Acute respiratory viral infections, such as pneumovirus and respiratory picornavirus infections, exacerbate disease in COPD and asthma patients. A research program targeting respiratory syncytial virus (RSV) led to the discovery of GS-7682 (1), a novel phosphoramidate prodrug of a 4 '-CN-4-aza-7,9-dideazaadenosine C-nucleoside GS-646089 (2) with broad antiviral activity against RSV (EC50 = 3-46 nM), human metapneumovirus (EC50 = 210 nM), human rhinovirus (EC50 = 54-61 nM), and enterovirus (EC50 = 83-90 nM). Prodrug optimization for cellular potency and lung cell metabolism identified 5 '-methyl [(S)-hydroxy(phenoxy)phosphoryl]-l-alaninate in combination with 2 ',3 '-diisobutyrate promoieties as being optimal for high levels of intracellular triphosphate formation in vitro and in vivo. 1 demonstrated significant reductions of viral loads in the lower respiratory tract of RSV-infected African green monkeys when administered once daily via intratracheal nebulized aerosol. Together, these findings support additional evaluation of 1 and its analogues as potential therapeutics for pneumo- and picornaviruses.

Acute respiratory viral infections (ARVI), such as pneumovirus and respiratory picornavirus infections, exacerbate disease in COPD and asthma patients. A research program targeting respiratory syncytial virus (RSV) led to the discovery of GS-7682 ( 1 ) a novel phosphoramidate prodrug of a 4′-CN-4-aza-7,9-dideazaadenosine C -nucleoside GS-646089 ( 2 ) with broad antiviral activity against RSV EC50 = 3-46 nM, human metapneumovirus (hMPV) EC50 = 210 ± 50 nM, human rhinovirus (RV) EC50 = 54-61 nM, and enterovirus (EV) EC50 = 83-90 nM. Prodrug optimization for cellular potency and lung cell metabolism identified the 5’-methyl(( S )-hydroxy(phenoxy)phosphoryl)-L-alaninate in combination with 2’,3’-diisobutyrate promoieties as optimal for high intracellular triphosphate formation in vitro and in vivo. 1 demonstrated significant reductions of viral loads in the lower respiratory tract of RSV-infected African green monkeys when administered once daily via intratracheal nebulized aerosol. Together these finding support additional evaluation of 1 and its analogs as a potential therapeutic for pneumo- and picornaviruses. ### Competing Interest Statement Some authors are current or former employees of Gilead Sciences and may own company stock.

Cocrystallization of 6-methylpyridine-3-carboxamide, with mono-to dicarboxylic acids coformers afforded a total of six novel adducts including three co-crystals ( 2 , and 5 -6 ) and two salts ( 1 , and 3 - 4 ). They have been featured by SCXRD, IR and EA, their m.p. were also measured. Their structural and supramolecular facets are fully inspected. The result tells that in all salts the aryl N in 6-methylpyridine-3-carboxamide is the only protonated position. The crystal packing is woven by the strong N-H center dot center dot center dot O, O-H center dot center dot center dot N and O-H center dot center dot center dot O H-bonds. The CONH2 dimers were made in 1 and 6 by a pair of N -H center dot center dot center dot O H-bonds. Deep view of the crystal packing uncovered that different sets of subsidiary CH center dot center dot center dot O/CH3 center dot center dot center dot O, O center dot center dot center dot I, I center dot center dot center dot I, O center dot center dot center dot pi, pi center dot center dot center dot C, CH center dot center dot center dot pi and pi center dot center dot center dot pi contacts contribute to the stabilization and expansion of the final 2D -3D structures. For the delicate balance of the various non-covalent bonds these structures contained homo/hetero supramolecular synthons or both, the common R (2) (2) (8) graph set has been enclosed in all for the cooperation of H-bonds and non-covalent contacts.(c) 2022 Elsevier B.V. All rights reserved.

A discovery program targeting respiratory syncytial virus (RSV) identified C-nucleoside 4 (RSV A2 EC50 = 530 nM) as a phenotypic screening lead targeting the RSV RNA-dependent RNA polymerase (RdRp). Prodrug exploration resulted in the discovery of remdesivir (1, GS-5734) that is >30-fold more potent than 4 against RSV in HEp-2 and NHBE cells. Metabolism studies in vitro confirmed the rapid formation of the active triphosphate metabolite, 1-NTP, and in vivo studies in cynomolgus and African Green monkeys demonstrated a >10-fold higher lung tissue concentration of 1-NTP following molar normalized IV dosing of 1 compared to that of 4. A once daily 10 mg/kg IV administration of 1 in an African Green monkey RSV model demonstrated a >2-log10 reduction in the peak lung viral load. These early data following the discovery of 1 supported its potential as a novel treatment for RSV prior to its development for Ebola and approval for COVID-19 treatment.

