Fracture gap and working length are important actionable factors affecting bone union after minimally invasive plate osteosynthesis for the treatment of simple diaphyseal or distal metaphyseal tibia fractures.

INTRODUCTION: Indirect reduction of minimally invasive plate osteosynthesis (MIPO) can often result in delayed union in tibia fractures. This study evaluated several factors in MIPO in relation to bone union. HYPOTHESIS: We hypothesized that the fracture gap, plate - tibia distance, or working length would have a substantial effect on the tibia union rate. MATERIALS AND METHODS: Forty-one patients with simple diaphyseal or distal metaphyseal tibia fractures who underwent internal fixation surgery using the MIPO technique were divided into two groups: patients with delayed union and patients without delayed union. Non-actionable factors involving AO/OTA classification, fibula fracture and actionable factors including postoperative fracture gap, plate - tibia distance, working length in relation to parameters of bone union were compared between the two groups. Also cumulative rates of bone union and risk factors of delayed union according to variables of interest were investigated. RESULTS: AO/OTA classification, site of fibula fracture, postoperative fracture gap, working length, and bone union rate of the two groups significantly differed (p<0.05). The cumulative rate of bone union during 1-year follow-up according to 43A tibia fracture, distal fibula fracture, fracture gap, and working length significantly differed between the two groups (p<0.05). By univariate Cox proportional hazards model, 43A tibia fracture, distal fibula fracture, facture gap, and short working length were risk factors for delayed union (p<0.05). DISCUSSION: Non-actionable factors involving AO/OTA classification, distal fibula fracture and actionable factors including postoperative fracture gap, working length were significant factors affecting bone union after MIPO. The present study indicated that small fracture gap and long working length during MIPO might facilitate bone healing in tibia fracture. LEVEL OF EVIDENCE: IV; single-center retrospective cohort study.

Analogs of the Catechol Derivative Dynasore Inhibit HIV-1 Ribonuclease H, SARS-CoV-2 nsp14 Exoribonuclease, and Virus Replication.

Viral replication often depends on RNA maturation and degradation processes catalyzed by viral ribonucleases, which are therefore candidate targets for antiviral drugs. Here, we synthesized and studied the antiviral properties of a novel nitrocatechol compound (1c) and other analogs that are structurally related to the catechol derivative dynasore. Interestingly, compound 1c strongly inhibited two DEDD box viral ribonucleases, HIV-1 RNase H and SARS-CoV-2 nsp14 3'-to-5' exoribonuclease (ExoN). While 1c inhibited SARS-CoV-2 ExoN activity, it did not interfere with the mRNA methyltransferase activity of nsp14. In silico molecular docking placed compound 1c in the catalytic pocket of the ExoN domain of nsp14. Finally, 1c inhibited SARS-CoV-2 replication but had no toxicity to human lung adenocarcinoma cells. Given its simple chemical synthesis from easily available starting materials, these results suggest that 1c might be a lead compound for the design of new antiviral compounds that target coronavirus nsp14 ExoN and other viral ribonucleases.

Use of a comprehensive systemic ultrasound evaluation in the diagnosis and analysis of acute lateral region ankle sprain.

BACKGROUND: For the diagnosis of acute lateral ankle sprain, many clinicians use ultrasound; they typically focus on the lateral ligament complex, which is the most common site of lesions in ankle sprain. However, this approach risks missing other foot and ankle lesions. The present study aimed to provide and analyze the results of a new ultrasound method of diagnosis for acute lateral ankle sprain which can thoroughly investigate overall lesions of the foot and ankle. METHODS: Retrospective cross-sectional cohort study of 123 patients who underwent diagnostic ultrasound within 1 week of acute lateral ankle injury was performed. Causes of ankle sprain, incidence and severity of each ligament injury, location of anterior talofibular ligament (ATFL) injury, accompanying ligament injury, and occult fracture were analyzed. RESULTS: Among the 102 cases of ATFL injuries, 60 (58.5%) had islolated ATFL injury, 28 (27.5%) had accompanying calcaneofibular ligament injury (CFL), and 14 (13.7%) had accompanying midtarsal or syndesmosis injury. ATFL injuries occurred on the fibula attachment in 48 (47.1%) cases, ligament mid-substance in 24 (23.5%) cases, and talus attachment in 30 (29.4%) cases. Among the 165 lesions from 123 cases, injuries of the fourth or fifth dorsal tarsometatarsal (12 cases, 7.3%), bifurcate (11 cases, 6.7%), and anterior tibiofibular (11 cases, 6.7%) ligaments were not rare. CONCLUSION: These findings suggest that an ultrasound examination involving investigation of the midtarsal joint and syndesmotic ligament, as well as the ATFL and CFL, is useful for comprehensive, systemic diagnosis of acute lateral ankle sprain.

