Clinical characteristics and antibiotic treatment of peritoneal dialysis-associated peritonitis caused by Pseudomonas species: a review of 15 years' experience from southern China.

Pseudomonas can lead to peritoneal dialysis-associated peritonitis, which is characterized by a poor prognosis, such as a substantial failure rate and a high death rate. This study aimed to provide an overview of Pseudomonas peritonitis's clinical features, the regimens of antibiotic, antibiotic resistance, and outcomes in peritoneal dialysis (PD) patients. This study observed patients with Pseudomonas peritonitis in two large PD centers in South China from January 2008 to December 2022. The demographics, symptomatology, antibiotics regimens, resistance to common antibiotics, and clinical outcomes of all included patients were reviewed. A total of 3,459 PD patients were included, among them 57 cases of peritonitis caused by Pseudomonas, including 48 cases (84.2%) of Pseudomonas aeruginosa. The incidence rate of Pseudomonas peritonitis was 0.0041 episode per patient-year. Of them, 28.1% (16 cases) of the patients were accompanied by exit site infection (ESI), and all had abdominal pain and turbid ascites at the time of onset. The most commonly used antibiotic combination was ceftazidime combined with amikacin. Approximately 89% of Pseudomonas species were sensitive to ceftazidime, and 88% were sensitive to amikacin. The overall primary response rate was 28.1% (16 patients), and the complete cure rate was 40.4% (23 patients). There was no significant difference in the complete cure rate of peritonitis using three and other antibiotic treatment regimens (44.8% vs 46.4%; P = 0.9). The successful treatment group had higher baseline albumin level (35.9 ± 6.2; P = 0.008) and residual urine volume (650.7 ± 375.5; P = 0.04). Although the incidence of peritonitis caused by Pseudomonas was low, the symptoms were serious, and prognosis was very poor. Pseudomonas was still highly susceptible to first-line antibiotics currently in use against Gram-negative bacteria. Patients with successful treatment had higher albumin levels and higher urine output. IMPORTANCE: Although the incidence of peritoneal dialysis-associated peritonitis caused by Pseudomonas is very low, it seriously affects the technique survival of peritoneal dialysis patients. However, there are few studies and reports on Pseudomonas peritonitis in the Chinese mainland area. Therefore, the purpose of this study is to describe the clinical characteristics, the regimens of antibiotic, drug resistance, and outcome of peritoneal dialysis patients in southern China in the past 15 years and summarize the clinical experience in the treatment of Pseudomonas peritonitis.

Activation of the PERK-CHOP signaling pathway during endoplasmic reticulum stress contributes to olanzapine-induced dyslipidemia.

Olanzapine (OLZ) is a widely prescribed antipsychotic drug with a relatively ideal effect in the treatment of schizophrenia (SCZ). However, its severe metabolic side effects often deteriorate clinical therapeutic compliance and mental rehabilitation. The peripheral mechanism of OLZ-induced metabolic disorders remains abstruse for its muti-target activities. Endoplasmic reticulum (ER) stress is implicated in cellular energy metabolism and the progression of psychiatric disorders. In this study, we investigated the role of ER stress in the development of OLZ-induced dyslipidemia. A cohort of 146 SCZ patients receiving OLZ monotherapy was recruited, and blood samples and clinical data were collected at baseline, and in the 4th week, 12th week, and 24th week of the treatment. This case-control study revealed that OLZ treatment significantly elevated serum levels of endoplasmic reticulum (ER) stress markers GRP78, ATF4, and CHOP in SCZ patients with dyslipidemia. In HepG2 cells, treatment with OLZ (25, 50 µM) dose-dependently enhanced hepatic de novo lipogenesis accompanied by SREBPs activation, and simultaneously triggered ER stress. Inhibition of ER stress by tauroursodeoxycholate (TUDCA) and 4-phenyl butyric acid (4-PBA) attenuated OLZ-induced lipid dysregulation in vitro and in vivo. Moreover, we demonstrated that activation of PERK-CHOP signaling during ER stress was a major contributor to OLZ-triggered abnormal lipid metabolism in the liver, suggesting that PERK could be a potential target for ameliorating the development of OLZ-mediated lipid dysfunction. Taken together, ER stress inhibitors could be a potentially effective intervention against OLZ-induced dyslipidemia in SCZ.

