genetically-undetermined cerebellar ataxia in the Han Chinese cohort in Taiwan. These findings highlight the importance of investigating m.3243A>G in patients with genetically-undetermined cerebellar ataxia., Competing Interests: Declaration of interest The authors disclose no conflicts of interest., (Copyright © 2023 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

The dynamics of a bubble in a pressure gradient is investigated experimentally and numerically with particular emphasis on the behavior at reentrant jet impact and break through the opposite side of the bubble with corresponding energy loss and vorticity generation. High speed photography observations of a bubble generated by electric spark energy deposit in a low ambient pressure tank are coupled with wavelet based Optical Flow Velocimetry (wOFV) and Boundary Element Method (BEM) numerical analysis to examine the flow field resulting from the reentrant jet formation and break through. We study, as an illustration, the effects of the constant pressure gradient due to gravity on the bubble dynamics. Energy losses between the first and second cycle are measured for the bubbles generated under various conditions characterized by a non-dimensional pressure gradient parameter, and the corresponding measured energy loss is used in the numerical simulations. Good correspondence is seen between the image analysis, the wOFV computations, and the BEM results and insight is gained on the involved physics., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Bryan Schmidt reports administrative support was provided by Naval Surface Warfare Center Carderock Division. Georges Chahine reports a relationship with Naval Surface Warfare Center Indian Head Explosive Ordnance Disposal Technology Division that includes: funding grants., (Copyright © 2023 Dynaflow, inc. Published by Elsevier B.V. All rights reserved.)

Shock index (SI) and national early warning score (NEWS) are more frequently used as assessment tools in acute illnesses, patient disposition and early identification of critical condition. Both they are consisted of common vital signs and parameters including heart rate, systolic blood pressure, respiratory rate, oxygen saturation and level of conscious, which made it easy to evaluate in medical facilities. Its ability to predict mortality in patients with necrotizing fasciitis (NF) in the emergency department remains unclear. This study was conducted to compare the predictive capability of the risk scores among NF patients. A retrospective cohort study of hospitalized patients with NF was conducted in 2 tertiary teaching hospitals in Taiwan between January 2013 and March 2015. We investigated the association of NEWS and SI with mortality in NF patients. Of the 395 NF patients, 32 (8.1%) died in the hospital. For mortality, the area under the receiver curve value of NEWS (0.81, 95% confidence interval 0.76-0.86) was significantly higher than SI (0.76, 95% confidence interval 0.73-0.79, P = .016). The sensitivities of NEWS of 3, 4, and 5 for mortality were 98.1%, 95.6%, and 92.3%. On the contrast, the sensitivities of SI of 0.5, 0.6, and 0.7 for mortality were 87.8%, 84.7%, and 81.5%. NEWS had advantage in better discriminative performance of mortality in NF patients. The NEWS may be used to identify relative low risk patients among NF patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Bacteremia is a life-threatening complication of infectious diseases. Bacteremia can be predicted using machine learning (ML) models, but these models have not utilized cell population data (CPD)., Methods: The derivation cohort from emergency department (ED) of China Medical University Hospital (CMUH) was used to develop the model and was prospectively validated in the same hospital. External validation was performed using cohorts from ED of Wei-Gong Memorial Hospital (WMH) and Tainan Municipal An-Nan Hospital (ANH). Adult patients who underwent complete blood count (CBC), differential count (DC), and blood culture tests were enrolled in the present study. The ML model was developed using CBC, DC, and CPD to predict bacteremia from positive blood cultures obtained within 4 h before or after the acquisition of CBC/DC blood samples., Results: This study included 20,636 patients from CMUH, 664 from WMH, and 1622 patients from ANH. Another 3143 patients were included in the prospective validation cohort of CMUH. The CatBoost model achieved an area under the receiver operating characteristic curve of 0.844 in the derivation cross-validation, 0.812 in the prospective validation, 0.844 in the WMH external validation, and 0.847 in the ANH external validation. The most valuable predictors of bacteremia in the CatBoost model were the mean conductivity of lymphocytes, nucleated red blood cell count, mean conductivity of monocytes, and neutrophil-to-lymphocyte ratio., Conclusions: ML model that incorporated CBC, DC, and CPD showed excellent performance in predicting bacteremia among adult patients with suspected bacterial infections and blood culture sampling in emergency departments., Competing Interests: Declaration of competing interest All authors have no conflicts of interest to declare., (Copyright © 2023. Published by Elsevier B.V.)

Cirrhosis always goes with profound immunity compromise, and makes those patients easily be the target of skin and soft-tissue infections (SSTIs). Cirrhotic patients with SSTIs have a dramatically increased mortality. To recognize the risk factors of gram-negative infections are critical for improving survival rate. A retrospective cohort study of hospitalized cirrhotic patients with SSTIs and gram-negative bacteremia (GNB) was conducted in 2 tertiary hospitals in southern Taiwan between March 2015 and January 2020. Another group were matched by controls with non-GNB based on time, demographics and immune status. Data such as infectious location, comorbidities, and laboratory findings were recorded and compared. Receiver operating curve and the area under the curve were used to evaluate its discriminating ability. A total of 186 patients were included, 62 in GNB group and 124 in non-GNB group. Comorbidities that were significant risk factors for gram-negative bacteremia included acute kidney injury. Significant risk factors evident in laboratory evaluations included higher model for end-stage liver disease score, higher serum lactate, higher C-reactive protein and higher creatinine level. This study found acute kidney injury, or those exhibiting hyperlactatemia (>16 mg/dL), high MELD score (>14), high CRP (>50 mg/dL), and high creatinine (>2.0 mg/dL) were risk factors associated with gram-negative bacteremia. Cirrhotic patients with SSTIs with aforementioned risk factors should pay more attention by clinicians due to higher mortality., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

