Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors.

A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019-2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19)1-4. Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (Mpro) of SARS-CoV-2: Mpro is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-25,6. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of Mpro of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds-including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds-as inhibitors of Mpro. Six of these compounds inhibited Mpro, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 µM. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.

Cystathionine γ-lyase-derived H2S negatively regulates thymic egress via allosteric inhibition of sphingosine-1-phosphate lyase.

Thymic egress is a crucial process for thymocyte maturation, strictly regulated by sphingosine-1-phosphate lyase (S1PL). Recently, cystathionine γ-lyase (CSE), one of the enzymes producing hydrogen sulfide (H2S), has emerged as a vital immune process regulator. However, the molecular connection between CSE, H2S and thymic egress remains largely unexplored. In this study, we investigated the regulatory function of CSE in the thymic egress of immune cells. We showed that genetic knockout of CSE or pharmacological inhibition by CSE enzyme inhibitor NSC4056 or D,L-propargylglycine (PAG) significantly enhanced the migration of mature lymphocytes and monocytes from the thymus to the peripheral blood, and this redistribution effect could be reversed by treatment with NaHS, an exogenous donor of H2S. In addition, the CSE-generated H2S significantly increased the levels of S1P in the peripheral blood, thymus and spleen of mice, suppressed the production of proinflammatory cytokines and rescued pathogen-induced sepsis in cells and in vivo. Notably, H2S or polysulfide inhibited S1PL activity in cells and an in vitro purified enzyme assay. We found that this inhibition relied on a newly identified C203XC205 redox motif adjacent to the enzyme's active site, shedding light on the biochemical mechanism of S1PL regulation. In conclusion, this study uncovers a new function and mechanism for CSE-derived H2S in thymic egress and provides a potential drug target for treating S1P-related immune diseases.

Prediction of osteoporosis using radiomics analysis derived from single source dual energy CT.

BACKGROUND: With the aging population of society, the incidence rate of osteoporosis is increasing year by year. Early diagnosis of osteoporosis plays a significant role in the progress of disease prevention. As newly developed technology, computed tomography (CT) radiomics could discover radiomic features difficult to recognize visually, providing convenient, comprehensive and accurate osteoporosis diagnosis. This study aimed to develop and validate a clinical-radiomics model based on the monochromatic imaging of single source dual-energy CT for osteoporosis prediction. METHODS: One hundred sixty-four participants who underwent both single source dual-energy CT and quantitative computed tomography (QCT) lumbar-spine examination were enrolled in a study cohort including training datasets (n = 114 [30 osteoporosis and 84 non-osteoporosis]) and validation datasets (n = 50 [12 osteoporosis and 38 non-osteoporosis]). One hundred seven radiomics features were extracted from 70-keV monochromatic CT images. With QCT as the reference standard, a radiomics signature was built by using least absolute shrinkage and selection operator (LASSO) regression on the basis of reproducible features. A clinical-radiomics model was constructed by incorporating the radiomics signature and a significant clinical predictor (age) using multivariate logistic regression analysis. Model performance was assessed by its calibration, discrimination and clinical usefulness. RESULTS: The radiomics signature comprised 14 selected features and showed good calibration and discrimination in both training and validation cohorts. The clinical-radiomics model, which incorporated the radiomics signature and a significant clinical predictor (age), also showed good discrimination, with an area under the receiver operating characteristic curve (AUC) of 0.938 (95% confidence interval, 0.903-0.952) in the training cohort and an AUC of 0.988 (95% confidence interval, 0.967-0.998) in the validation cohort, and good calibration. The clinical-radiomics model stratified participants into groups with osteoporosis and non-osteoporosis with an accuracy of 94.0% in the validation cohort. Decision curve analysis (DCA) demonstrated that the radiomics signature and the clinical-radiomics model were clinically useful. CONCLUSIONS: The clinical-radiomics model incorporating the radiomics signature and a clinical parameter had a good ability to predict osteoporosis based on dual-energy CT monoenergetic imaging.

Efficacy of rotator cuff suture and arthroscopic 360° capsular release in patients with rotator cuff tear with limited shoulder movement.