Broadly neutralizing antibodies to combat influenza virus infection.

The diversified classification and continuous alteration of influenza viruses underscore for antivirals and vaccines that can counter a broad range of influenza subtypes. Hemagglutinin (HA) and neuraminidase (NA) are two principle viral surface targets for broadly neutralizing antibodies. A series of monoclonal antibodies, targeting HA and NA, have been discovered and characterized with a wide range of neutralizing activity against influenza viruses. Clinical studies have demonstrated the safety and efficacy of some HA stem-targeting antibodies against influenza viruses. Broadly neutralizing antibodies (bnAbs) can serve as both prophylactic and therapeutic agents, as well as play a critical role in identifying antigens and epitopes for the development of universal vaccines. In this review, we described and summarized the latest discoveries and advancements of bnAbs against influenza viruses in both pre- and clinical development. Additionally, we assess whether bnAbs can serve as a viable alternative to vaccination against influenza. Finally, we discussed the rationale behind reverse vaccinology, a structure-guided universal vaccine design strategy that efficiently identifies candidate antigens and conserved epitopes that can be targeted by antibodies.

Left ventricular strain and myocardial work in short-term peritoneal dialysis patients.

BACKGROUND: Initiation of dialysis encompasses new cardiovascular challenges on patients with end-stage renal disease (ESRD). This study used two-dimensional speckle-tracking echocardiography (2D-STE) to investigate the change of left ventricular (LV) myocardial function undergoing peritoneal dialysis (PD) within 1-3 months. METHODS: A total of 56 patients with ESRD and 27 healthy controls were enrolled in this prospective study. Mean duration of PD was 44.41 ± 16.44 days. We evaluated LV myocardial function of patients with ESRD in baseline and within 1-3 months after PD by 2D-STE with global longitudinal strains (GLS) and myocardial work (MW). Based on the level of serum phosphate before PD, patients were divided into two groups: the group with normal serum phosphate or hyperphosphatemia. RESULTS: Compared with healthy controls, patients with ESRD had impaired GLS (p < .001) and increased global work index (GWI) (p = .034), global constructive work (GCW) (p < .001), global wasted work (GWW) (p < .001), and lower global work efficiency (GWE) (p = .002). After PD therapy, GWI (p = .001), GCW (p < .001), and GWW (p = .023) decreased and closed to healthy subjects (p > .05) and no significant improvement was observed in GLS (p = .387). GLS of basal segments worsened in the hyperphosphatemia group (p = .005) and GWW reduced remarkably in the group with normal serum phosphate after PD treatment (p = .008). The change of left ventricular internal diameter in diastole (LVIDd) was the only parameter influenced GWI in post-dialysis patients (ß = 0.324, p = .013). CONCLUSIONS: Short-term PD treatment improved LV MW in ESRD patients. They benefited more when receiving treatment before the increase of serum phosphorus.

The centre-calculated cutoff value is better for identifying fast peritoneal solute transfer of patients on peritoneal dialysis than the traditional value: a retrospective cohort study.

Background: The mean 4-h dialysate to plasma ratio of creatinine (4-h D/Pcr) is a vital cutoff value for recognizing the fast peritoneal solute transfer rate (PSTR) in patients on peritoneal dialysis (PD); however, it shows a noticeable centre effect. We aimed to investigate our centre-calculated cutoff value (CCV) of 4-h D/Pcr and compare it with the traditional cutoff value (TCV) (0.65). Methods: In this study, we enrolled incident PD patients at our centre from 2008 to 2019, and divided them into fast or non-fast PSTR groups according to baseline 4-h D/Pcr-based CCV or TCV. We compared the efficiency of the fast PSTR recognized by two cutoff values in predicting mortality, ultrafiltration (UF) insufficiency and technical survival. Results: In total, 1905 patients were enrolled, with a mean 4-h D/Pcr of 0.71 ± 0.11. Compared with TCV (0.65), CCV (0.71) showed superiority in predicting mortality of PD patients [hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.02-1.59 vs HR 1.24, 95% CI 0.97-1.59]. The odds ratio (OR) of the fast PSTR in centre classification was slightly higher than traditional classification in predicting UF insufficiency (OR 1.67, 95% CI 1.25-2.24 vs OR 1.60, 95% CI 1.15-2.22). Additionally, the restricted cubic splines 4-h D/Pcr has an S-shaped association with mortality and UF insufficiency, and the inflection points of 4-h D/Pcr were 0.71 (equal to CCV). Conclusions: The CCV of 4-h D/Pcr for identifying fast PSTR was 0.71. It was superior to TCV in predicting mortality and UF insufficiency.

