Updated therapeutic options for human brucellosis: A systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: In clinical practice guidelines, there is no consensus about the medications that should be initially offered to patients with brucellosis. To provide informative evidence, we compared and ranked brucellosis medications based on their efficacy and safety. METHODS: For this systematic review and network meta-analysis, we searched 4 English databases and 3 Chinese databases, from the date of database inception to December 13, 2023. We included randomized controlled trials (RCTs) involving children and adolescents with brucellosis, comparing different antibiotic regimens. We excluded studies explicitly targeting patients with spondylitis brucellosis, endocarditis brucellosis, and neuro-brucellosis. The primary outcomes were overall failure (efficacy) and side effects (safety). Secondary outcomes were relapse and therapeutic failure. Pairwise meta-analysis was first examined. Data were analyzed using random effects network meta-analysis, with subgroup and sensitivity analyses performed. The Confidence in Network Meta-Analysis (CINeMA) framework was used to assess the certainty of evidence. The protocol was preregistered in PROSPERO (CRD42023491331). RESULTS: Of the 11,747 records identified through the database search, 43 RCTs were included in the network meta-analysis. Compared with standard therapy (Doxycycline + Rifampicin), Rifampicin + Tetracyclines (RR 4.96; 95% CI 1.47 to 16.70; very low certainty of evidence), Doxycycline + TMP/SMX (RR 0.18; 95% CI 0.06 to 0.52; low certainty of evidence), Doxycycline + Quinolones (RR 0.27; 95% CI 0.11 to 0.71; low certainty of evidence), Streptomycin + Tetracyclines (RR 0.04; 95% CI 0.01 to 0.16; low certainty of evidence), and Single (RR 0.05; 95% CI 0.02 to 0.16; moderate certainty of evidence) were less efficacious. Doxycycline + Gentamicin ranked the best in efficacy (SUCRA values: 0.94), the second is Triple (SUCRA values: 0.87), and the third is Doxycycline + Streptomycin (SUCRA values: 0.78). CONCLUSIONS: Brucellosis medications differ in efficacy and safety. Doxycycline + Gentamicin, Triple, and Doxycycline + Streptomycin have superior efficacy and safety. Treatment of brucellosis should strike a balance between efficacy, safety, and cost.

Risk effects of meteorological factors on human brucellosis in Jilin province, China, 2005-2019.

Background: The impact of climate on zoonotic infectious diseases (or can be referred to as climate-sensitive zoonotic diseases) is confirmed. Yet, research on the association between brucellosis and climate is limited. We aim to understand the impact of meteorological factors on the risk of brucellosis, especially in northeastern China. Methods: Monthly incidence data for brucellosis from 2005 to 2019 in Jilin province was obtained from the China Information System for Disease Control and Prevention (CDC). Monthly meteorological data (average temperature (°C), wind velocity (m/s), relative humidity (%), sunshine hours (h), air pressure (hPa), and rainfall (mm)) in Jilin province, China, from 2005 to 2019 were collected from the China Meteorological Information Center (http://data.cma.cn/). The Spearman's correlation was used to choose among the several meteorological variables. A distributed lag non-linear model (DLNM) was used to estimate the lag and non-linearity effect of meteorological factors on the risk of brucellosis. Results: A total of 24,921 cases of human brucellosis were reported in Jilin province from 2005 to 2019, with the peak epidemic period from April to June. Low temperature and low sunshine hours were protective factors for the brucellosis, where the minimum RR values were 0.50 (95 % CI = 0.31-0.82) for -13.7 °C with 1 month lag and 0.61 (95 % CI = 0.41-0.91) for 110.5h with 2 months lag, respectively. High temperature, high sunshine hours, and low wind velocity were risk factors for brucellosis. The maximum RR values were 2.91 (95 % CI = 1.43-5.92, lag = 1, 25.7 °C), 1.85 (95 % CI = 1.23-2.80, lag = 2, 332.6h), and 1.68 (95 % CI = 1.25-2.26, lag = 2, 1.4 m/s). The trends in the impact of extreme temperature and extreme sunshine hours on the transmission of brucellosis were generally consistent. Conclusion: High temperature, high sunshine hours, and low wind velocity are more conducive to the transmission of brucellosis with an obvious lag effect. The results will deepen the understanding of the relationship between climate and brucellosis and provide a reference for formulating relevant public health policies.