The diagnostic accuracy of laboratory risk indicator for necrotizing fasciitis (LRINEC) score system in specific Vibrio vulnificus (V vulnificus ) necrotizing fasciitis (NF) have not been fully investigated yet. This aim of our study is to validate the LRINEC score in patients with V vulnificus NF. A retrospective study of hospitalized patients was conducted in a hospital in southern Taiwan between January 2015 and December 2022. Clinical characteristics, variables and outcomes were compared among V vulnificus NF, non- Vibrio NF and cellulitis patients. A total of 260 patients were included, 40 in V vulnificus NF group, 80 in non- Vibrio NF group and 160 patients in cellulitis group. In V vulnificus NF group with an LRINEC cutoff score ≥ 6, the sensitivity was 35% (95% confidence interval [CI]: 29%-41%), specificity was 81% (95% CI: 76%-86%), PPV was 23% (95% CI: 17%-27%), and NPV was 90% (95% CI: 88%-92%). The AUROC for accuracy of the LRINEC score in V vulnificus NF was 0.614 (95% CI: 0.592-0.636). Multi-variable logistic regression analysis revealed that LRINEC > 8 was significantly associated with higher in-hospital mortality (adjusted odds ratio = 1.57; 95% CI: 1.43-2.08; P < .01). The LRINEC score may not be an accurate tool for V vulnificus NF. That should be used with caution as a routine diagnostic tool. However, LRINEC > 8 is significantly associated with higher mortality in V vulnificus NF patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Objectives: The aim of this study is to compare the performance of six clinical physiological-based scores, including the pre-endoscopy Rockall score, shock index (SI), age shock index (age SI), Rapid Acute Physiology Score (RAPS), Rapid Emergency Medicine Score (REMS), and Modified Early Warning Score (MEWS), in predicting in-hospital mortality in elderly and very elderly patients in the emergency department (ED) with acute upper gastrointestinal bleeding (AUGIB). Materials and Methods: Patients older than 65 years who visited the ED with a clinical diagnosis of AUGIB were enrolled prospectively from July 2016 to July 2021. The six scores were calculated and compared with in-hospital mortality. Results: A total of 336 patients were recruited, of whom 40 died. There is a significant difference between the patients in the mortality group and survival group in terms of the six scoring systems. MEWS had the highest area under the curve (AUC) value (0.82). A subgroup analysis was performed for a total of 180 very elderly patients (i.e., older than 75 years), of whom 27 died. MEWS also had the best predictive performance in this subgroup (AUC, 0.82). Conclusions: This simple, rapid, and obtainable-by-the-bed parameter could assist emergency physicians in risk stratification and decision making for this vulnerable group.

Objectives: The purpose of this prospective study was to investigate the different microorganisms associated with mortality, to evaluate the bullous skin sign, and to identify the positive predictive factors for differentiating necrotizing fasciitis (NF) from cellulitis on initial onset at the emergency department., Methods: This prospective study was conducted in 145 consecutive patients with NF and 159 patients with cellulitis. Age, sex, comorbidities, infection site, microbiological results, condition of skin lesions, laboratory findings, vital signs, and clinical outcomes were compared between the two groups at the time of admission to the emergency room., Results: A total of 15 patients in the NF group and two patients in the cellulitis group died, resulting in a mortality rate of 10.3% and 1.3%, respectively. The NF group had a significantly higher incidence of white blood cell counts, band form neutrophil, and C-reactive protein than the patients in the cellulitis group. Hemorrhagic bullae presentation appeared to have significantly associated with NF and death., Conclusion: The following diagnostic indicators can be effectively used to differentiate NF from cellulitis at the initial onset: presence of hemorrhagic bullae, white blood cell counts >11,000 cells/mm 3 , band forms >0%, C-reactive protein >100 mg/l, and systolic blood pressure ≤90 mm Hg at the time of consultation., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Mutations in the neurofilament light polypeptide gene (NEFL) are an uncommon cause of Charcot-Marie-Tooth disease (CMT). The aim of this study is to elucidate the clinical characteristics and genetic spectrum of NEFL-related neuropathy in a Taiwanese CMT cohort., Methods: Mutational analysis of the coding regions of NEFL was performed by Sanger sequencing or targeted resequencing. Twenty-one patients from nine CMT pedigrees, identified from a cohort of 508 unrelated CMT patients, were found to have a NEFL mutation. Genetic, clinical and electrophysiological features were analyzed., Results: Six NEFL mutations were identified, including two novel ones (p.P8S, p.N98Y). NEFL p.E396K was the most common mutation, accounting for 33.3% of the patients in our cohort. All patients manifested sensorimotor polyneuropathy with a mean age of disease onset of 13.5 ± 9.6 (1-40) years. Their motor nerve conduction velocities (MNCVs) of the ulnar nerve ranged from 22.1 to 48.7 m/s. Seventy percent of the patients could be classified as intermediate CMT with ulnar MNCVs between 25 and 45 m/s. Six of the 21 patients (28.6%) had additional features of central nervous system (CNS) involvement, including motor developmental delay, spasticity, cerebellar signs, neuropathic pain and scoliosis., Conclusion: NEFL mutations account for 1.8% (9/508) of the CMT patients in Taiwan. The present study delineates the clinical and genetic characteristics of NEFL-related neuropathy in Taiwan, and highlights that ulnar MNCV above 25 m/s and CNS involvement may serve as diagnostic clues for NEFL-related neuropathy., (Copyright © 2022 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background: Aeromonas necrotizing fasciitis (NF) causes high rates of amputation and mortality, even after aggressive surgical debridement and antibacterial therapy. This study investigated the effects of rational use of antibiotics and education by infectious disease (ID) physicians on Aeromonas NF treatment outcomes., Methods: Retrospective review for conducted for four years (period I, without an ID physician, December 2001 to December 2005) and 15 years (period II, with an ID physician, January 2006 to March 2021). In period II, the hospital-wide computerized antimicrobial approval system (HCAAS) was also implemented. A pretest-posttest time series analysis compared the two periods. Differences in clinical outcomes, demographics, comorbidities, signs and symptoms, laboratory findings, Aeromonas antibiotic susceptibility, and antibiotic regimens were compared between the two periods., Results: There were 19 patients in period I and 53 patients in period II. Patients had a lower rate of amputation or mortality in period II (35.8%) compared with period I (63.2%). Forty-four patients (61.1%) had polymicrobial infections. In the emergency room, the rate of misdiagnosis decreased from 47.4% in period I to 28.3% in period II, while effective empiric antibiotic usage increased from 21.1% in period I to 66.0% in period II. After the ID physician's adjustment, 69.4% received monotherapy in period II compared to 33.3% in period I., Conclusions: Because Aeromonas NF had a high mortality rate and was often polymicrobial, choosing an antibiotic regimen was difficult. Using the HCAAS by an experienced ID physician can improve rational antibiotic usage and clinical outcomes in Aeromonas NF.

