Inhibition of endocytic uptake of severe acute respiratory syndrome coronavirus 2 and endo-lysosomal acidification by diphenoxylate.

Cell culture-based screening of a chemical library identified diphenoxylate as an antiviral agent against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The observed 50% effective concentrations ranged between 1.4 and 4.9 µM against the original wild-type strain and its variants. Time-of-addition experiments indicated that diphenoxylate is an entry blocker targeting a host factor involved in viral infection. Fluorescence microscopic analysis visualized that diphenoxylate prevented SARS-CoV-2 particles from penetrating the cell membrane and also impaired endo-lysosomal acidification. Diphenoxylate exhibited a synergistic inhibitory effect on SARS-CoV-2 infection in human lung epithelial Calu-3 cells when combined with a transmembrane serine protease 2 (TMPRSS2) inhibitor, nafamostat. This synergy suggested that efficient antiviral activity is achieved by blocking both TMPRSS2-mediated early and endosome-mediated late SARS-CoV-2 entry pathways. The antiviral efficacy of diphenoxylate against SARS-CoV-2 was reproducible in a human tonsil organoids system. In a transgenic mouse model expressing the obligate SARS-CoV-2 receptor, human angiotensin-converting enzyme 2, intranasal administration of diphenoxylate (10 mg/kg/day) significantly reduced the viral RNA copy number in the lungs by 70% on day 3. This study underscores that diphenoxylate represents a promising core scaffold, warranting further exploration for chemical modifications aimed at developing a new class of clinically effective antiviral drugs against SARS-CoV-2.

Prognostic Impact of Visceral Adipose Tissue Imaging Parameters in Patients with Cholangiocarcinoma after Surgical Resection.

Visceral adiposity is known to be related to poor prognosis in patients with cholangiocarcinoma; however, the prognostic significance of the qualitative features of adipose tissue in cholangiocarcinoma has yet to be well defined. This study investigated the prognostic impact of adipose tissue imaging parameters reflecting the quantity and qualitative characteristics of subcutaneous (SAT) and visceral (VAT) adipose tissue on recurrence-free survival (RFS) and overall survival (OS) in 94 patients undergoing resection of cholangiocarcinoma. The area, mean computed tomography (CT) attenuation, and mean 2-deoxy-2-[18F]fluoro-D-glucose (FDG) uptake of SAT and VAT on positron emission tomography (PET)/CT for staging work-up were measured, and the relationship of these adipose tissue imaging parameters with clinicopathological factors and survival was assessed. TNM stage, histologic grade, lymphovascular invasion, and the size of cholangiocarcinoma showed positive correlations with adipose tissue imaging parameters. Multivariate survival analysis demonstrated that the visceral-to-subcutaneous adipose tissue area ratio (VSR) (p = 0.024; hazard ratio, 1.718) and mean FDG uptake of VAT (p = 0.033; hazard ratio, 9.781) were significant predictors for RFS, but all of the adipose tissue imaging parameters failed to show statistical significance for predicting OS. In addition to visceral adiposity, FDG uptake of VAT might be a promising prognostic parameter for predicting RFS in patients with cholangiocarcinoma.

Intermolecular Interactions between Cysteine and Aromatic Amino Acids with a Phenyl Moiety in the DNA-Binding Domain of Heat Shock Factor 1 Regulate Thermal Stress-Induced Trimerization.

In this study, we investigated the trimerization mechanism and structure of heat shock factor 1 (HSF1) using western blotting, tryptophan (Trp) fluorescence spectroscopy, and molecular modeling. First, we examined the DNA-binding domains of human (Homo sapiens), goldfish (Carassius auratus), and walleye pollock (Gadus chalcogrammus) HSF1s by mutating key residues (36 and 103) that are thought to directly affect trimer formation. Human, goldfish, and walleye pollock HSF1s contain cysteine at residue 36 but cysteine (C), tyrosine (Y), and phenylalanine (F), respectively, at residue 103. The optimal trimerization temperatures for the wild-type HSF1s of each species were found to be 42, 37, and 20 °C, respectively. Interestingly, a mutation experiment revealed that trimerization occurred at 42 °C when residue 103 was cysteine, at 37 °C when it was tyrosine, and at 20 °C when it was phenylalanine, regardless of the species. In addition, it was confirmed that when residue 103 of the three species was mutated to alanine, trimerization did not occur. This suggests that in addition to trimerization via disulfide bond formation between the cysteine residues in human HSF1, trimerization can also occur via the formation of a different type of bond between cysteine and aromatic ring residues such as tyrosine and phenylalanine. We also confirmed that at least one cysteine is required for the trimerization of HSF1s, regardless of its position (residue 36 or 103). Additionally, it was shown that the trimer formation temperature is related to growth and survival in fish.