First Report of Tobacco Root Rot Caused by Fusarium falciforme in China.

China is the largest producer of tobacco (Nicotiana tabacum L.) in the world with an estimated production of 2.4 million ton per year (Berbec and Matyka 2020). In June 2021, a root disease was observed on tobacco in three surveyed counties (Xiangcheng, Linying and Jiaxian) in central Henan. Diseased plants exhibited leaf chlorosis and brown to purplish vascular discoloration of the taproot and lateral roots. Approximately 10 to 15% of the plants were symptomatic in the nine fields surveyed, representing 60 ha in total. Root segments (0.5 to 1 cm) from ten diseased plants were surface sterilized in 75% ethanol for 30 s followed by rinsing with sterile distilled water three times. Thirty air dried root pieces were placed on potato dextrose agar (PDA) and incubated at 25℃ in the dark for 2 days. Typical Fusarium spp. colonies were obtained from all root samples. Ten pure cultures were obtained by single-spore culturing (Yz01 to Yz10). Colonies on PDA showed abundant white to cream aerial mycelia with a yellowish-brown center on the reverse side after 7 days, and an average growth rate of 5 mm/day. From 7-day-old cultures grown on carnation leaf agar (CLA), macroconidia had three to four septa, were falciform, with blunt apical cells and slightly hooked basal cell, and measured 20 to 41×3-6.5 µm (n=50). Spherical conidia clusters were formed at the apex of the conidiophores. Abundant reniform and cylindrical microconidia were one to two-celled, with apexes rounded, measuring 7 to 15×2 to 5 µm (n=50). The roughly spherical chlamydospores were intercalary or terminal, single or in chains, and rough walled. Such characteristics were consistent with the Fuarium solani species complex (FSSC) (Leslie and Summerell 2006). The translation elongation factor 1-alpha (EF1-α) gene of the ten cultures was amplified with primers EF1/EF2 (O'Donnell et al. 1998), and sequenced. Maximum likelihood analysis was carried out using the EF1-α sequences of the ten cultures (Kumar et al. 2016). The RNA polymerase I largest subunit (RPB1) and second largest subunit (RPB2) genes of the cultures were amplified with primers F5/G2R and RPB2F/R respectively (O'Donnell et al. 1998, 2010), and sequenced. The EF1-α, RPB1 and RPB2 sequences (GenBank accession nos. ON186742.1-ON186751.1, ON241133.1-ON241148.1, ON324054.1-ON324057.1) were 99.4 to 100% identical to the corresponding DNA sequences of Fusarium falciforme based on FUSARIUM-ID BLASTn analysis. Morphological and molecular results confirmed this species as F. falcifome (Díaz-Nájera et al. 2021; Velarde-Félix et al. 2022). Pathogenicity tests were performed in tobacco seedlings grown on autoclaved soil. Healthy six-leaf stage tobacco seedlings (n=30; Zhongyan 100) were inoculated by placing 7-days old wheat seed (15 seeds per plant) infested with the representative culture Yz07 around the root. Thirty seedlings inoculated with sterile wheat seeds served as controls. All the plants were maintained in a growth chamber at 25±0.5℃ and 70% relative humidity. The assay was conducted three times. Typical symptoms of foliage chlorosis and root browning were observed 7 to 14 days after inoculation for all the 90 inoculated seedlings. Fifteen diseased seedlings were randomly selected for tissue isolation, and F. falciforme was reisolated from the 15 seedlings and showed the same morphology and EF1-α gene sequence as the original isolate. Control plants remained asymptomatic and no pathogen was recovered. The results showed that F. falciforme can cause root rot of tobacco. F. falciforme was reported to cause tobacco wilt and root rot in Northwestern Argentina (Berruezo et al. 2018); however, this is the first report of F. falciforme causing root rot of tobacco in China. This species was previously reported in China affecting Weigela florida (Shen et al. 2019) and Dioscorea polystachya (Zhang et al. 2020), showing that F. falciforme has a broad host range in this country. These results may inform control tobacco root rot through improve crop rotations. Funding: Funding was provided by the Science and Technology Project of Henan Provincial Tobacco Company (2020410000270012), Outstanding Youth Science and Technology Fund Project of Henan Academy of Agricultural Sciences (2022YQ09) and Science and Technology Innovation Team project of Henan Academy of Agricultural Sciences (2022TD26). References: Berbec, A. K., and Matyka, M. 2020. Agric. 10:551. Berruezo, L. A., et al. 2018. Eur. J. Plant. Pathol. 151:1065. Díaz-Nájeraet, J. F., et al. 2021. Plant Dis. 105:710. Douriet-Angulo, A., et al. 2019. Plant Dis. 103:11. Kumar, S., et al. 2016. Mol. Biol. Evol. 33:1870. Leslie, J. F., and Summerell, B. A., eds. 2006. The Fusarium Laboratory Manual. Blackwell Publishing, Ames, IA. O'Donnell, K., et al. 1998. PNAS. 95:2044. O'Donnell, K., et al. 2010. J. Clin. Microbiol. 48:3708. Vega-Gutierrez, T. A., et al. 2018. Plant Dis. 103:1. Velarde-Félix, S., et al. 2022. Plant Dis. 106:329. Zhang, X., et al. 2020. Plant Dis. 104:5. The author(s) declare no conflict of interest. Keywords: tobacco root rot, Fusarium falciforme, China.