Background: To study whether oral presentation (OP) assessment could reflect the novice learners' interpretation skills and reading behaviour on brain computed tomography (CT) reading., Methods: Eighty fifth-year medical students were recruited, received a 2-hour interactive workshop on how to read brain CT, and were assigned to read two brain CT images before and after instruction. We evaluated their image reading behaviour in terms of overall OP post-test rating, the lesion identification, and competency in systematic image reading after instruction. Students' reading behaviour in searching for the target lesions were recorded by the eye-tracking technique and were used to validate the accuracy of lesion reports. Statistical analyses, including lag sequential analysis (LSA), linear mixed models, and transition entropy (TE) were conducted to reveal temporal relations and spatial complexity of systematic image reading from the eye movement perspective., Results: The overall OP ratings [pre-test vs. post-test: 0 vs. 1 in case 1, 0 vs. 1 in case 2, p < 0.001] improved after instruction. Both the scores of systematic OP ratings [0 vs.1 in both cases, p < 0.001] and eye-tracking studies (Case 1: 3.42 ± 0.62 and 3.67 ± 0.37 in TE, p = 0.001; Case 2: 3.42 ± 0.76 and 3.75 ± 0.37 in TE, p = 0.002) showed that the image reading behaviour changed before and after instruction. The results of linear mixed models suggested a significant interaction between instruction and area of interests for case 1 (p < 0.001) and case 2 (p = 0.004). Visual attention to the target lesions in the case 1 assessed by dwell time were 506.50 ± 509.06 and 374.38 ± 464.68 milliseconds before and after instruction (p = 0.02). However, the dwell times in the case 2, the fixation counts and the frequencies of accurate lesion diagnoses in both cases did not change after instruction., Conclusion: Our results showed OP performance may change concurrently with the medical students' reading behaviour on brain CT after a structured instruction., (© 2022. The Author(s).)

Human cervicovaginal fluid (CVF) is a complex, functionally important and glycan rich biological fluid, fundamental in mediating physiological events associated with reproductive health. Using a comprehensive glycomic strategy we reveal an extremely rich and complex N-glycome in CVF of pregnant and non-pregnant women, abundant in paucimannose and high mannose glycans, complex glycans with 2-4 N-Acetyllactosamine (LacNAc) antennae, and Poly-LacNAc glycans decorated with fucosylation and sialylation. N-glycosylation profiles were observed to differ in relation to pregnancy status, microbial composition, immune activation, and pregnancy outcome. Compared to CVF from women experiencing term birth, CVF from women who subsequently experienced preterm birth showed lower sialylation, which correlated to the presence of a diverse microbiome, and higher fucosylation, which correlated positively to pro-inflammatory cytokine concentration. This study is the first step towards better understanding the role of cervicovaginal glycans in reproductive health, their contribution to the mechanism of microbial driven preterm birth, and their potential for preventative therapy., (© 2022. The Author(s).)

Background/purpose: The implementation of competency-based medical education is a social construction process within a local and cultural context. However, little is known about the process of adaptation to different systems, known as "glocalization". We analyzed the documents in the development of a milestone project from adapting global standards into a local context and identified a framework underlying this process., Methods: Taiwan Society of Emergency Medicine (TSEM) had developed learning milestones based on the ACGME's version through series of consensus methods including committee work, nominal group technique (NGT), and a modified Delphi method. We applied qualitative content analysis to characterize the evolution of the three versions of TSEM and the original ACGME milestones documents and to explore the meaning behind the differences revealed by the glocalization process., Results: We found 48 differences between ACGME and TSEM milestones. Among these differences, one was made by committee work, 44 came from NGT, and 3 were from the modified Delphi process. Two themes and seven sub-themes emerged from the coding process to explain the contextualization process of the milestones., Conclusion: We identified a framework that incorporates local expression and local needs into the process called glocalization through which global models of competency-based standards could be optimally implemented in a local context with different systems and cultures., Competing Interests: Declaration of competing interest FC Chou, CT Hsiao, and CW Yang are all members of Task Force of EM Model and Milestone (TEMM) of Taiwan Society of Emergency Medicine., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

The fasting blood glucose (FBG) values extracted from electronic medical records (EMR) are assumed valid in existing research, which may cause diagnostic bias due to misclassification of fasting status. We proposed a machine learning (ML) algorithm to predict the fasting status of blood samples. This cross-sectional study was conducted using the EMR of a medical center from 2003 to 2018 and a total of 2,196,833 ontological FBGs from the outpatient service were enrolled. The theoretical true fasting status are identified by comparing the values of ontological FBG with average glucose levels derived from concomitant tested HbA1c based on multi-criteria. In addition to multiple logistic regression, we extracted 67 features to predict the fasting status by eXtreme Gradient Boosting (XGBoost). The discrimination and calibration of the prediction models were also assessed. Real-world performance was gauged by the prevalence of ineffective glucose measurement (IGM). Of the 784,340 ontologically labeled fasting samples, 77.1% were considered theoretical FBGs. The median (IQR) glucose and HbA1c level of ontological and theoretical fasting samples in patients without diabetes mellitus (DM) were 94.0 (87.0, 102.0) mg/dL and 5.6 (5.4, 5.9)%, and 92.0 (86.0, 99.0) mg/dL and 5.6 (5.4, 5.9)%, respectively. The XGBoost showed comparable calibration and AUROC of 0.887 than that of 0.868 in multiple logistic regression in the parsimonious approach and identified important predictors of glucose level, home-to-hospital distance, age, and concomitantly serum creatinine and lipid testing. The prevalence of IGM dropped from 27.8% based on ontological FBGs to 0.48% by using algorithm-verified FBGs. The proposed ML algorithm or multiple logistic regression model aids in verification of the fasting status., (© 2022. The Author(s).)

Background: Recent changes in medical education calls for a shift toward student-centered learning. Therefore, it is imperative that clinical educators transparently assess the work-readiness of their medical residents through entrustment-based supervision decisions toward independent practice. Similarly, it is critical that medical residents are vocal about the quality of supervision and feedback they receive. This study aimed to explore the factors that influence entrustment-based supervision decisions and feedback receptivity by establishing a general consensus among Taiwanese clinical educators and medical residents regarding entrustment decisions and feedback uptake, respectively., Methods: In Q-methodology studies, a set of opinion statement (i.e., the Q-sample) is generated to represent the phenomenon of interest. To explore the factors that influence entrustment-based supervision decisions and feedback receptivity, a Q-sample was developed using a four-step approach: (1) literature search using electronic databases, such as PubMed and Google Scholar, and interviews with emergency clinical educators and medical residents to generate opinion statements, (2) thematic analysis and grouping using The Model of Trust, the Ready, Wiling, and Able model, and the theory of self-regulated learning, (3) translation, and (4) application of a Delphi technique, including two expert panels comprised of clinical educators and medical residents, to establish a consensus of the statements and validation for a subsequent Q-study., Results: A total of 585 and 1,039 statements from the literature search and interviews were extracted to populate the sample of statements (i.e., the concourse) regarding entrustment-based supervision decisions for clinical educators and feedback receptivity emergency medicine residents, respectively. Two expert panels were invited to participate in a Delphi Technique, comprised of 11 clinical educators and 13 medical residents. After two-rounds of a Delphi technique, the panel of clinical educators agreed on 54 statements on factors that influence entrustment-based supervision decisions and were categorized into five themes defined by the Model of Trust. Similarly, a total of 60 statements on the factors that influence feedback receptivity were retained by the panel of medical residents and were categorized into five themes defined by the Ready, Willing, and Able model and the theory of self-regulated learning., Conclusion: Though not exhaustive, the key factors agreed upon by clinical educators and medical residents reflect the characteristics of entrustment-based supervision decisions and feedback receptivity across specialties. This study provides insight on an often overlooked issue of the paths to teaching and learning in competency-based residency training programs. Additionally, incorporation of the Delphi technique further adds to the existing literature and puts emphasis as an important tool that can be used in medical education to rigorously validate Q-statements and develop Q-samples in various specialties., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chang, Chuang, Hsiao, Khwepeya and Nkambule.)

