Antibiotic resistance in bacteria has become a great threat to global public health. Tigecycline is a next‐generation tetracycline that is the final line of defense against severe infections by ...pan‐drug‐resistant bacterial pathogens. Unfortunately, this last‐resort antibiotic has been challenged by the recent emergence of the mobile Tet(X) orthologs that can confer high‐level tigecycline resistance. As it is reviewed here, these novel tetracycline destructases represent a growing threat to the next‐generation tetracyclines, and a basic framework for understanding the molecular epidemiology and resistance mechanisms of them is presented. However, further large‐scale epidemiological and functional studies are urgently needed to better understand the prevalence and dissemination of these newly discovered Tet(X) orthologs among Gram‐negative bacteria in both human and veterinary medicine.
The novel mobile tetracycline‐inactivating enzymes, Tet(X3)–Tet(X5), could confer high‐level tigecycline resistance. They have been disseminated in diverse bacterial hosts from a wide range of ecological niches through promiscuous plasmids and ISCR2. This complex dissemination can be driven by selective pressure from the massive use of the early tetracyclines.
We report acute antibody responses to SARS-CoV-2 in 285 patients with COVID-19. Within 19 days after symptom onset, 100% of patients tested positive for antiviral immunoglobulin-G (IgG). ...Seroconversion for IgG and IgM occurred simultaneously or sequentially. Both IgG and IgM titers plateaued within 6 days after seroconversion. Serological testing may be helpful for the diagnosis of suspected patients with negative RT-PCR results and for the identification of asymptomatic infections.
Tigecycline is one of the last-resort antibiotics to treat complicated infections caused by both multidrug-resistant Gram-negative and Gram-positive bacteria
. Tigecycline resistance has sporadically ...occurred in recent years, primarily due to chromosome-encoding mechanisms, such as overexpression of efflux pumps and ribosome protection
. Here, we report the emergence of the plasmid-mediated mobile tigecycline resistance mechanism Tet(X4) in Escherichia coli isolates from China, which is capable of degrading all tetracyclines, including tigecycline and the US FDA newly approved eravacycline. The tet(X4)-harbouring IncQ1 plasmid is highly transferable, and can be successfully mobilized and stabilized in recipient clinical and laboratory strains of Enterobacteriaceae bacteria. It is noteworthy that tet(X4)-positive E. coli strains, including isolates co-harbouring mcr-1, have been widely detected in pigs, chickens, soil and dust samples in China. In vivo murine models demonstrated that the presence of Tet(X4) led to tigecycline treatment failure. Consequently, the emergence of plasmid-mediated Tet(X4) challenges the clinical efficacy of the entire family of tetracycline antibiotics. Importantly, our study raises concern that the plasmid-mediated tigecycline resistance may further spread into various ecological niches and into clinical high-risk pathogens. Collective efforts are in urgent need to preserve the potency of these essential antibiotics.
ObjectiveType 2 diabetes mellitus is increasing in young adults, and greater adiposity is considered a major risk factor. However, whether there is an association between obesity and diabetes and how ...this might be impacted by age is not clear. Therefore, we investigated the association between body mass index (BMI) and diabetes across a wide range of age groups (20–30, 30–40, 40–50, 50–60, 60–70 and ≥70 years old).DesignWe performed a retrospective cohort study using healthy screening programme data.SettingA total of 211 833 adult Chinese persons >20 years old across 32 sites and 11 cities in China (Shanghai, Beijing, Nanjing, Suzhou, Shenzhen, Changzhou, Chengdu, Guangzhou, Hefei, Wuhan, Nantong) were selected for the study; these persons were free of diabetes at baseline.Primary and secondary outcome measuresFasting plasma glucose levels were measured and information regarding the history of diabetes was collected at each visit. Diabetes was diagnosed as fasting plasma glucose ≥7.00 mmol/L and/or self-reported diabetes. Patients were censored at the date of diagnosis or the final visit, whichever came first.ResultsWith a median follow-up of 3.1 years, 4174 of the 211 833 participants developed diabetes, with an age-adjusted incidence rate of 7.35 per 1000 persons. The risk of incident diabetes increased proportionally with increasing baseline BMI values, with a 23% increased risk of incident diabetes with each kg/m2 increase in BMI (95% CI 1.22 to 1.24). Across all age groups, there was a linear association between BMI and the risk of incident diabetes, although there was a stronger association between BMI and incident diabetes in the younger age groups (age×BMI interaction, p<0.0001).ConclusionsAn increased BMI is also independently associated with a higher risk of developing diabetes in young adults and the effects of BMI on incident diabetes were accentuated in younger adults.