Short-term inhalation exposure to cigarette smoke induces oxidative stress and inflammation in lungs without systemic oxidative stress in mice.

Smoking is a well-established risk factor for various pathologies, including pulmonary diseases, cardiovascular disorders, and cancers. The toxic effects of cigarette smoke (CS) are mediated through multiple pathways and diverse mechanisms. A key pathogenic factor is oxidative stress, primarily induced by excessive formation of reactive oxygen species. However, it remains unclear whether smoking directly induces systemic oxidative stress or if such stress is a secondary consequence. This study aimed to determine whether short-term inhalation exposure to CS induces oxidative stress in extrapulmonary organs in addition to the lung in a murine model. In the experiment, 3R4F reference cigarettes were used to generate CS, and 8-week-old male BALB/c mice were exposed to CS at a total particulate matter concentration of either 0 or 800 µg/L for four consecutive days. CS exposure led to an increase in neutrophils, eosinophils, and total cell counts in bronchoalveolar lavage fluid. It also elevated levels of lactate dehydrogenase and malondialdehyde (MDA), markers indicative of tissue damage and oxidative stress, respectively. Conversely, no significant changes were observed in systemic oxidative stress markers such as total oxidant scavenging capacity, MDA, glutathione (GSH), and the GSH/GSSG ratio in blood samples. In line with these findings, CS exposure elevated NADPH oxidase (NOX)-dependent superoxide generation in the lung but not in other organs like the liver, kidney, heart, aorta, and brain. Collectively, our results indicate that short-term exposure to CS induces inflammation and oxidative stress in the lung without significantly affecting oxidative stress in extrapulmonary organs under the current experimental conditions. NOX may play a role in these pulmonary-specific events.

pH Dependence of HSF1 trimerization is shaped by intramolecular interactions.

Heat shock factor 1 (HSF1) primarily regulates various cellular stress responses. Previous studies have shown that low pH within the physiological range directly activates HSF1 function in vitro. However, the detailed molecular mechanisms remain unclear. This study proposes a molecular mechanism based on the trimerization behavior of HSF1 at different pH values. Extensive mutagenesis of human and goldfish HSF1 revealed that the optimal pH for trimerization depended on the identity of residue 103. In particular, when residue 103 was occupied by tyrosine, a significant increase in the optimal pH was observed, regardless of the rest of the sequence. This behavior can be explained by the protonation state of the neighboring histidine residues, His101 and His110. Residue 103 plays a key role in trimerization by forming disulfide or non-covalent bonds with Cys36. If tyrosine resides at residue 103 in an acidic environment, its electrostatic interactions with positively charged histidine residues prevent effective trimerization. His101 and His110 are neutralized at a higher pH, which releases Tyr103 to interact with Cys36 and drives the effective trimerization of HSF1. This study showed that the protonation state of a histidine residue can regulate the intramolecular interactions, which consequently leads to a drastic change in the oligomerization behavior of the entire protein.

Role of microsomal metabolism in bromfenac-induced cytotoxicity.

This study delves into the intricate mechanisms underlying drug-induced liver injury (DILI) with a specific focus on bromfenac, the withdrawn nonsteroidal anti-inflammatory drug. DILI is a pervasive concern in drug development, prompting market withdrawals and posing significant challenges to healthcare. Despite the withdrawal of bromfenac due to DILI, the exact role of its microsomal metabolism in inducing hepatotoxicity remains unclear. Herein, employing HepG2 cells with human liver microsomes and UDP-glucuronic acid (UDPGA), our investigation revealed a substantial increase in bromfenac-induced cytotoxicity in the presence of UDPGA, pointing to the significance of UDP-glucuronosyltransferase (UGT)-dependent metabolism in augmenting toxicity. Notably, among the recombinant UGTs examined, UGT2B7 emerged as a pivotal enzyme in the metabolic activation of bromfenac. Metabolite identification studies disclosed the formation of reactive intermediates, with bromfenac indolinone (lactam) identified as a potential mediator of hepatotoxic effects. Moreover, in cytotoxicity experiments, the toxicity of bromfenac lactam exhibited a 34-fold increase, relative to bromfenac. The toxicity of bromfenac lactam was mitigated by nicotinamide adenine dinucleotide phosphate-dependent metabolism. This finding underscores the role of UGT-dependent metabolism in generating reactive metabolites that contribute to the observed hepatotoxicity associated with bromfenac. Understanding these metabolic pathways and the involvement of specific enzymes, such as UGT2B7, provides crucial insights into the mechanisms of bromfenac-induced liver injury. In conclusion, this research sheds light on the metabolic intricacies leading to cytotoxicity induced by bromfenac, especially emphasizing the role of UGT-dependent metabolism and the formation of reactive intermediates like bromfenac lactam. These findings offer insight into the mechanistic basis of DILI and emphasize the importance of understanding metabolism-mediated toxicity.