GRP78 Inhibitor YUM70 Suppresses SARS-CoV-2 Viral Entry, Spike Protein Production and Ameliorates Lung Damage.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, has given rise to many new variants with increased transmissibility and the ability to evade vaccine protection. The 78-kDa glucose-regulated protein (GRP78) is a major endoplasmic reticulum (ER) chaperone that has been recently implicated as an essential host factor for SARS-CoV-2 entry and infection. In this study, we investigated the efficacy of YUM70, a small molecule inhibitor of GRP78, to block SARS-CoV-2 viral entry and infection in vitro and in vivo. Using human lung epithelial cells and pseudoviral particles carrying spike proteins from different SARS-CoV-2 variants, we found that YUM70 was equally effective at blocking viral entry mediated by original and variant spike proteins. Furthermore, YUM70 reduced SARS-CoV-2 infection without impacting cell viability in vitro and suppressed viral protein production following SARS-CoV-2 infection. Additionally, YUM70 rescued the cell viability of multi-cellular human lung and liver 3D organoids transfected with a SARS-CoV-2 replicon. Importantly, YUM70 treatment ameliorated lung damage in transgenic mice infected with SARS-CoV-2, which correlated with reduced weight loss and longer survival. Thus, GRP78 inhibition may be a promising approach to augment existing therapies to block SARS-CoV-2, its variants, and other viruses that utilize GRP78 for entry and infection.

Risk Factors for Contralateral Tendon Rupture in Patients With Acute Achilles Tendon Rupture.

The present study was performed to determine the incidence and risk factors of contralateral Achilles tendon rupture after an initial tendon rupture, and to identify the associated patient characteristics. Medical records of 181 adult patients with acute Achilles tendon rupture were reviewed. We investigated the risk factors for contralateral Achilles tendon rupture and calculated the incidence density (per 100 person-years), survival rate, hazard ratios, and 95% confidence intervals. The risk factors were extracted, including blood type, age, body mass index (BMI), occupation, underlying comorbidities, history of alcohol intake or smoking, injury mechanism, and fluoroquinolone antibiotic or steroid use. Military personnel and manual laborers, including farmers and firefighters were considered to have an occupation involving physical activity. Ten patients (5.5%) were identified as having nonsimultaneous, contralateral Achilles tendon rupture a mean of 3.3 years (range 1.0-8.3 years) after the initial tendon rupture. The incidence density of contralateral tendon rupture was 0.89 per 100 person-years. The 8-year survival rate of contralateral tendon rupture was 92.2%. Unadjusted and adjusted hazard ratios (with 95% confidence intervals, p value) of blood type O were 3.71 (1.07-12.82, p = .038) and 2.90 (0.81-10.32, p = .101), respectively, and those of occupations involving physical activity were 5.87 (1.64-20.98, p = .006) and 4.69 (1.27-17.28, p = .02), respectively. Based on the present data, blood type O and occupations involving physical activity are significantly associated with an increased risk of contralateral tendon rupture in adult patients who have sustained Achilles tendon rupture.

Acid mine drainage and smelter-derived sources affecting water geochemistry in the upper Nakdong River, South Korea.