BACKGROUND: To determine the clinical efficacy of rotator cuff suture and arthroscopic 360° capsular release in patients with rotator cuff tendinopathy to improve the Constant-Murley and Visual Analogue Scale (VAS) scores, and shoulder flexion. METHODS: Fifty-one patients with full-thickness rotator cuff tears and limited shoulder movement who were admitted to our hospital from October 2017 to October 2020 were selected; all patients were treated with arthroscopic rotator cuff suture and 360° capsular release. The Constant-Murley score, VAS score, and shoulder flexion angle were used to evaluate shoulder joint function before and during follow-up. Rotator cuff healing was assessed by MRI with the Sugaya classification. RESULTS: After treatment, the Constant-Murley score (58.98 ± 9.84) was significantly improved compared with pre-treatment (29.33 ± 9.71), the VAS score (1.23 ± 0.87) was significantly lower than pre-treatment (7.54 ± 1.22), and the shoulder flexion angle (142.67 ± 8.59°) was significantly improved compared with pre-treatment (51.50 ± 2.10°); the difference was statistically significant (P < 0.05). CONCLUSIONS: Arthroscopic rotator cuff suture and simultaneous 360° capsular release have a significant effect on the treatment of rotator cuff tear with limited shoulder movement.

Antagonistic Activity and Mechanism of Bacillus subtilis XZ16-1 Suppression of Wheat Powdery Mildew and Growth Promotion of Wheat.

Wheat powdery mildew caused by Blumeria graminis f. sp. tritici (Bgt) is one of the most serious wheat diseases in the world. Biological control is considered an environmentally safe approach to control plant diseases. Here, to develop effective biocontrol agents for controlling wheat powdery mildew, antagonistic strain XZ16-1 was isolated and identified as Bacillus subtilis based on the morphological, biochemical, and physiological characteristics and 16S rDNA sequence. The culture filtrate of B. subtilis XZ16-1 and its extracts had a significant inhibitory effect on the spore germination of Bgt. Moreover, the therapeutic and prevention efficacy of the 100% culture filtrate on wheat powdery mildew reached 81.18 and 83.72%, respectively, which was better than that of chemical fungicide triadimefon. Further antimicrobial mechanism analysis showed that the XZ16-1 culture filtrate could inhibit the development of powdery mildew spores by disrupting the cell membrane integrity, causing reductions in the mitochondrial membrane potential, and inducing the accumulation of reactive oxygen species in the spores. Biochemical detection indicated that XZ16-1 could solubilize phosphate, fix nitrogen, and produce hydrolases, lipopeptides, siderophores, and indole-3-acetic acid. Defense-related enzymes activated in wheat seedlings treated with the culture filtrate indicated that disease resistance was induced in wheat to resist pathogens. Furthermore, a 106 CFU/ml suspension of XZ16-1 increased the height, root length, fresh weight, and dry weight of wheat seedlings by 77.13, 63.46, 76.73, and 19.16%, respectively, and showed good growth-promotion properties. This study investigates the antagonistic activity and reveals the action mechanism of XZ16-1, which can provide an effective microbial agent for controlling wheat powdery mildew.

Distribution characteristics of drug resistance mutations of HIV CRF01_AE, CRF07_BC and CRF08_BC from patients under ART in Ganzhou, China.

BACKGROUND: Drug resistance mutation (DRM)-associated virological failure has become a critical issue for ART and the elimination of HIV. OBJECTIVES: To investigate the distribution characteristics of DRMs of HIV CRF01_AE, CRF07_BC and CRF08_BC, the predominant subtypes in China. METHODS: Patients receiving ART up to 31 August 2020 in Ganzhou in China were recruited. Full-length sequences of the HIV pol gene were amplified from patients with virological failure. DRMs and antiretroviral susceptibility were explored using the Stanford University HIV Drug Resistance Database HIVdb Program. RESULTS: Overall, 279 of 2204 patients under ART were found to have virological failure. Nine HIV subtypes were identified among 211 sequences that were amplified successfully and CRF08_BC (37.0%), CRF01_AE (26.1%) and CRF07_BC (25.6%) were the most prevalent, with mutation frequencies of 44.9% (35/78), 52.7% (29/55) and 35.2% (19/54), respectively. The most common DRMs of these three subtypes were K103N and M184V, while the mutation frequencies of M41L, D67N, K70R, K101E, V106M, Y181C, K219E, H221Y and N348I were obviously different among subtypes. The resistance levels and frequencies for antiretroviral drugs for these three subtypes were similar and resistances to nevirapine, efavirenz, lamivudine and emtricitabine were the most frequently observed. Compared with CRF01_AE and CRF07_BC, CRF08_BC had higher proportions of DRMs for NRTIs and lower frequencies of resistance to NRTIs and NNRTIs. CONCLUSIONS: The distribution characteristics of DRMs of HIV CRF01_AE, CRF07_BC and CRF08_BC were inconsistent and should be considered when selecting antiretroviral strategies, developing new drugs and controlling HIV strains containing DRMs.