Current status of exercise and its impact on quality of life in patients undergoing peritoneal dialysis in the post-COVID-19 period.

OBJECTIVES: The aims of this study were to investigate the current status and the influence factors of exercise, and to explore the impact of exercise on the quality of life (QoL) in peritoneal dialysis (PD) patients in the post-COVID-19 period. MATERIALS AND METHODS: Those PD patients who were followed up between September 2020 and August 2021 were enrolled. The collected data included demographic information, clinical data, exercise data, and QoL. RESULTS: In total, 339 PD patients were included in this cross-sectional study. The mean age was 44.0 ± 13.0 years, with a median PD duration of 6.7 (1.7 - 41.9) months. The primary renal disease was glomerulonephritis (68.4%). 277 (81.7%) PD patients performed exercise, with median exercise time 5.0 (3.5 - 7.8) hours per week. The main type of exercise was slow walking. Pain (odds ratio (OR) = 0.311, p = 0.002) and lower hemoglobin level (OR = 1.016, p = 0.033) were independent risk factors for exercise. Moreover, male sex (B = 2.803, p < 0.001) was an independent protective factor, while advanced age (B = -0.097, p < 0.001), higher body mass index (B = -0.154, p < 0.001), and pain (B = -0.643, p = 0.023) were independent risk factors for exercise intensity. After adjustment for other confounders, exercise (B = 5.787, p = 0.037) was an independent protective factor for total score of QoL in PD patients. CONCLUSION: In the current study, 81.7% of PD patients performed exercise in the post-COVID-19 period. Pain and anemia were independent risk factors for exercise in PD patients. Advanced age, female sex, higher body mass index, and pain were independently associated with lower exercise capacity in PD patients. PD patients undergoing exercise had better QoL.

Triglyceride glucose-body mass index and cardiovascular mortality in patients undergoing peritoneal dialysis: a retrospective cohort study.

BACKGROUND: Recent studies have shown that triglyceride glucose-body mass index (TyG-BMI) is associated with the risk of ischemic stroke and coronary artery disease. However, little attention has been given to the association between TyG-BMI and cardiovascular disease (CVD) mortality in patients undergoing peritoneal dialysis (PD). Therefore, this study aimed to explore the relationship between TyG-BMI and CVD mortality in southern Chinese patients undergoing PD. METHODS: Incident patients receiving PD from January 1, 2006, to December 31, 2018, with baseline serum triglyceride, glucose, and body mass index (BMI) information, were recruited for this single-center retrospective cohort study. TyG-BMI was calculated based on fasting plasma glucose, triglyceride, and BMI values. The association between TyG-BMI, CVD and all-cause mortality was evaluated using a multivariate-adjusted Cox proportional hazard regression model. RESULTS: Of 2,335 patients, the mean age was 46.1 ± 14.8 years; 1,382 (59.2%) were male, and 564 (24.2%) had diabetes. The median TyG-BMI was 183.7 (165.5-209.2). Multivariate linear regression showed that advanced age, male sex, history of CVD, higher levels of albumin and low-density lipoprotein cholesterol, and higher urine output were correlated with a higher TyG-BMI (P < 0.05). During a median follow-up period of 46.6 (22.4-78.0) months, 615 patients died, of whom 297 (48.2%) died as a result of CVD. After adjusting for demographics and comorbidities, TyG-BMI was significantly associated with an increased risk of CVD mortality (hazard ratio [HR] 1.51, 95% confidence interval [CI] 1.05-2.17) and all-cause mortality (HR 1.36, 95% CI 1.05-1.75). After full adjustment, the 28% risk of CVD mortality (HR 1.28, 95% CI 1.13-1.45) and 19% risk of all-cause mortality were elevated (HR 1.19, 95% CI 1.09-1.31) when TyG-BMI increased by 1 stand deviation (SD) (34.2). CONCLUSIONS: A higher baseline TyG-BMI was independently associated with an increased risk of CVD and all-cause mortality in patients receiving PD.