Effect analysis on waste recycling by introducing a new policy, "Environmental Assessment of Recycling," for establishment of the ESG management system in the Republic of Korea.

To move away from linear system mining-manufacture-production-disposal, most countries have been trying to establish a circular economy, by reusing waste as resources. Responding to this paradigm change, the Ministry of Environment of Korea amended the Wastes Control Act in the 2010s. To increase the recycling rate in Korea, the environmental assessment of recycling (EAR) has been introduced to improve the Wastes Control Act. The whole process of new recycling technologies can be assessed in terms of environmental or technical aspects by assessment institutes of the EAR. Finally, the governmental research institute can approve of an application case, which proves environmental friendliness, even if the technology is not defined in the current act. Recently, 17 companies have been coassessed and approved to recycle steel codes in waste tires as resources for iron smelting via assessments of the whole process, such as environmental analysis and quality assessment. The EAR has been enforcing recycling materials for six years, and the total profit of the companies that were approved was estimated to be approximately 55 million USD. However, many amendments to the EAR continue to be requested by stakeholders. In this study, the effect of the EAR was evaluated, and additional tasks were found to enhance the EAR. Integr Environ Assess Manag 2024;00:1-13. © 2024 SETAC.

Incidence and risk factors of COVID-19 in a tertiary hospital and the effectiveness of booster vaccination among health care workers: A retrospective cohort study, January 2020 to June 2022.

BACKGROUND: Health care workers (HCWs) face a higher risk of infection and may transmit pathogens to patients during a pandemic. This study aims to evaluate infection-control measures by analyzing the incidence and risk factors of COVID-19 and estimating vaccine effectiveness (VE) at a tertiary hospital in Seoul, Republic of Korea. METHODS: This study included 2,516 HCWs from January 1, 2020, to June 30, 2022. Data were analyzed to determine the incidence density and cumulative incidence; the results were compared by the age- and gender-specific standardized incidence ratios (SIR). VE was estimated with multivariate Cox proportional-hazard models as 1-adjusted hazard ratio × 100%. RESULTS: SIR indicated a lower COVID-19 risk in the hospital population than in the general Korean population (SIR, 0.81; 95% confidence interval [CI]: 0.76-0.87). Multivariate Cox analysis indicated that, compared to doctors, nonmedical service supporters and other HCWs (excluding doctors and nurses) were high-risk groups (adjusted hazard ratio [95% CI], 1.72 [1.04-2.83] and 1.76 [1.20-2.58], respectively). Compared to the outpatient unit, the emergency department was a high-risk department (1.70 [1.16-2.50]). The VE of the booster dose was 55.47%, compared to no or incomplete vaccination (95% CI: 22.63-74.37). CONCLUSIONS: Besides encouraging HCWs vaccination, effective infection-control measures should target high-risk groups and departments.

Severe pulmonary edema occurred during endobronchial ultrasound under monitored anesthesia care - A case report.

BACKGROUND: Endobronchial ultrasound (EBUS) is widely used to diagnose lung cancer. Monitored anesthesia care (MAC) can enhance patient comfort and procedural conditions during EBUS. EBUS under MAC is usually safe but can lead to various complications. CASE: A 34-year-old male who had increased sputum for two months showed an enlarged paratracheal lymph node and planned for lymph node biopsy by EBUS. During EBUS under MAC, an unexpected oxygen saturation decline required intervention. After intubation, copious frothy fluid was suctioned from the bronchi, and oxygenation was recovered. A narrowed trachea and the EBUS bronchoscope might have resulted in upper airway obstruction, and suction performed under these conditions might have caused pulmonary edema. The patient received non-invasive ventilation and high-flow nasal cannula and recovered without complications. CONCLUSIONS: When there is an expected risk of upper airway obstruction during EBUS, careful preoperative evaluation and preparation are essential to prevent negative pressure pulmonary edema.