Background: It remains unclear whether Vibrio vulnificus necrotizing soft tissue infection (NSTI) is associated with higher mortality compared with non-Vibrio NSTI. This study's objective was to compare outcomes including in-hospital mortality and prognosis between patients with V. vulnificus NSTI and those with non-Vibrio NSTI., Method: A retrospective 1:2 matched-pair cohort study of hospitalized patients with NSTI diagnosed by surgical finding was conducted in two tertiary hospitals in southern Taiwan between January 2015 and January 2020. In-hospital outcomes (mortality, length of stay) were compared between patients with and without V. vulnificus infection. We performed multiple imputation using chained equations followed by multivariable regression analyses fitted with generalized estimating equations to account for clustering within matched pairs. All-cause in-hospital mortality and length of stay during hospitalization were compared for NSTI patients with and without V. vulnificus., Result: A total of 135 patients were included, 45 in V. vulnificus NSTI group and 90 in non-Vibrio group. The V. vulnificus NSTI patients had higher mortality and longer hospital stays. Multivariable logistic regression analysis revealed that V. vulnificus NSTI was significantly associated with higher in-hospital mortality compared with non-Vibrio NSTI (adjusted odds ratio = 1.52; 95% confidence interval 1.36-1.70; p < 0.01)., Conclusion: Vibrio vulnificus NSTI was associated with higher in-hospital mortality and longer hospital stay which may increase health care costs, suggesting that preventing V. vulnificus infection is essential., (© 2022. The Author(s).)

Fingerprints are the most common personal identification feature and key evidence for crime scene investigators. The prediction of fingerprints features include gender, height range (tall or short), left or right hand, and finger position can effectively narrow down the list of suspects, increase the speed of comparison, and greatly improve the effectiveness of criminal investigations. In this study, we used three commonly used CNNs (VGG16, Inception-v3, and Resnet50) to perform biometric prediction on 1000 samples, and the results showed that VGG16 achieved the highest accuracy in identifying gender (79.2%), left- and right-hand fingerprints (94.4%), finger position (84.8%), and height range (69.8%, using the ring finger of male participants). In addition, we visualized the CNN classification basis by the Grad-CAM technique and compared the results with those predicted by experts and found that the CNN model outperformed experts in terms of classification accuracy and speed, and provided good reference for fingerprints that were difficult to determine manually.

Background: We conducted this study to evaluate the characteristics of the infectious fluid in soft tissue infection and investigate the utility of the biochemical tests and Gram stain smear of the infectious fluid in distinguishing necrotizing soft tissue infection (NSTI) from cellulitis., Methods: This retrospective cohort study was conducted in a tertiary care hospital in Taiwan. From April 2019 to October 2020, patients who were clinically suspected of NSTI with infectious fluid accumulation along the deep fascia and received successful ultrasound-guided aspiration were enrolled. Based on the final discharge diagnosis, the patients were divided into NSTI group, which was supported by the surgical pathology report, or cellulitis group. The t test method and Fisher's exact test were used to compare the difference between two groups. The receiver-operator characteristic (ROC) curves and area under the ROC curve (AUC) were used to evaluate the discriminating ability., Results: Total twenty-five patients were enrolled, with 13 patients in NSTI group and 12 patients in cellulitis group. The statistical analysis showed lactate in fluid (AUC = 0.937) and LDH in fluid (AUC = 0.929) had outstanding discrimination. The optimal cut-off value of fluid in lactate was 69.6 mg/dL with corresponding sensitivity of 100% and specificity of 76.9%. The optimal cut-off value of fluid in LDH was 566 U/L with corresponding sensitivity of 83.3% and a specificity of 92.3%. In addition, albumin in fluid (AUC = 0.821), TP in fluid (AUC = 0.878) and pH in fluid (AUC = 0.858) also had excellent diagnostic accuracy for NSTI. The Gram stain smear revealed 50% bacteria present in NSTI group and all the following infectious fluid culture showed bacteria growth., Conclusions: The analysis of infectious fluid along the deep fascia might provide high diagnostic accuracy to differentiate NSTI from cellulitis., (© 2022. The Author(s).)

Mass spectrometry-based high-sensitivity mapping of terminal glycotopes relies on diagnostic MS 2 and/or MS 3 ions that can differentiate linkage and define the location of substituents including sulfates. Unambiguous identification of adult zebrafish glycotopes is particularly challenging due to the presence of extra β4-galactosylation on the basic building block of Galβ1-4GlcNAc that can be fucosylated and variably sialylated by N-acetyl, N-glycolyl, or deaminated neuraminic acids. Building on previous groundwork that have identified various organ-specific N- and O-glycans of adult zebrafish, we show here that all the major glycotopes of interest can be readily mapped by direct nano-LC-MS/MS analysis of permethylated glycans. Homing in on the brain-, intestine-, and ovary-derived samples, organ-specific glycomic reference maps based on overlaid extracted ion chromatograms of resolved glycan species, and composite charts of summed intensities of diagnostic MS 2 ions representing the distribution and relative abundance of each of the glycotopes and sialic acid variants were established. Moreover, switching to negative mode analysis of sample fractions enriched in negatively charged glycans, we show, for the first time, that a full range of sulfated glycotopes is expressed in adult zebrafish. In particular, 3-O-sulfation of terminal Gal was commonly found, whereas terminal sulfated HexNAc as in GalNAcβ1-4GlcNAc (LacdiNAc), and 3-O-sulfated hexuronic acid as in HNK-1 epitope (SO 3 -3GlcAβ1-3Galβ1-4GlcNAc) were identified only in the brain and not in the intestine or ovaries analyzed in parallel. Other characteristic structural features of sulfated O- and N-glycans along with their diagnostic ions detected in this discovery mode sulfoglycomic work collectively expand our adult zebrafish glycome atlas, which can now allow for a more complete navigation and probing of the underlying sulfotransferases and glycosyltransferases, in search of the functional relevance of zebrafish-specific glycotopes. Of particular importance is the knowledge of glycomic features distinct from those of humans when using adult zebrafish as an alternative vertebrate model, rather than mouse, for brain-related glyco-neurobiology studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tseng, Hsiao, Yamakawa, Guérardel and Khoo.)