Remnant cholesterol predicts cardiovascular mortality beyond low-density lipoprotein cholesterol in patients with peritoneal dialysis.

BACKGROUND: Patients undergoing peritoneal dialysis (PD) are prone to dyslipidemia. However, studies concerning remnant cholesterol (RC) in such patients are limited. OBJECTIVE: We aimed to investigate the association between RC and cardiovascular (CV) mortality in patients on PD. METHODS: Patients who initiated PD at our center (2006-2018) were retrospectively enrolled. Adjusted Cox models were used to evaluate the independent association between baseline RC levels and CV mortality. We classified patients into 4 concordant/discordant categories according to their baseline lipid profiles. Cox models were then used to determine the association between different low-density lipoprotein cholesterol (LDL-C) and RC levels and CV mortality risk. RESULTS: The study enrolled 2333 individuals, with a mean RC of 33.4 mg/dL. RC levels were positively associated with CV mortality risk independent of LDL-C in patients on PD (hazard ratio [HR]: 1.05; 95% confidence interval [CI]: 1. 00-1.10). In the concordant/discordant categories, patients with high LDL-C and RC levels had a higher CV mortality risk (HR: 1.52; 95% CI: 1.01-2.28) than those with low LDL-C and RC levels in the entire cohort. Moreover, in older patients, a higher RC level increased CV mortality risk regardless of the LDL-C level (HR: 2.41, 95% CI: 1.22-4.74; HR: 2.15, 95% CI: 1.12-4.14). CONCLUSIONS: RC levels are elevated in patients on PD and can predict CV mortality beyond LDL-C levels. RC levels should be considered alongside LDL-C levels when assessing prognostic lipid levels in these patients. More attention should be given to RC than to LDL-C in older patients undergoing PD.

Solar ultraviolet B radiation promotes α-MSH secretion to attenuate the function of ILC2s via the pituitary-lung axis.

The immunomodulatory effects of ultraviolet B (UVB) radiation in human diseases have been described. Whether type 2 lung inflammation is directly affected by solar ultraviolet (UV) radiation is not fully understood. Here, we show a possible negative correlation between solar UVB radiation and asthmatic inflammation in humans and mice. UVB exposure to the eyes induces hypothalamus-pituitary activation and α-melanocyte-stimulating hormone (α-MSH) accumulation in the serum to suppress allergic airway inflammation by targeting group 2 innate lymphoid cells (ILC2) through the MC5R receptor in mice. The α-MSH/MC5R interaction limits ILC2 function through attenuation of JAK/STAT and NF-κB signaling. Consistently, we observe that the plasma α-MSH concentration is negatively correlated with the number and function of ILC2s in the peripheral blood mononuclear cells (PBMC) of patients with asthma. We provide insights into how solar UVB radiation-driven neuroendocrine α-MSH restricts ILC2-mediated lung inflammation and offer a possible strategy for controlling allergic diseases.

Incremental peritoneal dialysis and survival outcomes: a propensity-matched cohort study.