The proximity of Cu metal sites and Lewis acid–oxygen vacancy pairs (Zr3–□) dictates the catalytic performance of the upgrading of ethanol to n-butanol.

Cocrystallization of4-methylbenzo[d]thiazol-2-amine with an array of carboxylic acids got a total of 11 crystalline adducts. The 11 adducts have been examined by XRD, IR and EA, the melting points of all adducts were also gauged.Their structural and supramolecular aspects are fully analyzed. The result reveals that among the investigated crystalline solids1-4, 6-7 and 9-10 the aryl N in thiazole cores are protonated when the organic acids are deprotonated and the crystal packing is interpreted by the strong charge-assisted N-H⋯O H-bond from the NH+ and the carboxylates. 5, 8 and 11 are cocrystals sustained by the neutral N-H⋯O/O-H⋯N H-bonds. Except the N-H⋯O H-bonds, the O-H···OH-bonds were also present at 3, 6, 7 and 9-11. 1 has the additional N-H···S H-bonds.The O-H···S H-bond was created in 10. 1 and 5 contained the N-H···N H-bond. 4 showed the N-H···Cl H-bond.Further analysis of the crystal packing of the adducts told that a different set of additional O-H···C,C-C,O-C, O-O, O-S,Cl-O, Cl-Cl, Cl-S, Br-Br,CH3-N, CH-O/CH2-O/CH3-O, CH3-Cl/CH-Cl, C-π, CH3-CH3/CH3-CH/CH-CH, NH-π, CH3-π/CH2-π/CH-π, Cl-π andπ-π contacts contribute to the stabilization and expansion of the totalstructures. For the interplay of the various weak nonbonding contacts these structures took on homo/hetero supramolecular synthons.The recognition of the base-acid in all the multicomponent crystalsis based on thetypical R22(8) synthon. Due to the cooperation of these weak bonds,1-11 display 1D-3D motifs.

前言:儿童及青少年骨折是创伤骨科不可分割的一部分,其诊治具有特殊性.目前我国专业的小儿骨科医师较少,且主要集中在我国一、二线城市,很多成人骨科医生兼任儿童骨折的处理.从儿童骨折的诊治特点出发,为骨科医生讲述儿童骨折治疗原则和注意事项,希望广大骨科医生能经历必要的小儿骨科专业培训,并提倡小儿骨科的专业化发展.

Objective To explore the influence of preoperative magnetic resonance imaging (MRI) on the choice of operative methods in children aged under 2 years with developmental dislocation of hip.Methods Retrospective analysis was performed for children with developmental dislocation of hip from July 2013 to February 2017.According to the Bowen's radiographic standards,they were divided into 3 groups of closed reduction (A,n =26),failure of closed reduction (B,n =24) and impossibility of reduction (C,n =7).On standard MRI,the preoperative measurement of MRI in joint sacs were anterior access angle,inferior access angle,maximal coronal entrance diameter,maximal axial entrance diameter,axial diameter of femoral head,coronal diameter of femoral head,coronal diameter ratio (CMAD/AFHD) and axial diameter ratio (AMAD/CFHD).And the significant differences of data were compared among three groups.Logistic regression analysis was performed for the correlations of gender,age,degree of dislocation,weight bearing time and final treatment.And receiver operating characteristic (ROC) curve was used for assessing the sensitivity and specificity of closed reduction group and determine the cutoff point.Results No significant difference existed in AAA/CFHD/AFHD among 3 groups (P＞0.05).IAA angle (108.2 ± 9.8)° was significantly higher in group A than that in group B (98.8 ± 11.2)° and group C (91.7 ± 6.9)°(P＜0.05);significant differences in CMAD,AMAD,CMAD/AFHD existed between groups A & B and groups A & C (P＜0.05).AMAD/CFHD were different in groups A & B;there was no statistical difference between group A/C;CMAD,AMAD,CMAD/AFHD,AMAD/CFHD were not statistically different between groups B & C (P＞0.05).Logistic regression analysis revealed that,except for age,no correlation existed in gender,measurement,degree of dislocation,weight bearing time or final treatment (P＞0.05).The maximal area of ROC curve was 0.515 (AMAD/CFHD),its specificity (92.3％) and inflection point (0.515).Conclusions Preoperative measurements of MRI of IAA,CMAD,AMAD,CMAD/AFHD,AMAD/CFHD offer certain guiding values for treatment.When AMAD/CFHD ratio is ＞0.515,closed reduction is recommended.