Anatomical knee variables result in worse outcomes of lateral meniscal allograft transplantation with discoid lateral menisci than with nondiscoid lateral menisci.

PURPOSE: To compare the clinical results of meniscal allograft transplantation (MAT) between patients with discoid lateral meniscus (DLM) and non-DLM (NDLM) and to analyse whether anatomical deformities cause worse clinical results in DLM patients. METHODS: Patients who underwent unilateral MAT from 2005 to 2017, including 115 patients with DLMs or NDLMs, were included in this study. Clinical outcomes [International Knee Documentation Committee (IKDC) scores, Lysholm scores, Tegner scores, and visual analogue scale (VAS) scores] and radiographic and MRI data were assessed. Clinical outcomes and anatomical knee variables were analysed by multivariate stepwise regression. RESULTS: After more than 2 years of follow-up, 9 patients were lost to follow-up, and 59 patients with DLM and 47 patients with NDLM were included. The mean postoperative results were significantly better than the preoperative data (P < 0.05) in both the DLM and NDLM groups. In addition, postoperative IKDC, Lysholm, and VAS scores but not Tegner scores were better in the NDLM group than in the DLM group. Several anatomical knee variables differed significantly between the NDLM and DLM groups and were associated with MAT outcomes. The condylar prominence ratio of the lateral and medial femoral condyles adjacent to the intercondylar notch and squaring of the lateral femoral condyle (the distance of the straight articular condylar surface) were independent factors significantly correlated with the Lysholm scores for MAT at last follow-up. CONCLUSION: MAT improved knee function in both patients with DLM and patients with NDLM, but patients NDLM had better clinical outcomes than patients with DLM. The condylar prominence ratio and squaring of the lateral femoral condyle may underlie this result. LEVEL OF EVIDENCE: III.

Identification of recombination in novel goose parvovirus isolated from domesticated Jing-Xi partridge ducks in South China.

Outbreaks of short beak and dwarfism syndrome (SBDS), caused by a novel goose parvovirus (NGPV), have occurred in China since 2015. This rapidly spreading, infectious disease affects ducks in particular, with a high morbidity and low mortality rate, causing huge economic losses. This study analyzed the evolution of NGPV isolated from Jing-Xi partridge duck with SBDS in South China. Complete genome sequences of the NGPV strains GDQY1802 and GDSG1901 were homologous with other GPV/NGPV and Muscovy duck parvovirus (MDPV) strains. Phylogenetic analysis showed that the NGPV isolated from mainland China was related to the Taiwan 82-0321v strain of GPV. In contrast to 82-0321v and the SDLC01 strain, which was first isolated from China, the two isolates showed no deletions in the inverted terminal repeat (ITR) region. Further, in these isolates, 24 amino acid sites of the replication protein were different compared to that of GPV live vaccine strain 82-0321v, and 12 sites were unique across all NGPV isolates. These isolates also showed differences in 17 amino acid sites of the capsid protein from that of 82-0321v, two of which were the same as those in MDPV. Recombination analysis identified the major parents of GDSG1901 and GDQY1802 as the NGPV-GD and NGPV-Hun18 strains, and the minor parents as the classical GPV 06-0329 and GPV LH strains, respectively. GDQY1802 and GDSG1901 are recombinant GPV-related parvovirus isolated from domesticated partridge duck. Recombination is evident in the evolution of NGPV, and as such, the use of live attenuated vaccines for NGPV requires further study.

Checkrein Deformity of the Hallux Caused by Misplaced Suture-Button Syndesmosis Fixation: A Case Report.

Ankle fractures are common injuries. If an ankle fracture is combined with tibiofibular syndesmosis separation, then tibiofibular transfixation should be used to stabilize the syndesmosis; in such cases, flexible (suture-button) fixation is an option. We surgically treated a male patient's unstable ankle fracture with internal fixation devices, including a suture-button fixator, and observed the development of a flexor hallucis longus checkrein deformity in the postoperative period. The aim of this report is to describe this rare postoperative complication associated with the use of suture-button transfixation of the tibiofibular syndesmosis.