Background: The lactate/albumin (L/A) ratio has been proposed as a prognostic marker because the ratio is associated with multiple organ failure and mortality in critically ill patients. We aimed to investigate the clinical utility of the L/A ratio as a good prognostic indicator of mortality in a cohort of necrotizing fasciitis patients., Method: This retrospective study was conducted in two tertiary hospitals in Taiwan between 2015 and 2020. We reviewed adult patients with measured serum lactate and albumin on the emergency department (ED) arrival to evaluate the prognostic performance of the lactate and lactate/albumin (L/A) ratio for outcome prediction., Result: Of the 262 NF patients, 20 (7.63%) died in the hospital. The area under the receiver operating characteristic curve (AUROC) value of the L/A ratio (0.76, 95% confidence interval [CI] 0.69-0.81, P < 0.01) was higher than lactate alone (0.71, 95% CI 0.65-0.74 P < 0.01) for predicting in-hospital mortality. The optimal cutoff of the L/A ratio was 1.61. The AUROC value of the L/A ratio was better than lactate alone regardless of normal lactate level. The cutoff of L/A ratio and hypoalbuminemia showed further discriminative value for in-hospital mortality even in patients with normal lactate levels., Conclusion: The prognostic performance of the L/A ratio was superior to a single measurement of lactate for predicting in-hospital mortality and intensive care unit (ICU) lengths in necrotizing fasciitis patients. Aggressive intervention and intensive care were necessary for high-risk NF patients upon ED arrival., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Kiew-Kii Lau et al.)

Background: Vibrio vulnificus has been reported as the leading causative pathogen of necrotizing fasciitis (NF) and related fatality in the coastal area. Necrotizing fasciitis caused by methicillin-resistant Staphylococcus aureus (MRSA) and V. vulnificus have high mortality rates. The purpose of this prospective study was to clarify the clinical characteristics between death and survival NF patients, to investigate bacteriologic profile and mortality of NF patients, and to compare risk indicators of MRSA and V. vulnificus NF patients., Methods: This prospective study was conducted in 184 consecutive NF patients over a period of three years in a tertiary coastal hospital. Differences in mortality, laboratory findings, microbiology and clinical outcomes were compared between the death and survival groups, and the V. vulnificus and MRSA subgroups., Results: Twenty patients died, resulting in a mortality rate of 10.9%, and there were 108 patients with a monomicrobial infection (58.7%). The death group had a significantly higher incidence of shock at emergency room and bacteremia than did the survival group. Vibrio species (40 cases) and S. aureus (31 cases) were the two major pathogens. Significant differences with respect to hepatic dysfunction, shock, the event with seawater or seafood contact, bacteremia, C-reactive protein, mean platelet counts, and the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score were observes between V. vulnificus and MRSA groups., Conclusions: NF patients with both hepatic dysfunction and diabetes mellitus, bacteremia and shock have significantly higher mortality. We should be aware of the increasing incidence of monomicrobial NF and higher mortality rates of Gram-negative pathogens in the warm coastal area. LRINEC score is not a suitable diagnostic indicator for V. vulnificus NF, which is more rapidly progressive and fulminant than MRSA NF. NF needed team works by early suspicion, immediate surgical intervention and aggressive care, which can successfully decrease mortality., (© 2021. The Author(s).)

Loss-of-function mutations in the K V 4.3 channel-encoding KCND3 gene are linked to neurodegenerative cerebellar ataxia. Patients suffering from neurodegeneration associated with iron deposition may also present with cerebellar ataxia. The mechanism underlying brain iron accumulation remains unclear. Here, we aim to ascertain the potential pathogenic role of KCND3 variant in iron accumulation-related cerebellar ataxia. We presented a patient with slowly progressive cerebellar ataxia, parkinsonism, cognitive impairment, and iron accumulation in the basal ganglia and the cerebellum. Whole exome sequencing analyses identified in the patient a heterozygous KCND3 c.1256G>A (p.R419H) variant predicted to be disease-causing by multiple bioinformatic analyses. In vitro biochemical and immunofluorescence examinations revealed that, compared to the human K V 4.3 wild-type channel, the p.R419H variant exhibited normal protein abundance and subcellular localization pattern. Electrophysiological investigation, however, demonstrated that the K V 4.3 p.R419H variant was associated with a dominant increase in potassium current amplitudes, as well as notable changes in voltage-dependent gating properties leading to enhanced potassium window current. These observations indicate that, in direct contrast with the loss-of-function KCND3 mutations previously reported in cerebellar ataxia patients, we identified a rare gain-of-function KCND3 variant that may expand the clinical and molecular spectra of neurodegenerative cerebellar disorders associated with brain iron accumulation.

The ClC-2 channel plays a critical role in maintaining ion homeostasis in the brain and the testis. Loss-of-function mutations in the ClC-2-encoding human CLCN2 gene are linked to the white matter disease leukodystrophy. Clcn2 -deficient mice display neuronal myelin vacuolation and testicular degeneration. Leukodystrophy-causing ClC-2 mutant channels are associated with anomalous proteostasis manifesting enhanced endoplasmic reticulum (ER)-associated degradation. The molecular nature of the ER quality control system for ClC-2 protein remains elusive. In mouse testicular tissues and Leydig cells, we demonstrated that endogenous ClC-2 co-existed in the same protein complex with the molecular chaperones heat shock protein 90β (Hsp90β) and heat shock cognate protein (Hsc70), as well as the associated co-chaperones Hsp70/Hsp90 organizing protein (HOP), activator of Hsp90 ATPase homolog 1 (Aha1), and FK506-binding protein 8 (FKBP8). Further biochemical analyses revealed that the Hsp90β-Hsc70 chaperone/co-chaperone system promoted mouse and human ClC-2 protein biogenesis. FKBP8 additionally facilitated membrane trafficking of ClC-2 channels. Interestingly, treatment with the Hsp90-targeting small molecule 17-allylamino-17-demethoxygeldanamycin (17-AAG) substantially boosted ClC-2 protein expression. Also, 17-AAG effectively increased both total and cell surface protein levels of leukodystrophy-causing loss-of-function ClC-2 mutant channels. Our findings highlight the therapeutic potential of 17-AAG in correcting anomalous ClC-2 proteostasis associated with leukodystrophy.