Regulated necrosis (necroptosis) and apoptosis are crucially involved in severe cardiac pathological conditions, including myocardial infarction, ischemia-reperfusion injury and heart failure. ...Whereas apoptotic signaling is well defined, the mechanisms that underlie cardiomyocyte necroptosis remain elusive. Here we show that receptor-interacting protein 3 (RIP3) triggers myocardial necroptosis, in addition to apoptosis and inflammation, through activation of Ca(2+)-calmodulin-dependent protein kinase (CaMKII) rather than through the well-established RIP3 partners RIP1 and MLKL. In mice, RIP3 deficiency or CaMKII inhibition ameliorates myocardial necroptosis and heart failure induced by ischemia-reperfusion or by doxorubicin treatment. RIP3-induced activation of CaMKII, via phosphorylation or oxidation or both, triggers opening of the mitochondrial permeability transition pore and myocardial necroptosis. These findings identify CaMKII as a new RIP3 substrate and delineate a RIP3-CaMKII-mPTP myocardial necroptosis pathway, a promising target for the treatment of ischemia- and oxidative stress-induced myocardial damage and heart failure.
The catalytic nucleophilic substitution of tertiary alcohols using carbon or heteroatom based nucleophiles is a versatile methodology for the efficient, diverse and atom economical construction of ...fully substituted carbon centres, including both quaternary carbons and heteroatom substituted tetrasubstituted carbons, which only produces water as the by-product. This review summarizes the recent progress in this field, including the catalytic asymmetric studies and their application in the natural product synthesis, briefly discusses the reaction mechanism and challenges, and outlines synthetic opportunities that are still open.
Ship detection is one of important applications for synthetic aperture radar (SAR). Speckle effects usually make SAR image understanding difficult and speckle reduction becomes a necessary ...pre-processing step for majority SAR applications. This work examines different speckle reduction methods on SAR ship detection performances. It is found out that the influences of different speckle filters are significant which can be positive or negative. However, how to select a suitable combination of speckle filters and ship detectors is lack of theoretical basis and is also data-orientated. To overcome this limitation, a speckle-free SAR ship detection approach is proposed. A similar pixel number (SPN) indicator which can effectively identify salient target is derived, during the similar pixel selection procedure with the context covariance matrix (CCM) similarity test. The underlying principle lies in that ship and sea clutter candidates show different properties of homogeneity within a moving window and the SPN indicator can clearly reflect their differences. The sensitivity and efficiency of the SPN indicator is examined and demonstrated. Then, a speckle-free SAR ship detection approach is established based on the SPN indicator. The detection flowchart is also given. Experimental and comparison studies are carried out with three kinds of spaceborne SAR datasets in terms of different polarizations. The proposed method achieves the best SAR ship detection performances with the highest figures of merits (FoM) of 97.14%, 90.32% and 93.75% for the used Radarsat-2, GaoFen-3 and Sentinel-1 datasets, accordingly.
Data on sofosbuvir‐based therapy for pregnant women and infants with severe chronic hepatitis C (CHC) are lacking. Two late pregnant women and one female infant with severe CHC were enrolled for ...treatment. Pregnant Women 1 and 2 and Infant 3 were 30, 33, and 1.2 years old, respectively; the gestational ages of pregnant Women 1 and 2 were 31 and 26 weeks, respectively. Notably, pregnant Women 1 and 2 and Infant 3 had hepatitis C virus (HCV) RNA levels of 139 000, 198 000, and 8 450 000 IU/ml; alanine aminotransferase levels of 420, 781, and 220 U/L; and received sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, and sofosbuvir/ledipasvir for 12 weeks, respectively. All three patients were safely cured with favorable tolerance, and two newborns were both breastfeeding and were consistently negative for the anti‐HCV antibody during the 1‐year follow‐up after birth. Additionally, two newborns and Infant 3 had normal growth parameters during the follow‐up year one. In conclusion, this case series study found that sofosbuvir‐based therapy for pregnant women and infants with severe CHC is safe and effective. The data may fill the gap and provide evidence of the use of sofosbuvir‐based therapy as a reference when similar severe CHC situations are encountered during clinical practice.