Molecular and Biological Characterization of the First Mymonavirus Identified in Fusarium oxysporum.

We characterized a negative sense single-stranded RNA mycovirus, Fusarium oxysporum mymonavirus 1 (FoMyV1), isolated from the phytopathogenic fungus Fusarium oxysporum. The genome of FoMyV1 is 10,114 nt, including five open reading frames (ORFs1-5) that are non-overlapping and linearly arranged. The largest, ORF5, encodes a large polypeptide L containing a conserved regions corresponding to Mononegavirales RNA-dependent RNA polymerase and mRNA-capping enzyme region V; the putative functions of the remaining four ORFs are unknown. The L protein encoded by ORF5 shared a high amino acid identity of 65% with that of Hubei rhabdo-like virus 4, a mymonavirus that associated with arthropods. However, the L protein of FoMyV1 also showed amino acid similarity (27-36%) with proteins of mynonaviruses that infect the phytopathogenic fungi Sclerotinia sclerotiorum and Botrytis cineaea. Phylogenetic analysis based on L protein showed that FoMyV1 is clustered with the members of the genus Hubramonavirus in the family Mymonaviridae. Moreover, we found that FoMyV1 could successfully transfer by hyphal anastomosis to a virus-free strain. FoMyV1 reduced the vegetative growth and conidium production of its fungal host but did not alter its virulence. To the best of our knowledge, this is not only the first mymonavirus described in the species F. oxysporum, but also the first Hubramonavirus species found to infect a fungus. However, the incidence of FoMyV1 infections in the tested F. oxysporum strains was only 1%.

Unraveling the expression of differentially expressed proteins and enzymatic activity in response to Phytophthora nicotianae across different flue-cured tobacco cultivars.