The aim of this study was to describe the radiographic appearance and to evaluate the elbow function with the Mayo elbow performance score (MEPS) in children with medial condyle fracture of the distal humerus (MCFH) who were treated surgically. During the period of 2011-2017, a total of 10 patients (three boys, seven girls) were retrospectively reviewed after obtaining institutional review board approval. All patients underwent open reduction and percutaneous pinning fixation. The average age at the time of injury was 7.7 years (range: 4.0-12.5 years), and the mean follow up was 43.9 months (range: 8.1-67.1 months). The clinical and radiographic outcomes of medial condyle fracture were retrospectively evaluated. Among 10 patients, half were diagnosed with MCFH initially by the radiograph, four out of 10 patients had their diagnosis confirmed with the aid of MRI, and an intraoperative diagnosis was made in only one individual. The average humeral-ulnar angles of the injured and noninjured sides were 9.7 degrees +/- 5.3 degrees and 9.3 degrees +/- 4.7 degrees, respectively (P = 0.679). The average MEPSs of the injured and noninjured sides were 95.5 +/- 2.8 and 96.5 +/- 2.4 points, respectively (P = 0.168). In this retrospectively evaluated cohort submitted to surgical management of medial condyle fracture of the distal humerus, MRI has been proven beneficial assisting the diagnosis and allowing effective joint restoration with mid-term good functional outcome.

Emtricitabine (FTC) and lamivudine (3TC), containing an oxathiolane ring with unnatural (−)-stereochemistry, are widely used nucleoside reverse transcriptase inhibitors (NRTIs) in anti-HIV therapy. Treatment with FTC or 3TC primarily selects for the HIV-1 RT M184V/I resistance mutations. Here we provide a comprehensive kinetic and structural basis for inhibiting HIV-1 RT by (−)-FTC-TP and (−)-3TC-TP and drug resistance by M184V. (−)-FTC-TP and (−)-3TC-TP have higher binding affinities (1/ K d ) for wild-type RT but slower incorporation rates than dCTP. HIV-1 RT ternary crystal structures with (−)-FTC-TP and (−)-3TC-TP corroborate kinetic results demonstrating that their oxathiolane sulfur orients toward the DNA primer 3′-terminus and their triphosphate exists in two different binding conformations. M184V RT displays greater (>200-fold) K d for the L -nucleotides and moderately higher (>9-fold) K d for the D -isomers compared to dCTP. The M184V RT structure illustrates how the mutation repositions the oxathiolane of (−)-FTC-TP and shifts its triphosphate into a non-productive conformation.

Objective To review the imaging features and treatment outcomes of medial humeral condylar fracture in children.Methods Retrospective review was conducted for 10 children with medial condylar humeral fractures.There were 3 boys and 7 girls with an average age at injury of 7.7(4-12.5) years.The average interval between injury and management was 13.5 (1-79) days.Five fractures were diagnosed initially by radiography.Four initially missed cases were diagnosed late by magnetic resonance imaging (MRI).All of them underwent open reduction and internal fixation of Kirschner's wire.The imaging data were reviewed retrospectively and the Mayo elbow performance score (MEPS) was used for assessing the functional outcome of elbow.Results The average follow-up period was 43.9 (8.1-67.1) months.At the last follow-up,the average humeral-ulnar angle was 9.7° ± 5.3° at involved elbow versus 9.3° ± 4.7° at contralateral side (P =0.679).The value of MEPS was 95.5 ± 2.8 points at affected side versus 96.5 ± 2.4 at normal side (P =0.168).Therefore the functional outcomes of injured elbow were excellent in all of them.There was no onset of such complications as nonunion,avascular necrosis or cubitus varus.Conclusions Missed or delayed diagnosis of medial humeral condylar fracture is common in children.However,an excellent functional outcome is still achievable if early diagnosis and treatment are pursued.For any injured elbow with negative radiographic examination but swelling and pain at medial aspect of elbow,a further MRI assessment of cartilaginous injury is mandatory.