Arthroscopic subscapularis augmentation combined with capsulolabral reconstruction is safe and reliable.

PURPOSE: The study aimed to compare modified arthroscopic subscapularis augmentation (MASA) with tenodesis of the upper third of the subscapularis tendon using a tendon combined with capsulolabral reconstruction (Group A) or Bankart repair (Group B) for recurrent anterior shoulder instability (RASI). METHODS: A retrospective series of 49 patients underwent primary surgery for RASI with glenoid bone loss (GBL) < 25%. Outcomes included the Oxford Shoulder Instability Score (OSIS), Visual Analogue Scale (VAS) score, Rowe score, and American Shoulder and Elbow Surgeons (ASES) functional outcome scale score. Recurrent instability, sports activity level, and range of motion (ROM) were also analysed. RESULTS: No significant differences were observed at baseline. Forty-six patients were available for more than 2 years of follow-up. At the last follow-up after surgery, the patients in both groups had experienced significant improvements in all outcome scores (P < 0.05 for all), and obvious decreases in forward flexion and external rotation were noted in both groups (P < 0.05 for all). Group A had superior ASES scores, VAS scores, and OSISs (P < 0.05) but did not experience significant differences in either the Rowe score or ROM compared to Group B. Group A had lower rates of recurrent instability and superior outcomes for the return to sports activities. One patient in Group A had subluxation, and 4 patients in Group B had dislocation or subluxation. No patients in either group experienced neurovascular injury, joint stiffness, or surgical wound infection. CONCLUSION: For RASI with GBL < 25%, MASA with tenodesis of the upper third of the subscapularis tendon using a tendon combined with capsulolabral reconstruction was a safe technique that produced better outcomes in terms of ASES scores, VAS scores, OSISs, the return to sports, and postoperative recurrent instability and did not decrease the ROM compared to that achieved by arthroscopic Bankart repair. LEVEL OF EVIDENCE: III.

Synthesis and antitumor activity of a series of lactone-opened camptothecin derivatives.

A series of E-ring lactone-opened camptothecin (CPT) derivatives bearing with terminal aza-heterocyclic groups were synthesized, and their antitumor activity was evaluated both in vitro and in vivo. Hydroxyl-amide analogues with morpholin-4-yl displayed excellent antitumor activity in vitro and efficient inhibition on tumor xenograph model in nude mice. Ester-amide compounds acted less active in vitro cytotoxicity and lower inhibition activity in vivo. Substitutions at 7- and 10- positions favored the antitumor activity.

Arthroscopic revision release of gluteal muscle contracture after failed primary open surgery.

PURPOSE: The treatment of gluteal muscle contracture (GMC) after failed primary open release surgery has rarely been reported in the literature. GMC is a troublesome health problem in some developing countries, and it can result in the limitation of patients' hip function, leading to the development of inferiority complexes. The aim of this study is to evaluate the effect of arthroscopic revision surgery after failed primary open release on patients with GMC. METHODS: A total of 278 hips of 140 patients who underwent arthroscopic revision procedures after failed primary open surgeries were gathered from the department files. All patients were treated using a "three-step" arthroscopic release procedure by the same surgeon group. RESULTS: The mean follow-up for the 136 patients was 38.9 months. There was significant difference (P < 0.05) between the patients' mean post-revision and pre-operative results on the Harris scoring system. Unreleased contracture tissues that needed revision operations included the gluteus maximus, tensor fasciae latae muscle, and gluteus medius in all patients, and the gluteus minimus and hip capsule in 11.0% and 8.1% of patients, respectively. Short-term complications included subcutaneous bruising of the abdomen in 11 patients, extensive ecchymosis in the lateral thigh in 12 patients, and a transient reduction of muscle strength in all patients. No complications involving postoperative incision infection, nerve and blood vessel damage, or positive Trendelenburg sign occurred. Symptoms of hip snapping and limitation of range of motion (ROM), combined with a positive Trendelenburg sign in two patients after the primary open surgery, were all resolved except for the Trendelenburg sign through arthroscopic revision release. The overall satisfaction rate of the revision operations was 90.4%. CONCLUSION: The three-step arthroscopic release procedure is effective for failed primary open GMC surgeries as shown by improved post-operative function and patient satisfaction regardless of which primary procedure was performed.

Characteristic arthroscopic signs of cartilage injuries indicating concomitant occult medial meniscal peripheral tears of posterior horn.