BACKGROUND: The advantages of an incremental dialysis start are not fully clear. We aimed to evaluate the association of incremental initiation of peritoneal dialysis with mortality. METHODS: Incident peritoneal dialysis patients with a catheter placed at our hospital between 2008 and 2017 were included. All patients were followed up until December 31, 2019. Patients were categorized into different groups according to the initial daily dialysis exchanges, and were matched at a ratio of 1:2 with propensity score matching. Multiple variables including age, sex, residual kidney function, urine volume, hemoglobin, serum albumin and other important variables were included for the matching. Primary outcomes were all-cause and cardiovascular mortality. RESULTS: A total of 1315 patients with a mean age of 45.9 years were enrolled. The mean glomerular filtration rate was 4.32 ml/min/1.73 m2 at start of dialysis. Two hundred eighty-five patients in the incremental group and 502 in the full dose group were matched for age, sex, residual kidney function, urine volume, hemoglobin, serum albumin and other important variables. Patient survival and cardiovascular event-free survival were similar between the two groups. However, during the first 6 years of peritoneal dialysis, patients in the incremental group had better survival (P = 0.011) and cardiovascular event-free survival (P = 0.044) than the full dose group, while such advantages disappeared when dialysis vintage became longer. Further analysis showed that the incremental group (vs full dose dialysis) had a 39% lower risk (95% CI 0.42-0.90, P = 0.012) of all-cause mortality and a 41% decreased risk (95% CI 0.35-0.99, P = 0.047) of cardiovascular mortality during the first 6 years of dialysis. Additionally, the cumulative hazard for anuria was significantly lower in the incremental group versus the full dose group (P = 0.006). CONCLUSIONS: Our study shows a time-related survival advantage for incremental peritoneal dialysis patients, suggesting that an incremental regimen for starting peritoneal dialysis is feasible and is not associated with worse outcomes. Graphical Abstract presenting schematically the measurements of the solvation response function by processing the relevant streak camera images and the time-correlated photon counting (TCSPC) data and appropriately combining them together.

The TRIM37 variants in Mulibrey nanism patients paralyze follicular helper T cell differentiation.

The Mulibrey (Muscle-liver-brain-eye) nanism caused by loss-of-function variants in TRIM37 gene is an autosomal recessive disorder characterized by severe growth failure and constrictive pericarditis. These patients also suffer from severe respiratory infections, co-incident with an increased mortality rate. Here, we revealed that TRIM37 variants were associated with recurrent infection. Trim37 FINmajor (a representative variant of Mulibrey nanism patients) and Trim37 knockout mice were susceptible to influenza virus infection. These mice showed defects in follicular helper T (TFH) cell development and antibody production. The effects of Trim37 on TFH cell differentiation relied on its E3 ligase activity catalyzing the K27/29-linked polyubiquitination of Bcl6 and its MATH domain-mediated interactions with Bcl6, thereby protecting Bcl6 from proteasome-mediated degradation. Collectively, these findings highlight the importance of the Trim37-Bcl6 axis in controlling the development of TFH cells and the production of high-affinity antibodies, and further unveil the immunologic mechanism underlying recurrent respiratory infection in Mulibrey nanism.

A Noncoding A-to-U Kozak Site Change Related to the High Transmissibility of Alpha, Delta, and Omicron VOCs.

Three prevalent SARS-CoV-2 variants of concern (VOCs) emerged and caused epidemic waves. It is essential to uncover advantageous mutations that cause the high transmissibility of VOCs. However, viral mutations are tightly linked, so traditional population genetic methods, including machine learning-based methods, cannot reliably detect mutations conferring a fitness advantage. In this study, we developed an approach based on the sequential occurrence order of mutations and the accelerated furcation rate in the pandemic-scale phylogenomic tree. We analyzed 3,777,753 high-quality SARS-CoV-2 genomic sequences and the epidemiology metadata using the Coronavirus GenBrowser. We found that two noncoding mutations at the same position (g.a28271-/u) may be crucial to the high transmissibility of Alpha, Delta, and Omicron VOCs although the noncoding mutations alone cannot increase viral transmissibility. Both mutations cause an A-to-U change at the core position -3 of the Kozak sequence of the N gene and significantly reduce the protein expression ratio of ORF9b to N. Using a convergent evolutionary analysis, we found that g.a28271-/u, S:p.P681H/R, and N:p.R203K/M occur independently on three VOC lineages, suggesting that coordinated changes of S, N, and ORF9b proteins are crucial to high viral transmissibility. Our results provide new insights into high viral transmissibility co-modulated by advantageous noncoding and nonsynonymous changes.

Vitamin B6 regulates IL-33 homeostasis to alleviate type 2 inflammation.