Both the smelter and acid mine drainage (AMD) in uppermost streams impact water geochemistry and deteriorate water quality. Efficient water quality management requires identifying the contribution of each source to stream water geochemistry. In this study, we aimed to determine the natural and anthropogenic sources (AMD and smelting) affecting water geochemistry by considering seasonality. Water samples were collected, from May 2020 to April 2021, in a main channel (Nakdong River) and tributaries in a small watershed including mines and smelters. The watershed is characterized by a carbonate-rich area in the upper-middle reaches and silicate-rich area in the middle-lower reaches. On the plots of Ca/Na vs. Mg/Na and 2(Ca + Mg) vs. HCO3 + 2SO4, the water geochemistry was predominantly explained by the carbonate and silicate weathering associated with sulfuric and carbonic acids. According to typical δ15N values for sources, nitrate contribution from soil-N mainly impacted water geochemistry, regardless of seasonality; the contribution from agricultural activity and sewage was negligible. Water geochemistry in the main channel samples was discriminated before and after passing through the smelter. The effects of the smelter were evident in elevated SO4, Zn, and Tl concentrations and in δ66Zn values; this was further supported by the relationships between Cl/HCO3 and SO4/HCO3 and between δ66Zn and Zn. These results were pronounced during winter, when the flush-out effect was absent. Our results suggest that multi-isotopes and chemical composition analyses can trace multiple sources influencing the water geochemistry in watersheds containing AMD and smelters.

National-scale investigation of dual nitrate isotopes and chloride ion in South Korea: Nitrate source apportionment for stream water.

Nitrate sources in surface water have been identified using dual-isotope compositions of nitrate with various tools to efficiently manage the water quality at the local scale. Correlation between Cl and NO3 has also been used to identify NO3. In this study, we assess the reliability of the dual-isotope approach and Cl in terms of nitrate source apportionment. To this end, we collected stream water samples throughout South Korea to estimate nitrate sources in streams and determine whether the land-use pattern was closely related to nitrate sources. The δ15N-NO3 ranging from -1.3 to 14.8‰ showed a spatial distribution that was lower in mountain ranges (<7‰) than plain areas (>8‰). The Cl concentration in this national-scale distribution was also assessed. The relationship between the proportion of Cl and δ15N-NO3 classifies nitrate sources into areas characterized by three land-use patterns: (1) agricultural and business areas, (2) forests in highlands, and (3) lowland forests, of which (1) had proportions of Cl >50%, while (2) and (3) were <50%. The samples in (3) showed δ15N-NO3 values > 6‰, similar to those of (1). Deuterium excess of samples was negatively correlated (R2 = 0.53) with δ15N-NO3, accounting for the fact that δ15N-NO3 reflected land-use patterns. Samples were dominantly affected by agriculture-derived sources and domestic sewage showed NO3/Cl of <0.4 and δ15N-NO3 of >6‰. These results suggest that nitrate source apportionment should be comprehensively evaluated considering the dual-isotope approach, land-use patterns, and Cl proportions.

Efficacy of Lavage by Tube under Local Anesthesia versus Arthroscopic Treatment of Acute Septic Arthritis of Native Knee.

Although arthroscopic treatment is a minimally invasive surgery that effectively treats septic arthritis of the knee joint, it requires general or regional anesthesia. This study aimed to compare the clinical results of lavage after tube insertion versus arthroscopic treatment. Patients treated with arthroscopic treatment were included in group I (n = 76), while those treated with lavage by tube were included in group II (n = 34). We investigated the following in all patients: demographics, underlying disorders, initial serum white blood cell (WBC) count, C-reactive protein (CRP) level, synovial fluid WBC and polymorphonuclear cell counts, causative organism, initial Kellgren-Lawrence grade, lavage number, interventional delay, hospitalization days, CRP normalization time, and Western Ontario McMaster Universities Osteoarthritis index scores for clinical outcomes at 3 months postoperative. The mean interventional delay was significantly greater in group I (23.6 ± 15.6 h vs. 8.7 ± 9.3 h, p < 0.001). The lavage by tube featured a significantly shorter interventional delay time than arthroscopy, while the CRP decrease rate did not differ between groups. Moreover, lavage by tube showed no significant differences in outcomes, including laboratory results and functional outcomes at 3 months postoperative.