BACKGROUND: Medial posterior horn meniscal tear is difficult to visualise during arthroscopy and is occasionally undetected by preoperative magnetic resonance imaging (MRI). Consequently, attention should be paid to performing a thorough examination and to some characteristic signs that indicate occult meniscal tear. The purpose of this study was to assess an indicative correlation between arthroscopic features of cartilage injury and a concomitant occult meniscal tear. METHODS: We performed a retrospective clinical and radiographic study of a consecutive series of patients between January 2013 and December 2014. Of 1,596 patients, all 78 with wave-like chondral injury of the medial femoral condyle diagnosed at arthroscopy were included in the study. The occurrence, pattern, location and concomitant pathology of medial meniscal injury were analysed. RESULTS: The characteristic wave sign associated with chondral injury in the medial femoral condyle was detected by MRI preoperatively in two cases only; all others were discovered intraoperatively at arthroscopy. Cartilage injury was rated as Outerbridge type II in 53 patients, type III in 24, and type IV in one. Wave sign defects were all characterised by their transverse orientation in the load-bearing femoral condyle. The occult longitudinal peripheral meniscus tear of the posterior horn was seen in all patients with a positive wave sign visualised under arthroscopy. The wave sign was positively correlated with medial peripheral meniscal injury of the posterior horn (P < 0.01). CONCLUSION: Wave sign chondral injury in the medial femoral condyle seen at arthroscopy is a characteristic indicator for concomitant occult medial longitudinal peripheral meniscus tears of the posterior horn. LEVEL OF EVIDENCE: Case series, Level IV.

Roles of TGF-ß/Smad signaling pathway in pathogenesis and development of gluteal muscle contracture.

PURPOSE OF THE STUDY: Gluteal muscle contracture (GMC) is a chronic fibrotic disease of gluteal muscles which is characterized by excessive deposition of collagen in the extracellular matrix. Transforming growth factor (TGF)-ßs have been shown to play an important role in the progression of GMC. However, the underlying mechanisms are not entirely clear. We sought to explore the expression of TGF-ß/Smad pathway proteins and their downstream targets in gluteal muscle contracture disease. MATERIALS AND METHODS: The expression levels of collagens type I/III, TGF-ß1, Smad2/3/4/7 and PAI-1 (plasminogen activator inhibitor type 1) in gluteal muscle contraction (GMC) patients were measured using immunohistochemistry, reverse transcription and polymerase chain reaction (RT-PCR) and western blot assays. RESULTS: The expressions of collagens type I/III and TGF-ß1 were significantly increased in the contraction band compared with unaffected muscle. In addition, R-Smad phosphorylation and Smad4 protein expression in the contraction band were also elevated, while the expression of Smad7 was significantly decreased in the fibrotic muscle of the GMC patients compared to the unaffected adjacent muscle. The protein and mRNA levels of PAI-1 were also remarkably increased in the contraction band compared with adjacent muscle. Immunohistochemical analysis also demonstrated that the expression levels of TGF-ß1 and PAI-1 were higher in contraction band than those in the adjacent muscle. CONCLUSION: Our data confirm the stimulating effects of the TGF-ß/Smad pathway in gluteal muscle contracture disease and reveal the internal changes of TGF-ß/Smad pathway proteins and their corresponding targets in gluteal muscle contracture patients.

Efficacy and prognosis of neoadjuvant chemotherapy is correlated with breast cancer molecular classification.

Breast cancer is one of the most common cancers affecting women globally. Recent studies have begun to investigate the possibility of customized treatment options for individuals based on the specific cancer type. Here, we sought to analyze the relationship between the molecular classification of breast cancer and the efficacy and prognosis of neoadjuvant chemotherapy (NCT). The study included 100 breast cancer patients treated with an NCT regimen of epirubicin and docetaxel (ET) who were divided into groups based on cancer subtype (luminal, HER2 over-expression, and basal-like subtype). The nuclear classification, number of NCT cycles, pathological remission rate, and clinical curative effect, as well as the disease-free survival time (DFS) and the overall survival (OS), were compared across groups. The nuclear grade of participants in the basal-like group was significantly higher than those in the other groups but this group had fewer preoperative NCT cycles and lower pathological remission and clinical efficacy (Z=53.245, 50.077, 62.467, χ2=16.082, p<0.05). The OS and DFS of participants in the luminal subtype group were significantly higher than those in other groups while those in the basal-like subtype group were the lowest. The OS and DFS of participants who achieved pathological complete remission (pCR) through NCT treatment were significantly higher than those of the patients who had not achieved pCR through NCT treatment (χ2=9.558, 10.139, p<0.05). Therefore, we conclude that when NCT (ET regimen) is used in the treatment of breast cancer, the curative effects and prognosis appear to be correlated with the molecular classification of the tumor. Based on these results, clinicians should consider the molecular classification of the individual tumor to design the most effective treatment option.