An Overview of Polymer Composite Films for Antibacterial Display Coatings and Sensor Applications.

The escalating presence of pathogenic microbes has spurred a heightened interest in antimicrobial polymer composites tailored for hygiene applications. These innovative composites ingeniously incorporate potent antimicrobial agents such as metals, metal oxides, and carbon derivatives. This integration equips them with the unique ability to offer robust and persistent protection against a diverse array of pathogens. By effectively countering the challenges posed by microbial contamination, these pioneering composites hold the potential to create safer environments and contribute to the advancement of public health on a substantial scale. This review discusses the recent progress of antibacterial polymer composite films with the inclusion of metals, metal oxides, and carbon derivatives, highlighting their antimicrobial activity against various pathogenic microorganisms. Furthermore, the review summarizes the recent developments in antibacterial polymer composites for display coatings, sensors, and multifunctional applications. Through a comprehensive examination of various research studies, this review aims to provide valuable insights into the design, performance, and real-time applications of these smart antimicrobial coatings for interactive devices, thus enhancing their overall user experience and safety. It concludes with an outlook on the future perspectives and challenges of antimicrobial polymer composites and their potential applications across diverse fields.

How do carbon trading price and carbon tax rate affect power project portfolio investment and carbon emission: An analysis based on uncertainty theory.

Responding to the social, economic, and environmental call to resolve current sustainability challenges, the concern about carbon dioxide emission reduction should be incorporated into the power investment decision process. Reflecting the low carbon emission requirement, this paper proposes a new optimization model for power project portfolio selection that simultaneously considers both of carbon emission trading scheme and carbon tax imposition. In this model, the initial investment outlay, the power sale price, the carbon trading price, and carbon tax rate are treated as uncertain variables considering the fast-changing environment and complex market situation. Incorporating the constraint on whether the carbon quota is exceeded into the model, two investment strategies are proposed for investors. Using the proposed model, the impact of the rises in carbon trading price and carbon tax rate on the investor's investment strategy selection and the carbon emission is simulated and analyzed through a case study. When the expected carbon price is 203.50 RMB/tCO2-eq or less, a company should invest based on the strategy that annual emissions exceed the quota to obtain a maximum expected NPV which is larger than 408588 million RMB. When future carbon prices are 352.00, 500.50 and 649.00 RMB/tCO2-eq, the government should impose carbon tax rates of 30, 30, and 40 RMB/tCO2 on a power company, respectively, to obtain carbon emission reduction effect. At last, to see the contrast effect of the results from simultaneous implementation of both carbon trading and carbon tax, the results considering the carbon trading alone or carbon tax alone are discussed, respectively.

Healthy immigrants, unhealthy ageing? Analysis of health decline among older migrants and natives across European countries.

The probability of having multiple chronic conditions simultaneously, or multimorbidity, tends to increase with age. Immigrants face a particularly high risk of unhealthy ageing. This study investigates the immigrant-native disparities in the speed of age-related chronic disease accumulation, focusing on the number of chronic health conditions; and considers the heterogeneity of this trajectory within immigrant populations by origin and receiving country. We use data from the Survey of Health, Ageing and Retirement in Europe from 2004 to 2020 on adults aged 50 to 79 from 28 European countries and employ both cross-sectional and longitudinal analyses. For longitudinal panel analyses, we use fixed-effects regression models to account for the unobserved heterogeneity related to individual characteristics including migration background. Our results indicate that immigrants report a higher number of chronic conditions at all ages relative to their native-born peers, but also that the immigrant-native differential in the number of chronic conditions decreases from age 65 onwards. When considering differences by origin country, we find that the speed of chronic disease accumulation is slower among immigrants from the Americas and the Asia and Oceania country groups than it is among natives. When looking at differences by receiving country group, we observe that the speed of accumulating chronic diseases is slower among immigrants in Eastern Europe than among natives, particularly at older ages. Our findings suggest that age-related trajectories of health vary substantially among immigrant populations by origin and destination country, which underscore that individual migration histories play a persistent role in shaping the health of ageing immigrant populations throughout the life course.