National-scale distribution of strontium isotope ratios in environmental samples from South Korea and its implications for provenance studies.

Successful application and accurate interpretation of strontium (Sr) isotope ratios (87Sr/86Sr) requires underlying information about the large-scale variabilities in their signatures from a variety of environmental samples, which can be correlated with the Sr isotopic signatures of underlying local geology. In this national-scale study, we analyzed 87Sr/86Sr in soil, plants, stream water, and Chinese mystery snail (Cipangopaludina chinensis) shells collected from South Korea to evaluate large-scale spatial variabilities, interpret relationships among isotopic signatures of various sample types, and generate spatial distribution isoscapes reflecting the heterogeneity of isotopic signatures across South Korea. Non-parametric comparisons among environmental samples showed non-significant differences in their isotopic ratios. The 87Sr/86Sr of plant and soil samples were strongly correlated (R2adj = 0.93), suggesting that both reflect national-scale lithological properties. Similarly, the 87Sr/86Sr of shells showed strong correlations with the 87Sr/86Sr of both plant and soil samples (R2adj = 0.90). The 87Sr/86Sr signatures of environmental samples in this study aligned with expected Sr isotopic values and generally reflected local geology. Spatial distribution maps of samples showed similar 87Sr/86Sr spatial patterns, with high radiogenic values from granitic and granitic gneiss rocks systems and low radiogenic values from volcanic and sedimentary rock systems. Stream water samples showed significant correlations with soil and plant isotopic ratios, but with a low coefficient of determination (R2adj = 0.68). The deviations were much larger for samples with 87Sr/86Sr > 0.720. Further study is needed to improve the accuracy of baseline determination and interpretation of stream water isotopic variations.

Expression of the cytokinesis regulator PRC1 results in p53-pathway activation in A549 cells but does not directly regulate gene expression in the nucleus.

Protein regulator of cytokinesis 1 (PRC1) is a microtubule-binding protein with essential roles in mitosis and cytokinesis. PRC1 is frequently overexpressed in cancer cells where it could contribute to chromosomal instability. Due to its nuclear localization in interphase, it has been speculated that PRC1 has additional functions that are involved in its pro-tumorigenic functions. In this study we investigated the potential nuclear functions of PRC1 in a lung cancer cell line. Genome wide expression profiling by RNA sequencing revealed that the expression of PRC1 results in activation of the p53 pathway and inhibition of the pro-proliferative E2F-dependent gene expression. A mutant of PRC1 that is unable to enter into the nucleus regulated the same gene sets as wildtype PRC1, suggesting that PRC1 has no nuclear-exclusive functions in A549 cells. Instead, induction of p53 by PRC1 correlates with multinucleation and depends on the localization of PRC1 to the midbody, suggesting that the induction of p53 is a consequence of overexpressed PRC1 to interfere with the normal function of PRC1 during cytokinesis. Activation of p53 by PRC1 results in cellular senescence but not in apoptosis. In conclusion, while PRC1 is frequently overexpressed in many cancers, the p53 pathways may initially protect cancer cells from the negative effects of PRC1 overexpression on cytokinesis. Because depletion of PRC1 also results in p53-pathway activation and senescence, levels of PRC1 need to be tightly regulated to allow unperturbed proliferation. Targeting the expression or function of PRC1 could create a therapeutic vulnerability for the treatment of cancer.

The effects of dyes and bleaches on the sorption and desorption of trace elements in human hair.