A Novel Predictor of the Length and Size of ACL Grafts in Chinese Han Adults for ACL Reconstruction: An MRI Study.

OBJECTIVE: Currently, there is no simple and valid method to predict the length and size of the native anterior cruciate ligament (ACL) in each adult patient who will undergo ACL reconstruction. This study aimed to develop an imaging prediction method that can predict the length and size of ACL grafts using the intact posterior cruciate ligament (PCL), in order to enhance the graft preparation individualized sizing. METHODS: Three hundred and nineteen patients aged 18 years or older who underwent magnetic resonance imaging (MRI) of the knee at an orthopaedic clinic between September 9, 2021, and February 5, 2023, were included. The length, sagittal diameter, and coronal diameter of the ACL and PCL were measured in all patients, and F-test were performed to explore linear relationship between ligament measurements. RESULTS: Equations were established to predict a variable of the native ACL for the corresponding variable of the intact PCL (i.e., sagittal diameter of the ACL = 4.32 + 1.08 × sagittal diameter of the PCL, and coronal diameter of the ACL = 2.45 + 0.59 × coronal diameter of the PCL, length of the male ACL = 10.92 + 0.64 × length of the male PCL, length of the female ACL = 11.76 + 0.58 × length of the female PCL) (R2 = 0.532; R2 = 0.417; R2 = 0.488; R2 = 0.509; respectively). CONCLUSIONS: The length and size of the intact PCL in cases without PCL buckling are predictors of the length and size of the native ACL in adults, respectively. The use of this information to optimize graft diameter may lower the rates of ACL graft failure in the future.

Efficacy of short- versus prolonged-courses of antimicrobial therapy for carbapenem-resistant Klebsiella pneumoniae bloodstream infections: A propensity score-matched cohort study.

BACKGROUND: As limited antibiotic options are available for the treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infections (BSIs), the optimal treatment duration for CRKP BSIs is unclear. Our objective was to investigate whether short courses (6-10 days) are as effective as prolonged courses (≥11 days) of active antibiotic therapy for CRKP BSIs. METHODS: A retrospective cohort study comprising adults with monomicrobial CRKP BSI receiving a short or prolonged course of in vitro active therapy at a medical center was conducted between 2010 and 2021. Comparisons of two therapeutic strategies were assessed by the logistic regression model and propensity score analysis. The primary endpoint was 30-day crude mortality. Secondary outcomes included recurrent BSIs, the emergence of multidrug-resistant organisms and candidemia during hospitalization after completing antibiotic therapy for CRKP BSIs. RESULTS: Of 263 eligible adults, 160 (60.8%) were male, and the median (interquartile range) age was 69.0 (53.0-76.0) years. Common comorbidities included diabetes (143 patients, 54.4%), malignancy (75, 28.5%), cerebrovascular accident (58, 22.1%), and hemodialysis (49, 18.6%). The 30-day mortality rate was 8.4% (22 patients). Of 84 propensity score well-balanced matched pairs, the 30-day mortality was similar in the short-course and prolonged-course group (6.0% and 7.1%, respectively; P = 1.00). However, there were less episodes candidemia in the short-course group (1.2% versus 13.1%; odds ratio, 0.08; 95% confidence interval, 0.01-0.63; P = 0.005). CONCLUSION: Short courses of active therapy for CRKP BSIs demonstrate comparable clinical outcomes to prolonged courses and are associated with a lower risk of subsequent candidemia.

Increased water content in multifidus muscles of young adults with chronic nonspecific low back pain detected by dual-energy CT and MRI.