Background: We conducted this study to promote a modified Laboratory Risk Indicator for Necrotizing Fasciitis (MLRINEC) score and evaluate the utility in distinguishing necrotizing fasciitis (NF) from other soft-tissue infections., Method: A retrospective cohort study of hospitalized patients with NF diagnosed by surgical finding was conducted in two tertiary hospital in southern Taiwan between January 2015 and January 2020. Another group was matched by controls with non-necrotizing soft tissue infections based on time, demographics, and immune status. Data such as infectious location, comorbidities, and laboratory findings were recorded and compared. Logistics regression were used to determine the association with NF after adjustment for confounders and MLRINEC score was developed by then. Receiver operating curve (ROC) and the area under the curve (AUC) were used to evaluate its discriminating ability., Result: A total of 303 patients were included; 101 in NF group and 202 in non-NF group. We added serum lactate and comorbid liver disease to the original LRINEC score and re-defined the cut-off values for 3 variables to develop the MLRINEC score. The cut-off value for MLRINEC score was 12 points with corresponding sensitivity of 91.8% and a specificity of 88.4%, and the area under ROC (AUC) was 0.893 (95% CI, 0.723 to 0.948; p < 0.01)., Conclusion: MLRINEC score shows a high sensitivity and specificity in distinguishing NF from non-necrotizing soft-tissue infections. Patients with a MLRINEC score > 12 points should be highly suspected of presence of necrotizing fasciitis.

KCND3 encodes the voltage-gated potassium channel K V 4.3 that is highly expressed in the cerebellum, where it regulates dendritic excitability and calcium influx. Loss-of-function K V 4.3 mutations have been associated with dominant spinocerebellar ataxia (SCA19/22). By targeted NGS sequencing, we identified two novel KCND3 missense variants of the K V 4.3 channel: p.S347W identified in a patient with adult-onset pure cerebellar syndrome and p.W359G detected in a child with congenital nonprogressive ataxia. Neuroimaging showed mild cerebellar atrophy in both patients. We performed a two-electrode voltage-clamp recording of K V 4.3 currents in Xenopus oocytes: both the p.G345V (previously reported in a SCA19/22 family) and p.S347W mutants exhibited reduced peak currents by 50%, while no K+ current was detectable for the p.W359G mutant. We assessed the effect of the mutations on channel gating by measuring steady-state voltage-dependent activation and inactivation properties: no significant alterations were detected in p.G345V and p.S347W disease-associated variants, compared to controls. K V 4.3 expression studies in HEK293T cells showed 53% (p.G345V), 45% (p.S347W) and 75% (p.W359G) reductions in mutant protein levels compared with the wildtype. The present study broadens the spectrum of the known phenotypes and identifies additional variants for KCND3 -related disorders, outlining the importance of SCA gene screening in early-onset and congenital ataxia.

The role of the difference and ratio of albuminuria (urine albumin-to-creatinine ratio, uACR) and proteinuria (urine protein-to-creatinine ratio, uPCR) has not been systematically evaluated with all-cause mortality. We retrospectively analyzed 2904 patients with concurrently measured uACR and uPCR from the same urine specimen in a tertiary hospital in Taiwan. The urinary albumin-to-protein ratio (uAPR) was derived by dividing uACR by uPCR, whereas urinary non-albumin protein (uNAP) was calculated by subtracting uACR from uPCR. Conventional severity categories of uACR and uPCR were also used to establish a concordance matrix and develop a corresponding risk matrix. The median age at enrollment was 58.6 years (interquartile range 45.4-70.8). During the 12,391 person-years of follow-up, 657 deaths occurred. For each doubling increase in uPCR, uACR, and uNAP, the adjusted hazard ratios (aHRs) of all-cause mortality were 1.29 (95% confidence interval [CI] 1.24-1.35), 1.12 (1.09-1.16), and 1.41 (1.34-1.49), respectively. For each 10% increase in uAPR, it was 1.02 (95% CI 0.98-1.06). The linear dose-response association with all-cause mortality was only observed with uPCR and uNAP. The 3 × 3 risk matrices revealed that patients with severe proteinuria and normal albuminuria had the highest risk of all-cause mortality (aHR 5.25, 95% CI 1.88, 14.63). uNAP significantly improved the discriminative performance compared to that of uPCR (c statistics: 0.834 vs. 0.828, p-value = 0.032). Our study findings advocate for simultaneous measurements of uPCR and uACR in daily practice to derive uAPR and uNAP, which can provide a better mortality prognostic assessment.

The effects of the viscoelastic shell properties of ultrasound contrast agents on heat deposition in bubble enhanced high intensity focused ultrasound (HIFU) are studied numerically using a model that solves the ultrasound acoustic field and the multi-bubble dynamics. The propagation of the nonlinear acoustic waves in the test medium is modeled using the compressible Navier-Stokes equations in a fixed Eulerian grid, while the microbubbles are modeled as discrete flow singularities, which are tracked in a Lagrangian fashion. These two models are intimately coupled such that both the acoustic field and the bubbles influence each other at each time step. The resulting temperature rise in the field is then calculated by solving a heat transfer equation applied over a much longer time scale than the computed high frequency dynamics. Three shell models for the contrast agent are considered, and the effect of each of these models on the heat deposition at the focus is studied. The differences obtained in the bubble dynamics results between the shell models are discussed. The importance of modeling the elasticity of the shell is addressed by comparing the results between Newtonian and non-Newtonian shell models. Next, a parametric study varying the shell properties is carried out, and the relative roles of the shell viscosity and elasticity in affecting the heat deposition are discussed. These observations are then used to give recommendations for the design of innovative contrast agents, specifically for the purpose of obtaining higher heat deposition in bubble enhanced HIFU.