Anesthetic management of an elderly COVID-19 patient with pulmonary thromboembolism for hip surgery - A case report.

BACKGROUND: COVID-19 and delayed hip surgery are well-known risk factors for thromboembolism in elderly patients. CASE: We report the case of an 88-year-old female patient with COVID-19 and pulmonary thromboembolism (PTE) who underwent delayed hip surgery 21 days after the injury. Heparinization and inferior vena cava filters were used to treat and prevent PTE. Transesophageal echocardiography and extracorporeal membrane oxygenation (ECMO) sheaths were inserted as a precaution in case of emergencies during surgery; the procedure was performed without any specific event. CONCLUSIONS: COVID-19-infected patients suffering from a hip fracture have a high risk of thromboembolism, and therefore, require utmost attention for appropriate evaluation and prevention.

Healthcare Utilization and Costs According to Frailty Transitions After Two Years: A Korean Frailty and Aging Cohort Study.

BACKGROUND: Korea's aging population has raised several challenges, especially concerning healthcare costs. Consequently, this study evaluated the association of frailty transitions with healthcare utilization and costs for older adults aged 70 to 84. METHODS: This study linked the frailty status data of the Korean Frailty and Aging Cohort Study to the National Health Insurance Database. We included 2,291 participants who had frailty measured by Fried Frailty phenotype at baseline in 2016-2017 and follow-up in 2018-2019. We conducted a multivariate regression analysis to determine the association between their healthcare utilization and costs by frailty transition groups. RESULTS: After 2 years, changes from "pre-frail" to "frail" (Group 6) and "frail" to "pre-frail" (Group 8) were significantly associated with increased inpatient days (P < 0.001), inpatient frequency (P < 0.001), inpatient cost (P < 0.001 and P < 0.01, respectively), and total healthcare cost (P < 0.001) than "robust" to "robust" (Group 1) older adults. A transition to frailty from "pre-frail" to "frail" (Group 6) resulted in a $2,339 total healthcare cost increase, and from "frail" to "pre-frail" (Group 8), a $1,605, compared to "robust" to "robust" older adults. CONCLUSION: Frailty among community-dwelling older adults is economically relevant. Therefore, it is crucial to study the burden of medical expenses and countermeasures for older adults to not only provide appropriate medical services but also to prevent the decline in their living standards due to medical expenses.

Peritoneal and Nodal Gliomatosis Mimicking Metastasis on FDG PET/CT in a Patient With Ovarian Immature Teratoma.

ABSTRACT: Peritoneal and nodal gliomatosis is a rare disease condition characterized by implants of mature glial tissue on the peritoneum and lymph nodes. It is typically associated with teratoma and has no adverse effect on prognosis. We present a case of 22-year-old woman who underwent FDG PET/CT for the staging of ovarian immature teratoma. PET/CT revealed mildly increased FDG uptake in the peritoneal cavity and increased FDG uptake in the internal mammary and cardiophrenic angle lymph nodes, which were histopathologically diagnosed as peritoneal and nodal gliomatosis. This case suggests that PET/CT findings of peritoneal and nodal gliomatosis could mimic metastasis.

Therapeutic extracellular vesicle production is substantially increased by inhibition of cellular cholesterol biosynthesis.

Extracellular vesicles (EVs) are a new therapeutic modality with the promise to treat many diseases through their ability to deliver diverse molecular cargo. As with other emerging modalities transitioning into the industrialization phase, all aspects of the manufacturing process are rich with opportunities to enhance the ability to deliver these medicines to patients. With the goal of improving cell culture EV productivity, we have utilized high throughput siRNA screens to identify the underlying genetic pathways that regulate EV productivity to inform rational host cell line engineering and media development approaches. The screens identified multiple metabolic pathways of potential interest; one of which was validated and shown to be a ready implementable, cost-effective strategy to increase EV titers. We show that both EV volumetric and specific productivity from HEK293 and CHO-S were increased in a dose and cell line-dependent manner up to ninefold when cholesterol synthesis was inhibited by the inclusion of statins in the cell culture media. In addition, we show in response to statin treatment, elevation of EV markers in mesenchymal stem cell (MSC) cell culture media suggesting this approach can also be applicable to MSC EVs. Furthermore, we show that the EVs produced from statin-treated HEK293 cultures are effectively loaded by both endogenous and exogenous loading methods and have equivalent in vitro or in vivo potency relative to EVs from untreated cultures.