Trace element concentrations and isotope ratios of hair reflect the blood levels at the time of hair formation, but can be affected by external factors such as dyeing, bleaching, and bathing. To investigate the effect of dyeing, bleaching, and bathing on hair, hair was immersed in tap water, and changes in trace element concentrations and the Sr isotope ratio were observed over time. During soaking, alkaline earth metals (Ca, Mg, and Sr) from tap water were gradually absorbed into the hair over time. After about one day, the adsorption capacity of hair reached a maximum and the reverse reaction started to occur. In contrast, alkaline metals (Na and K) behaved in reverse. In dyed and bleached hair, Na was significantly desorbed from the hair and gradually migrated to the water over time. The adsorption and desorption of trace elements were minimal in untreated original hair, but much higher in dyed and bleached hair. Thus, dyeing and bleaching appear to damage the hair surface structure and greatly promote the exchange of trace elements. The rapid exchange of trace elements, including Sr, between hair and tap water observed in this study indicates that hair samples can be easily contaminated during bathing.

Viral Mimicry of Interleukin-17A by SARS-CoV-2 ORF8.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection triggers cytokine-mediated inflammation, leading to a myriad of clinical presentations in COVID-19. The SARS-CoV-2 open reading frame 8 (ORF8) is a secreted and rapidly evolving glycoprotein. Patients infected with SARS-CoV-2 variants with ORF8 deleted are associated with mild disease outcomes, but the molecular mechanism behind this is unknown. Here, we report that SARS-CoV-2 ORF8 is a viral cytokine that is similar to but distinct from interleukin 17A (IL-17A) as it induces stronger and broader human IL-17 receptor (hIL-17R) signaling than IL-17A. ORF8 primarily targeted blood monocytes and induced the heterodimerization of hIL-17RA and hIL-17RC, triggering a robust inflammatory response. Transcriptome analysis revealed that besides its activation of the hIL-17R pathway, ORF8 upregulated gene expression for fibrosis signaling and coagulation dysregulation. A naturally occurring ORF8 L84S variant that was highly associated with mild COVID-19 showed reduced hIL-17RA binding and attenuated inflammatory responses. This study reveals how SARS-CoV-2 ORF8 by a viral mimicry of the IL-17 cytokine contributes to COVID-19 severe inflammation. IMPORTANCE Patients infected with SARS-CoV-2 variants lacking open reading frame 8 (ORF8) have been associated with milder infection and disease outcome, but the molecular mechanism behind how this viral accessory protein mediates disease pathogenesis is not yet known. In our study, we revealed that secreted ORF8 protein mimics host IL-17 to activate IL-17 receptors A and C (IL-17RA/C) and induces a significantly stronger inflammatory response than host IL-17A, providing molecular insights into the role of ORF8 in COVID-19 pathogenesis and serving as a potential therapeutic target.

Structure-Based Optimization of ML300-Derived, Noncovalent Inhibitors Targeting the Severe Acute Respiratory Syndrome Coronavirus 3CL Protease (SARS-CoV-2 3CLpro).

Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CLpro). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CLpro enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CLpro inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.

Spatial distributions of oxygen and hydrogen isotopes in multi-level groundwater across South Korea: A case study of mountainous regions.

This study presents the spatial distributions of stable isotopes for groundwater according to well depth and spring water across South Korea, using an interpolation model to provide baseline information for hydrological studies. In total, 888 groundwater and 108 spring water samples were collected across South Korea; their oxygen and hydrogen isotopic compositions (δ18O and δ2H) were analyzed. δ18O and δ2H values biased toward the summer local meteoric water line and low d-excess values indicate that summer precipitation is important for groundwater recharge. The δ18O and δ2H values for groundwater and spring water decrease progressively from the southwest to the northeast on the Korean Peninsula. Based on eight hydrological regions, the average δ18O values of groundwater and spring water are negatively correlated with latitude, but they are positively correlated with temperature. This result indicates that the spatial distributions of groundwater isotopic values in South Korea are significantly influenced by latitude and altitude effects associated with the movement of the North Pacific air mass in summer. Spring waters showed a negative correlation between δ18O and d-excess, with more depleted 18O values than groundwater, indicating that local recharge and flow within mountainous areas is dominant. Considering that the correlation in multi-level groundwater located in northern regions is similar to that of spring water, the contribution of regional groundwater flow, which is recharged in mountainous areas, is considered to be higher in the northern regions. The spatial distribution of δ18O in groundwater gradually approached the spatial distribution of spring water with increasing well depth, indicating that the contribution of regional groundwater flow may be greater in deep groundwater. Our results provide estimates for data-poor regions, supporting the investigation of links between groundwater and other hydrological factors.