Voltage-gated ClC-2 channels are essential for chloride homeostasis. Complete knockout of mouse ClC-2 leads to testicular degeneration and neuronal myelin vacuolation. Gain-of-function and loss-of-function mutations in the ClC-2-encoding human CLCN2 gene are linked to the genetic diseases aldosteronism and leukodystrophy, respectively. The protein homeostasis (proteostasis) mechanism of ClC-2 is currently unclear. Here, we aimed to identify the molecular mechanism of endoplasmic reticulum-associated degradation of ClC-2, and to explore the pathophysiological significance of disease-associated anomalous ClC-2 proteostasis. In both heterologous expression system and native neuronal and testicular cells, ClC-2 is subject to significant regulation by cullin-RING E3 ligase-mediated polyubiquitination and proteasomal degradation. The cullin 4 (CUL4)-damage-specific DNA binding protein 1 (DDB1)-cereblon (CRBN) E3 ubiquitin ligase co-exists in the same complex with and promotes the degradation of ClC-2 channels. The CRBN-targeting immunomodulatory drug lenalidomide and the cullin E3 ligase inhibitor MLN4924 promotes and attenuates, respectively, proteasomal degradation of ClC-2. Analyses of disease-related ClC-2 mutants reveal that aldosteronism and leukodystrophy are associated with opposite alterations in ClC-2 proteostasis. Modifying CUL4 E3 ligase activity with lenalidomide and MLN4924 ameliorates disease-associated ClC-2 proteostasis abnormality. Our results highlight the significant role and therapeutic potential of CUL4 E3 ubiquitin ligase in regulating ClC-2 proteostasis.

The optimal timing to initiate dialysis among patients with an estimated glomerular filtration rate (eGFR) of <5 mL/min/1.73 m2 is unknown. We hypothesized that dialysis initiation time can be deferred in this population even with high uremic burden. A case-crossover study with case (0-30 days before dialysis initiation [DI]) and control (90-120 days before DI) periods was conducted in 1,079 hemodialysis patients aged 18-90 years at China Medical University Hospital between 2006 and 2015. The uremic burden was quantified based on 7 uremic indicators that reached the predefined threshold in case period, namely hemoglobin, serum albumin, blood urea nitrogen, serum creatinine, potassium, phosphorus, and bicarbonate. Dialysis timing was classified as standard (met 0-2 uremic indicators), late (3-5 indicators), and very late (6-7 indicators). Median eGFR-DI of the 1,079 patients was 3.4 mL/min/1.73 m2 and was 2.7 mL/min/1.73 m2 in patients with very late initiation. The median follow-up duration was 2.42 years. Antibiotics, diuretics, antihypertensive medications, and non-steroidal anti-inflammatory drugs (NSAIDs) were more prevalently used during the case period. The fully adjusted hazards ratios of all-cause mortality for the late and very late groups were 0.97 (95% confidence interval 0.76-1.24) and 0.83 (0.61-1.15) compared with the standard group. It is safe to defer dialysis initiation among patients with chronic kidney disease (CKD) having an eGFR of <5 mL/min/1.73 m2 even when patients having multiple biochemical uremic burdens. Coordinated efforts in acute infection prevention, optimal fluid management, and prevention of accidental exposure to NSAIDs are crucial to prolong the dialysis-free survival., Competing Interests: The authors have declared that no competing interests exist.

Background: The increasingly complex medical environment highlights the importance of milestones and entrustable professional activities (EPAs) to realize the ideals of competency-based medical education (CBME). However, if enormous amounts of assessment results need to be compiled, the development of a digital system to manage, integrate, and synthesize learning and assessment data will be necessary. Furthermore, this system should be able to facilitate real-time assessment with feedback and therefore enhance users' learning through coaching in the moment in the clinical workplace., Objective: The main purpose of this study was to develop a competency-based electronic platform system to provide resident physicians with clinical assessments and learning in order to enhance the learning of trainees and reduce the burden of assessments., Methods: A competency-based learning and assessment system (CBLAS) for residency training was designed, developed, and evaluated in this study. Opinion interviews and a focus group consensus meeting of key users, including trainees, clinical teachers, and administrative staff, were conducted as needs assessments. The structure of the CBLAS was designed according to the thematic analysis of needs assessments. Clinical teachers' acceptance of using CBME assessments, according to the constructs of attitude, perceived usefulness, and perceived ease of use, was surveyed in the beginning and half a year after implementation of the CBLAS. Additionally, the satisfaction of using the CBLAS, according to information, system, and service qualities, was surveyed after implementation., Results: The main functions of the CBLAS, including milestones, EPAs, learning portfolios, teacher/student feedback, e-books, learning materials, assessment progress tracking, and statistical analysis of assessment results, were designed and developed for responding to nine themes, which emerged from the needs assessments of the three user groups. Twenty clinical teachers responded to the CBME assessment acceptance surveys before and after CBLAS implementation, which revealed a significant improvement in the factor of "attitude" (P=.02) but no significant differences in the two factors of "usefulness" (P=.09) and "ease of use" (P=.58) for CBME assessments. Furthermore, satisfaction surveys were performed in 117 users, and 87.2% (102/117) were satisfied with the CBLAS in terms of information, system, and service qualities. There was no significant difference in satisfaction among different user groups., Conclusions: The CBLAS is a user-centered platform that supports clinical teachers' assessment exercises and residents' learning, as well as administrative work for staff according to users' needs assessments and operationalized features of CBME assessments. With the system, clinical teachers had a more positive attitude to conduct the assessment activities of milestones and EPAs and learners could arrange their study schedules to enhance their learning effectiveness. The CBLAS sheds light on how to effectively design and develop a digital system to execute milestone- and EPA-based assessments for enhancing competency-based education among residents, according to our experiences in Taiwan., (©Cheng-Ting Hsiao, Fremen ChihChen Chou, Chih-Cheng Hsieh, Li Chun Chang, Chih-Ming Hsu. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 14.04.2020.)