What Is Known and Objective
Only a few studies about polymyxin B (PMB) against multidrug‐resistant gram‐negative bacteria (MDR GNB) infection were conducted in liver transplantation recipients ...(LTRs). The purpose of this study was to investigate the efficacy and safety of PMB in the treatment of MDR‐GNB in liver transplant recipients and to determine the risk factors affecting clinical cure and 30‐day all‐cause mortality.
Methods
Data of LTRs receiving PMB from January 2016 to February 2020 were collected. Clinical cure and 30‐day all‐cause mortality were the main efficacy outcomes, while the incidence of nephrotoxicity, neurotoxicity, and hyperpigmentation of PMB was the main safety outcome.
Results and Discussion
Data of 42 LTRs were included. Clinical cure with PMB was observed in 27 recipients (64.3%), and the 30‐day all‐cause mortality rate was 31.0% (13/42). The incidence of acute kidney injury (AKI), neurotoxicity, and hyperpigmentation was 57.1% (16/28), 4.8% (2/42), and 16.7% (7/42), respectively. Logistic regression analysis showed that Acute Physiology and Chronic Health Evaluation (APACHE) II score (OR, 1.203; 95% CI, 1.016–1.423, p = 0.032) was an independent risk factor for 30‐day all‐cause mortality, whereas renal replacement therapy (OR, 0.128; 95% CI, 0.019–0.860, p = 0.034) was an independent risk factor for clinical cure with PMB.
What Is New and Conclusions
This is the first study to evaluate the application of PMB in LTRs. If there were no better therapeutic options left for LTRs other than PMB, it can be used against MDR GNB infection in LTRs. We should closely observe adverse events or reactions, and adjust the dose based on the balance of efficacy and safety.
Bacterial infection is a significant cause of morbidity and mortality after liver transplantation. Polymyxin B is now reintroduced into clinical use as “last line” therapy against multidrug‐resistant gram‐negative bacteria infection. But there is a limited number of studies about its use in liver transplantation recipients (LTRs). Our study showed that the rate of clinical cure with PMB and 30‐day all‐cause mortality was 64.3% and 31.0%. APACHE II score was an independent risk factor for 30‐day all‐cause mortality, whereas RRT was an independent risk factor for clinical cure with PMB. The incidence of PMB‐associated acute kidney injury (AKI), neurotoxicity, and hyperpigmentation was 57.1% (16/28), 4.8% (2/42) and 16.7% (7/42), respectively. If there were no better therapeutic options left for LTRs other than PMB, it can be used against MDR GNB infection in LTRs.
Congenital hypothyroidism (CH), the most common neonatal metabolic disorder, is characterized by impaired neurodevelopment. Although several candidate genes have been associated with CH, ...comprehensive screening of causative genes has been limited.
One hundred ten patients with primary CH were recruited in this study. All exons and exon-intron boundaries of 21 candidate genes for CH were analyzed by next-generation sequencing. And the inheritance pattern of causative genes was analyzed by the study of family pedigrees.
Our results showed that 57 patients (51.82%) carried biallelic mutations (containing compound heterozygous mutations and homozygous mutations) in six genes (
,
,
,
,
and
) involved in thyroid hormone synthesis. Autosomal recessive inheritance of CH caused by mutations in
,
,
and
was confirmed by analysis of 22 family pedigrees. Notably, eight mutations in four genes (
,
,
and
) that lead to thyroid dysgenesis were identified in eight probands. These mutations were heterozygous in all cases and hypothyroidism was not observed in parents of these probands.
Most cases of congenital hypothyroidism in China were caused by thyroid dyshormonogenesis rather than thyroid dysgenesis. This study identified previously reported causative genes for 57/110 Chinese patients and revealed
was the most frequently mutated gene in these patients. Our study expanded the mutation spectrum of CH in Chinese patients, which was significantly different from Western countries.
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