Spatial distributions of strontium isotope ratios in human hair and tap water from South Korea.

Natural variations of 87Sr/86Sr ratios in biological samples, such as human hair, provide a biological record of provenance. Spatial distribution maps reflecting heterogeneity in isotopic signatures across large geographical regions are helpful for discerning the provenance and mobility of organisms. In this national-scale study conducted across South Korea, we investigated the spatial distribution patterns of 87Sr/86Sr ratios in human hair and tap water samples to determine their spatial variabilities and the relationships of isotopic signatures between hair and tap water. The strontium isoscapes of tap water and hair showed similar spatial distribution patterns. Non-parametric comparison indicated no significant differences in isotopic ratios between the two sample types. The 87Sr/86Sr ratios in human hair showed a significant and strong correlation with the ratios in tap water in eastern Korea, suggesting potential use of 87Sr/86Sr ratios in provenance studies. However, tap water and hair samples from western Korea did not show significant correlation between them, overall reducing the predictive power of the hair 87Sr/86Sr ratios for provenance studies. The deviation between 87Sr/86Srtap water and 87Sr/86Srhair was much larger in western coastal areas than in eastern Korea. Relatively high utilization of groundwater or exogenous materials, such as Asian dust, may have been responsible for this pattern. To fully utilize the potential of the strontium isotope signature as a biorecorder in provenance studies, it is essential to evaluate the effects of groundwater and other exogenous materials on the isotope signatures of hair and other biological samples. In this study, only hair samples from males were used to develop 87Sr/86Sr isoscapes. Therefore, further studies are required to examine the applicability of 87Sr/86Sr hair isoscapes based solely on human hair samples from males to forensic and provenance studies of human hair samples from females.

The systemic inflammatory landscape of COVID-19 in pregnancy: Extensive serum proteomic profiling of mother-infant dyads with in utero SARS-CoV-2.

While pregnancy increases the risk for severe COVID-19, the clinical and immunological implications of COVID-19 on maternal-fetal health remain unknown. Here, we present the clinical and immunological landscapes of 93 COVID-19 mothers and 45 of their SARS-CoV-2-exposed infants through comprehensive serum proteomics profiling for >1,400 cytokines of their peripheral and cord blood specimens. Prenatal SARS-CoV-2 infection triggers NF-κB-dependent proinflammatory immune activation. Pregnant women with severe COVID-19 show increased inflammation and unique IFN-λ antiviral signaling, with elevated levels of IFNL1 and IFNLR1. Furthermore, SARS-CoV-2 infection re-shapes maternal immunity at delivery, altering the expression of pregnancy complication-associated cytokines, inducing MMP7, MDK, and ESM1 and reducing BGN and CD209. Finally, COVID-19-exposed infants exhibit induction of T cell-associated cytokines (IL33, NFATC3, and CCL21), while some undergo IL-1ß/IL-18/CASP1 axis-driven neonatal respiratory distress despite birth at term. Our findings demonstrate COVID-19-induced immune rewiring in both mothers and neonates, warranting long-term clinical follow-up to mitigate potential health risks.

Dietary homogenization and spatial distributions of carbon, nitrogen, and sulfur isotope ratios in human hair in South Korea.

Dietary homogenization has progressed worldwide due to westernization and the globalization of food production systems. We investigated dietary heterogeneity in South Korea by examining the spatial distribution of carbon (C), nitrogen (N), and sulfur (S) isotope ratios using 264 human hair samples. Overall, variation in isotope values was small, indicating low dietary heterogeneity. We detected differences in δ13C, δ15N, and δ34S values between administrative provinces and metropolitan cities; inter-regional differences were typically < 1 ‰. Values of δ34S were significantly lower in hair samples from inland regions relative to those from coastal locations, and a similar pattern was observed in δ15N values. Understanding geographic variation in δ34S and δ15N values in human hair is useful for provenancing humans in South Korea.