Corrigendum: GWAS analysis to elucidate genetic composition underlying a photoperiod-insensitive rice population, North Korea.

[This corrects the article DOI: 10.3389/fgene.2022.1036747.].

Catatonia associated with prolonged stupor after general anesthesia in a patient with multiple neuropsychiatric disorders -a case report.

BACKGROUND: Delayed emergence after general anesthesia may significantly affect a patient's condition. We present the case of a patient who experienced prolonged delayed recovery of consciousness, language, and motor response due to catatonia after eight hours of total elbow arthroplasty under general anesthesia. CASE: A 68-year-old woman with neuropsychiatric disorders and Parkinson's disease did not respond adequately during recovery after more than eight hours of general anesthesia. Following the operation, the patient was semi-comatose and appeared to have nonconvulsive status epilepticus upon awakening from anesthesia. However, subsequent examinations did not reveal any organic causes. The patient was subsequently diagnosed with catatonia, treated, and discharged following gradual improvement. CONCLUSIONS: Although rare, patients taking psychiatric drugs for an extended period may experience delayed emergence after prolonged general anesthesia without identifiable causes. Catatonia should be considered in the differential diagnoses of these patients.

Phage engineering and phage-assisted CRISPR-Cas delivery to combat multidrug-resistant pathogens.

Antibiotic resistance ranks among the top threats to humanity. Due to the frequent use of antibiotics, society is facing a high prevalence of multidrug resistant pathogens, which have managed to evolve mechanisms that help them evade the last line of therapeutics. An alternative to antibiotics could involve the use of bacteriophages (phages), which are the natural predators of bacterial cells. In earlier times, phages were implemented as therapeutic agents for a century but were mainly replaced with antibiotics, and considering the menace of antimicrobial resistance, it might again become of interest due to the increasing threat of antibiotic resistance among pathogens. The current understanding of phage biology and clustered regularly interspaced short palindromic repeats (CRISPR) assisted phage genome engineering techniques have facilitated to generate phage variants with unique therapeutic values. In this review, we briefly explain strategies to engineer bacteriophages. Next, we highlight the literature supporting CRISPR-Cas9-assisted phage engineering for effective and more specific targeting of bacterial pathogens. Lastly, we discuss techniques that either help to increase the fitness, specificity, or lytic ability of bacteriophages to control an infection.

Safety and Efficacy of Allogeneic Umbilical Cord Blood Therapy for Global Development Delay and Intellectual Disability.

Most pediatric patients with global developmental delay (GDD) or intellectual disability (ID) have disrupted development. Since allogeneic umbilical cord blood (UCB) may exert neurotrophic effects, a prospective clinical trial was conducted to assess the efficacy and safety of UCB therapy for GDD and ID. A total of 13 children (ages 23-149 months) with GDD and ID were enrolled and followed up for 12 months. Under criteria of histocompatibility and cell number, allogeneic UCB units were selected and infused once intravenously, and adverse events were monitored. The Bayley Scale of Infant Development-II (BSID-II) was used as primary outcome measurement tool, and evaluations for various functional abilities were also implemented. Safety assessment did not reveal significant adverse effects. Functional improvements in mental and motor developments along with daily living activities and languages were observed at 12 months postintervention compared with the baseline abilities (P < 0.05). Furthermore, mental developmental quotient derived from BSID-II mental scale revealed significantly facilitated improvement during the first 3 months (P < 0.05). In the survey conducted 80.7 ± 13.0 months after UCB infusion to assess satisfaction and long-term safety, no long-term adverse effects were reported, and 70% of the guardians reported satisfaction with the UCB infusion. Long-term changes in two patients who were regularly followed up beyond the study completion were noticeable. One case observed for 4 years showed dramatic improvement until 12 months after UCB therapy, whereas she showed insignificant improvement beyond 12 months after the therapy. Another case showed alleviation of autism with findings of anti-inflammatory response in his peripheral blood after UCB infusion. This clinical study provides support for further applications of UCB as a therapeutic avenue for children with GDD or ID owing to its safety and partial efficacy. Due to patient heterogeneity, further studies focusing on specific clinical manifestations and etiologies are required. Registered at www.clinicaltrials.gov (NCT01769716).