Interleukin-33 (IL-33) is a crucial nuclear cytokine that induces the type 2 immune response and maintains immune homeostasis. The fine-tuned regulation of IL-33 in tissue cells is critical to control of the type 2 immune response in airway inflammation, but the mechanism is still unclear. Here, we found that healthy individuals had higher phosphate-pyridoxal (PLP, an active form of vitamin B6) concentrations in the serum than asthma patients. Lower serum PLP concentrations in asthma patients were strongly associated with worse lung function and inflammation. In a mouse model of lung inflammation, we revealed that PLP alleviated the type 2 immune response and that this inhibitory effect relied on the activity of IL-33. A mechanistic study showed that in vivo, pyridoxal (PL) needed to be converted into PLP, which inhibited the type 2 response by regulating IL-33 stability. In mice heterozygous for pyridoxal kinase (PDXK), the conversion of PL to PLP was limited, and IL-33 levels were increased in the lungs, aggravating type 2 inflammation. Furthermore, we found that the mouse double minute 2 homolog (MDM2) protein, an E3 ubiquitin-protein ligase, could ubiquitinate the N-terminus of IL-33 and sustain IL-33 stability in epithelial cells. PLP reduced MDM2-mediated IL-33 polyubiquitination and decreased the level of IL-33 through the proteasome pathway. In addition, inhalation of PLP alleviated asthma-related effects in mouse models. In summary, our data indicate that vitamin B6 regulates MDM2-mediated IL-33 stability to constrain the type 2 response, which might help develop a potential preventive and therapeutic agent for allergy-related diseases.

The Adaptive Evolution in the Fall Armyworm Spodoptera frugiperda (Lepidoptera: Noctuidae) Revealed by the Diversity of Larval Gut Bacteria.

Insect gut microbes have important roles in host feeding, digestion, immunity, development, and coevolution with pests. The fall armyworm, Spodoptera frugiperda (Smith, 1797), is a major migratory agricultural pest worldwide. The effects of host plant on the pest's gut bacteria remain to be investigated to better understand their coevolution. In this study, differences in the gut bacterial communities were examined for the fifth and sixth instar larvae of S. frugiperda fed on leaves of different host plants (corn, sorghum, highland barley, and citrus). The 16S rDNA full-length amplification and sequencing method was used to determine the abundance and diversity of gut bacteria in larval intestines. The highest richness and diversity of gut bacteria were in corn-fed fifth instar larvae, whereas in sixth instar larvae, the richness and diversity were higher when larvae were fed by other crops. Firmicutes and Proteobacteria were dominant phyla in gut bacterial communities of fifth and sixth instar larvae. According to the LDA Effect Size (LEfSe) analysis, the host plants had important effects on the structure of gut bacterial communities in S. frugiperda. In the PICRUSt2 analysis, most predicted functional categories were associated with metabolism. Thus, the host plant species attacked by S. frugiperda larvae can affect their gut bacterial communities, and such changes are likely important in the adaptive evolution of S. frugiperda to host plants.

A human antibody potently neutralizes RSV by targeting the conserved hydrophobic region of prefusion F.

Respiratory syncytial virus (RSV) continues to pose serious threats to pediatric populations due to the lack of a vaccine and effective antiviral drugs. RSV fusion (F) glycoprotein mediates viral-host membrane fusion and is a key target for neutralizing antibodies. We generated 23 full-human monoclonal antibodies (hmAbs) against prefusion F protein (pre-F) from a healthy adult with natural RSV infection by single B cell cloning technique. A highly potent RSV-neutralizing hmAb, named as 25-20, is selected, which targets a new site Ø-specific epitope. Site-directed mutagenesis and structural modelling analysis demonstrated that 25-20 mainly targets a highly conserved hydrophobic region located at the a4 helix and a1 helix of pre-F, indicating a site of vulnerability for drug and vaccine design. It is worth noting that 25-20 uses an unreported inferred germline (iGL) that binds very poorly to pre-F, thus high levels of somatic mutations are needed to gain high binding affinity with pre-F. Our observation helps to understand the evolution of RSV antibody during natural infection. Furthermore, by in silico prediction and experimental verification, we optimized 25-20 with KD values as low as picomolar range. Therefore, the optimized 25-20 represents an excellent candidate for passive protection against RSV infection.