OBJECTIVES: To demonstrate the feasibility of better diagnosing young adults with chronic nonspecific low back pain (CNLBP) by measuring water content in paraspinal muscles using water-muscle decomposition technique in dual-energy CT (DECT) and T2-mapping in MRI. METHODS: This prospective cross-sectional study included 110 young individuals (56 with CNLBP at age of 25.7 ± 2.0 years and 54 of asymptomatic at age of 25.1 ± 1.9 years) who underwent both MRI and DECT on the spine. T2 values on T2 mapping in MRI and water density (WD) value on water(muscle) images in DECT were generated at the L1-L4 levels for erector spinae muscle and L2-L5 for multifidus muscle. Pain duration time, Oswestry Disability Index (ODI), Visual Analogue Scale (VAS) were recorded for CNLBP patients. Difference of T2 value and WD between the two patient groups, and correlations between T2 value and WD, and T2 value and WD with clinical indicators were analyzed. RESULTS: Compared with asymptomatic participants, the mean WD of multifidus muscle at L4-L5 and mean T2 values of multifidus muscle at L5 were significantly higher in CNLBP patients (all P < 0.05). T2 values had moderate to strong positive correlations (r = 0.34-0.60, all P < 0.05) with DECT WD in CNLBP patients and healthy volunteers. There was a weak correlation between VAS and WD in L5-level multifidus muscle (r = 0.29, P < 0.05). CONCLUSIONS: The T2 values in MRI and WD in DECT are higher in multifidus muscles of lower vertebra levels for young CNLBP patients, and there exists positive correlation between WD and T2 values, providing useful information for diagnosing CNLBP.

Arthroscopic fixation techniques for tibial eminence fractures in pediatric patients: a review.

The introduction of new internal fixation devices and arthroscopic techniques has led to significant changes in the surgical treatment of tibial eminence fractures (TEFs) in children. In recent years, arthroscopic surgery has arisen as the gold standard for the treatment of TEFs. This popularity of arthroscopic techniques has reduced surgical complications and improved patient prognosis. In this paper, we investigate the current situation of the use of arthroscopic fixation techniques for pediatric TEFs. We searched the PubMed database using the terms "arthroscopic treatment and tibial eminence," "arthroscopic treatment and tibial spine," "tibial eminence avulsion", "tibial spine fracture", with no limit on the year of publication. From these articles, we reviewed the use of various arthroscopic TEFs fixation techniques reported in the current literature. Overall, we found that the choice of fixation method seems to have no effect on clinical outcomes or imaging results. However, if an easy, strong fixation that is less prone to epiphyseal damage is desired, as a junior practitioner, the anchor technique should be mastered first, whereas for senior practitioners, a variety of fixation techniques for TEFs should be mastered, including anchors, sutures, and screws, so that personalized fixation can be achieved with the least amount of trauma, operative time, and complications. Higher quality studies are needed in the future to provide Useful evidence to determine the optimal fixation technique in terms of clinical outcomes, function, and complications.

Drp1 regulated PINK1-dependent mitophagy protected duck follicular granulosa cells from acute heat stress injury.

The mitochondrial quality control system is crucial in maintaining cellular homeostasis during environmental stress. Granulosa cells are the main cells secreting steroid hormones, and mitochondria are the key organelles for steroid hormone synthesis. The impact of the mitochondrial quality control system on granulosa cells' steroid hormone synthesis and survival under heat stress is still unclear. Here, we showed that acute heat stress induces mitochondrial damage and significantly increases the number of mitophagy-like vesicles in the cytoplasm of duck ovary granulosa cells at the ultra-structural level. Meanwhile, we also found heat stress significantly increased mitochondrial fission and mitophagy-related protein expression levels both in vivo and in vitro. Furthermore, by confocal fluorescence analysis, we discovered that LC3 was distributed spot-like manner near the nucleus in the heat treatment group, and the LC3 spots and lysosomes were colocalized with Mito-Tracker in the heat treatment group. We further detected the mitophagy-related protein in the cytoplasm and mitochondria, respectively. Results showed that the PINK1 protein was significantly increased both in cytoplasm and mitochondria, while the LC3-Ⅱ/LC3-Ⅰ ratio increase only occurred in mitochondrial. In addition, the autophagy protein induced by acute heat treatment was effectively inhibited by the mitophagy inhibitor CysA. Finally, we demonstrated that the alteration of cellular mitophagy by siRNA interference with Drp1 and PINK1 inhibited the steroid synthesis of granulosa cells and increased cell apoptosis. Study provides strong evidence that the Drp1 regulated PINK1-dependent mitophagy pathway protects follicular granulosa cells from acute heat stress-induced injury.