The recent Ebola virus (EBOV) outbreak in West Africa was the largest recorded in history with over 28,000 cases, resulting in >11,000 deaths including >500 healthcare workers. A focused screening and lead optimization effort identified 4b (GS-5734) with anti-EBOV EC50 = 86 nM in macrophages as the clinical candidate. Structure activity relationships established that the 1'-CN group and C-linked nucleobase were critical for optimal anti-EBOV potency and selectivity against host polymerases. A robust diastereoselective synthesis provided sufficient quantities of 4b to enable preclinical efficacy in a non-human-primate EBOV challenge model. Once-daily 10 mg/kg iv treatment on days 3-14 postinfection had a significant effect on viremia and mortality, resulting in 100% survival of infected treated animals [ Nature 2016 , 531 , 381 - 385 ]. A phase 2 study (PREVAIL IV) is currently enrolling and will evaluate the effect of 4b on viral shedding from sanctuary sites in EBOV survivors.

A series of 2'-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2'-fluoro-2'-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading to the identification of the 1-aminocyclobutane-1-carboxylic acid isopropyl ester variant (53) with favorable pharmacokinetic properties including efficient liver delivery in animals.

Myositis ossificans (MO) is a benign condition characterized by abnormal heterotopic bone formation, typically involving the striated muscle and soft tissue. MO has an excellent prognosis but may appear clinically and radiologically as a malignant neoplasm. Sometimes the diagnosis of MO is very difficult to establish, even delayed. In the particular cases, when the calcific lesion appears in an atypical location in the body, MO is more likely to be misdiagnosed. A rare case of a MO in the lateral right knee was reported in this article, and surgical resection of the mass was performed. The final pathological diagnosis confirmed MO. Five months after the resective surgery a recurrence of MO took place and the patient underwent another surgical resection of the lesion. Three months later, the lesion reappeared for the third time in the same location. After a seven-year-four-month follow-up, the latest plain radiographs showed the MO to be still present in the lateral right knee. The range of motion of the affected knee and the neurologic examination of this patient were both normal. The cause of the multiple recurrence of MO was unknown. The biopsy of MO is the key factor to avoiding misdiagnosis.

Periosteal chondroma is a relatively rare benign cartilaginous neoplasm usually seen in young adults. We presented three cases of periosteal chondroma in the proximal tibia of a 7-year-old girl (Case 1), a 12-year-old boy (Case 2) and a 15-year-8-month old boy (Case 3). Meticulous analysis of initial and follow-up plain radiographs, Computed Tomography (CT) and Magnetic resonance imaging (MRI) of these painless lesions suggested the diagnosis of periosteal chondroma. This was confirmed by biopsy for Case 1 and Case 2. Local resection with curettage of the adjacent cortex and bone grafting were performed for Case 1 and Case 2. No biopsy or treatment was performed for Case 3. Recovery was uneventful in all three cases. There was no recurrence at the three years and eight months (Case 1), six months (Case 2), and seven years and one month (Case 3) follow-ups.

Osteochondroma of the cervical spine is rare. This is a report of an affected 9-year-old boy with no known familial predisposition for osteochondromas. Imaging revealed a sessile osteochondroma arising from the spinous process and a portion of the left lamina of the seventh cervical vertebrae. The patient was successfully treated with an en-bloc excision of the tumor. Histopathology confirmed that the tumor was an osteochondroma. A follow-up of five-year and five-month confirmed the positive outcome of the treatment with no signs of recurrence and resulting in patient satisfaction.

The discovery is reported of a small molecule drug, GS-5734, which has antiviral activity against Ebola virus and other filoviruses, and is capable of providing post-exposure therapeutic protection against lethal disease in 100% of drug-treated nonhuman primates infected with Ebola virus; the drug targets viral RNA polymerase and can distribute to sanctuary sites (such as testes, eyes and brain), suggesting that it may be able to clear persistent virus infection. These authors report the discovery of a small-molecule drug, GS-5734, which has antiviral activity against Ebola and other filoviruses, and is capable of providing post-exposure protection against Ebola virus in 100% of infected macaques tested. Now in clinical trials ( http://go.nature.com/PEW2Oi ), the drug targets the viral RNA-dependent RNA polymerase and is readily scalable for future outbreaks. GS-5734 is able to distribute to sanctuary sites for viral replication including the testes, eye and brain, offering the hope that this drug may also be able to clear recrudescent and persistent virus infection. The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae1. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg−1 GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.