BACKGROUND: Black shank disease caused by Phytophthora nicotianae is a serious threat to flue-cured tobacco production. Whole-plant resistance is characterized by the expression of a number of pathogenesis-related proteins, genes, and the activity of different defense-related enzymes. In this study, we investigated the activity of defense-related enzymes and expression of differentially expressed proteins through the iTRAQ technique across two flue-cured tobacco cultivars, i.e., K326 and Hongda, in response to the black shank pathogen. RESULTS: Results showed that the highest disease incidence was recorded in flue-cured tobacco cultivar Hongda compared with K326, which shows that Hongda is more susceptible to P. nicotianae than K326. A total of 4274 differentially expressed proteins were detected at 0 h and after 24 h, 72 h of post-inoculation with P. nicotianae. We found that 17 proteins induced after inoculation with P. nicotianae, including pathogenesis (5), photosynthesis (3), oxidative phosphorylation (6), tricarboxylic acid cycle (1), heat shock (1), and 14-3-3 (1) and were involved in the resistance of flue-cured tobacco against black shank disease. The expression of 5 pathogenesis-related proteins and the activities of defense-related enzymes (PPO, POD, SOD, and MDA) were significantly higher in the leaves of K326 than Hongda after inoculation with P. nicotianae. CONCLUSION: These results provide new molecular insights into flue-cured tobacco responses to P. nicotianae. It is concluded that differences in protein expressions and defense-related enzymes play an important role in developing resistance in flue-cured tobacco cultivars against black shank disease.

Role of STAT3/mTOR pathway in chronic kidney injury.

STAT3/mTOR pathway plays an important role in inflammation, cell growth, and proliferation. However, the role of STAT3/mTOR pathway in chronic kidney injury remains unclear. Folic acid was used to induce kidney injury C57BL/6 mouse model followed by analysis of serum creatinine, renal weight ratio changes, renal pathological changes and STAT3/mTOR pathway changes. Glomerular mesangial cells were divided into control group, model group, STAT3 inhibitor (S3I-201) group followed by analysis of cell proliferation by MTT assay, cell apoptosis by flow cytometry, formation of autophagosomes by electron microscopy, expression of STAT3/mTOR signaling proteins and autophagy proteins LC3II and p62 by Western blot, expression of E-cadherin and Vimentin by immunofluorescence. The serum creatinine and renal weight ratio was increased with obvious lesions and upregulated STAT3 and p-mTOR level. Compared with control group, the difference was statistically significant (P < 0.05). Folic acid-induced injury of mesangial cells showed inhibited cell proliferation, promoted apoptosis, increased LC3II expression, decreased p62 expression, increased autophagic vacuoles and expression of STAT3 and p-mTOR as well as decreased E-cadherin expression and increased Vimentin expression. The difference was statistically significant compared with control group (P < 0.05). All above changes were significantly reversed after treatment with STAT3 inhibitor S3I-201 (P < 0.05). Activated STAT3/mTOR pathway, enhanced autophagy, promoted apoptosis of mesangial cells and inhibited cell proliferation were found in mice with renal injury. Inhibition of STAT3/mTOR activation inhibits autophagy and cell apoptosis and promotes cell proliferation.

Outcomes of laparoscopic radical nephrectomy for elderly patients with localized renal cell carcinoma.

PURPOSE: This study was to compare the short- and long-term outcomes of elderly versus middle-aged patients with localized renal cell carcinoma who had undergone laparoscopic radical nephrectomy. METHODS: Between January 2012 and January 2018, a total of 54 patients aged 70 years and above with localized renal cell carcinoma (elderly group) underwent laparoscopic radical nephrectomy. The short- and long-term outcomes of these 54 patients were compared with those of 97 middle-aged patients (aged between 55 and 69 years; middle-aged group) who underwent laparoscopic radical nephrectomy due to localized renal cell carcinoma. RESULTS: The age, Charlson's comorbidity index, and American Society of Anesthesiologists (ASA) score were higher in the elderly group than in the middle-aged group. Other preoperative baseline data did not show any statistically significant differences. The differences in short-term outcomes, including operative time, intraoperative blood loss, transfer rate, postoperative 30-day complication rate and severity of complication, and pathological data were not statistically significant between the elderly and middle-aged groups. Long-term follow-up results showed that the tumor recurrence rates were similar in the two groups. Overall and disease-free survival rates were similar in the two groups. Multivariate analysis showed that age was not an independent predictor for overall and disease-free survival rates. CONCLUSIONS: Treatment with laparoscopic radical nephrectomy for elderly patients with localized renal cell carcinoma, could achieve short- and long-term outcomes, similar to those of middle-aged patients.