The voltage-dependent ClC-1 chloride channel, whose open probability increases with membrane potential depolarization, belongs to the superfamily of CLC channels/transporters. ClC-1 is almost exclusively expressed in skeletal muscles and is essential for stabilizing the excitability of muscle membranes. Elucidation of the molecular structures of human ClC-1 and several CLC homologs provides important insight to the gating and ion permeation mechanisms of this chloride channel. Mutations in the human CLCN1 gene, which encodes the ClC-1 channel, are associated with a hereditary skeletal muscle disease, myotonia congenita. Most disease-causing CLCN1 mutations lead to loss-of-function phenotypes in the ClC-1 channel and thus increase membrane excitability in skeletal muscles, consequently manifesting as delayed relaxations following voluntary muscle contractions in myotonic subjects. The inheritance pattern of myotonia congenita can be autosomal dominant (Thomsen type) or recessive (Becker type). To date over 200 myotonia-associated ClC-1 mutations have been identified, which are scattered throughout the entire protein sequence. The dominant inheritance pattern of some myotonia mutations may be explained by a dominant-negative effect on ClC-1 channel gating. For many other myotonia mutations, however, no clear relationship can be established between the inheritance pattern and the location of the mutation in the ClC-1 protein. Emerging evidence indicates that the effects of some mutations may entail impaired ClC-1 protein homeostasis (proteostasis). Proteostasis of membrane proteins comprises of biogenesis at the endoplasmic reticulum (ER), trafficking to the surface membrane, and protein turn-over at the plasma membrane. Maintenance of proteostasis requires the coordination of a wide variety of different molecular chaperones and protein quality control factors. A number of regulatory molecules have recently been shown to contribute to post-translational modifications of ClC-1 and play critical roles in the ER quality control, membrane trafficking, and peripheral quality control of this chloride channel. Further illumination of the mechanisms of ClC-1 proteostasis network will enhance our understanding of the molecular pathophysiology of myotonia congenita, and may also bring to light novel therapeutic targets for skeletal muscle dysfunction caused by myotonia and other pathological conditions., (Copyright © 2020 Jeng, Fu, You, Peng, Hsiao, Chen and Tang.)

Objectives: The Laboratory Risk Indicator for Necrotizing Fasciitis score was developed as a clinical decision tool for distinguishing necrotizing fasciitis from other soft tissue infections. We prospectively evaluated the performance of the Laboratory Risk Indicator for Necrotizing Fasciitis score for the diagnosis of patients with necrotizing fasciitis in the extremities., Methods: We conducted a prospective and observational cohort study of emergency department patients with necrotizing fasciitis or severe cellulitis in the extremities between April 2015 and December 2016. The Laboratory Risk Indicator for Necrotizing Fasciitis score was calculated for every enrolled patient. The sensitivity, specificity, positive predictive value, and negative predictive value of cut-off scores of 6 and 8 were evaluated. The accuracy of the Laboratory Risk Indicator for Necrotizing Fasciitis score was expressed as the area under the receiver operating characteristic curve., Results: A total of 106 patients with necrotizing fasciitis and 825 patients with cellulitis were included. With an Laboratory Risk Indicator for Necrotizing Fasciitis cut-off score ≥6, the sensitivity was 43% (95% confidence interval 34% to 53%), specificity was 83% (95% confidence interval 80% to 86%), positive predictive value was 25% (95% confidence interval 20% to 30%), and negative predictive value was 92% (95% confidence interval 91% to 93%); with an Laboratory Risk Indicator for Necrotizing Fasciitis cut-off score ≥8, the sensitivity was 27% (95% confidence interval 19% to 37%), specificity was 93% (95% confidence interval 91% to 94%), positive predictive value was 33% (95% confidence interval 25% to 42%), and negative predictive value was 91% (95% confidence interval 90% to 92%). The area under the receiver operating characteristic curve for accuracy of the Laboratory Risk Indicator for Necrotizing Fasciitis score was 0.696 (95% CI 0.640 to 0.751)., Conclusion: The Laboratory Risk Indicator for Necrotizing Fasciitis score may not be an accurate tool for necrotizing fasciitis risk stratification and differentiation between severe cellulitis and necrotizing fasciitis in the emergency department setting based on our study., Competing Interests: The authors have declared that no competing interests exist.

Background: Necrotizing fasciitis (NF) is a rare and life-threatening necrotizing skin and soft-tissue infection. Infectious pathogens of NF must be detected early and treated rapidly to prevent loss of limb or a fatal outcome. This study aimed to detect more reliable predictors between gram-negative and gram-positive monomicrobial NF of limbs., Methods: A total of 100 patients with limb monomicrobial NF were diagnosed prospectively from April 2015 to July 2018. These monomicrobial NF pathogens can be divided into gram-negative and gram-positive groups according to the result of Gram staining and final bacterial reports. Data such as demographics, seawater or seafood contact history, infectious location, comorbidities, presenting signs and symptoms, and laboratory findings were recorded and compared., Results: A total of 55 patients were infected with gram-negative organisms and 45 patients with gram-positive organisms. Among the 55 cases of monomicrobial gram-negative NF, 48 (87.3%) were caused mainly by Vibrio spp. (38, 69.1%) and Aeromonas spp. (10, 18.2%). A higher incidence of chronic kidney disease, cerebrovascular accident, tachypnea, and septic shock; a higher rate of band forms of leukocytes of more than 3%, serum lactate of more than 20 mg/dL, and C-reactive protein level of less than 150 mg/dL; prolonged prothrombin time; and a lower fibrinogen level were observed in patients with gram-negative infection. In a multivariate analysis, a higher incidence of seawater or seafood contact history (odds ratio [OR]: 66.301; 95% confidence interval [CI]: 7.467-588.702), a higher rate of hyperlactatemia (OR: 7.904; 95% CI: 1.231-50.744), and a low fibrinogen level (OR: 1.013; 95% CI: 1.004-1.023) indicated gram-negative infection., Conclusions: In southern Taiwan, NF of limbs mainly affected the lower limbs, exhibited monomicrobial infection, and was predominated by gram-negative bacteria. Gram-negative monomicrobial NF of limbs often occurred in individuals with the more seawater or seafood contact history, hyperlactatemia, and low fibrinogen levels.

Background: The overcrowded environments of emergency departments (EDs) lead to increased clinical workloads for nurses and infl uences the quality of patient care. This study aimed to evaluate whether the quality of patient care meets the expectations of emergency nurses in Taiwan by measuring the amount of time nurses spend on patient care activities., Methods: The direct observation study was conducted in one suburban academic hospital with approximately 80,000 annual ED visits. This study observed emergency nurses and the time they spent on their nursing activities. The directly measured times and nurse expected patient care nursing times were compared., Results: For all 88 types of nursing activities recorded, each measured nursing time was less than the expected nursing time. On average, the measured nursing time was 82% less than the expected nursing time (2.0 ± 0.3 minutes vs. 11.6 ± 1.5 minutes, p < 0.01). Among the 88 types of nursing activities recorded, the average measured time spent on 76 types (86%) was less than 3 minutes. The nursing activity on which the longest time was spent was cerebrospinal fl uid study nursing (7 minutes). The most frequent nursing activity was documentation., Conclusion: The nursing time spent on patient-care activities in EDs was much less than the nurses expected. The results may provide a basis for nursing quality measurements and manpower calculations for EDs., (Copyright © 2019 by Taiwan Society of Emergency Medicine & Ainosco Press. All Rights Reserved.)