Automatic mammographic breast density classification in Chinese women: clinical validation of a deep learning model.

BACKGROUND: High breast density is a strong risk factor for breast cancer. As such, high consistency and accuracy in breast density assessment is necessary. PURPOSE: To validate our proposed deep learning (DL) model and explore its impact on radiologists on density assessments. MATERIAL AND METHODS: A total of 3732 mammographic cases were collected as a validated set: 1686 cases before the implementation of the DL model and 2046 cases after the DL model. Five radiologists were divided into two groups (junior and senior groups) to assess all mammograms using either two- or four-category evaluation. Linear-weighted kappa (K) and intraclass correlation coefficient (ICC) statistics were used to analyze the consistency between radiologists before and after implementation of the DL model. RESULTS: The accuracy and clinical acceptance of the DL model for the junior group were 96.3% and 96.8% for two-category evaluation, and 85.6% and 89.6% for four-category evaluation, respectively. For the senior group, the accuracy and clinical acceptance were 95.5% and 98.0% for two-category evaluation, and 84.3% and 95.3% for four-category evaluation, respectively. The consistency within the junior group, the senior group, and among all radiologists improved with the help of the DL model. For two-category, their K and ICC values improved to 0.81, 0.81, and 0.80 from 0.73, 0.75, and 0.76. And for four-category, their K and ICC values improved to 0.81, 0.82, and 0.82 from 0.73, 0.79, and 0.78, respectively. CONCLUSION: The DL model showed high accuracy and clinical acceptance in breast density categories. It is helpful to improve radiologists' consistency.

Broad strategies for neutralizing SARS-CoV-2 and other human coronaviruses with monoclonal antibodies.

Antibody therapeutics and vaccines for coronavirus disease 2019 (COVID-19) have been approved in many countries, with most being developed based on the original strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 has an exceptional ability to mutate under the pressure of host immunity, especially the immune-dominant spike protein of the virus, which is the target of both antibody drugs and vaccines. Given the continuous evolution of the virus and the identification of critical mutation sites, the World Health Organization (WHO) has named 5 variants of concern (VOCs): 4 are previously circulating VOCs, and 1 is currently circulating (Omicron). Due to multiple mutations in the spike protein, the recently emerged Omicron and descendent lineages have been shown to have the strongest ability to evade the neutralizing antibody (NAb) effects of current antibody drugs and vaccines. The development and characterization of broadly neutralizing antibodies (bNAbs) will provide broad strategies for the control of the sophisticated virus SARS-CoV-2. In this review, we describe how the virus evolves to escape NAbs and the potential neutralization mechanisms that associated with bNAbs. We also summarize progress in the development of bNAbs against SARS-CoV-2, human coronaviruses (CoVs) and other emerging pathogens and highlight their scientific and clinical significance.

Neutralization mechanism of a human antibody with pan-coronavirus reactivity including SARS-CoV-2.

Frequent outbreaks of coronaviruses underscore the need for antivirals and vaccines that can counter a broad range of coronavirus types. We isolated a human antibody named 76E1 from a COVID-19 convalescent patient, and report that it has broad-range neutralizing activity against multiple α- and ß-coronaviruses, including the SARS-CoV-2 variants. 76E1 also binds its epitope in peptides from γ- and δ-coronaviruses. 76E1 cross-protects against SARS-CoV-2 and HCoV-OC43 infection in both prophylactic and therapeutic murine animal models. Structural and functional studies revealed that 76E1 targets a unique epitope within the spike protein that comprises the highly conserved S2' site and the fusion peptide. The epitope that 76E1 binds is partially buried in the structure of the SARS-CoV-2 spike trimer in the prefusion state, but is exposed when the spike protein binds to ACE2. This observation suggests that 76E1 binds to the epitope at an intermediate state of the spike trimer during the transition from the prefusion to the postfusion state, thereby blocking membrane fusion and viral entry. We hope that the identification of this crucial epitope, which can be recognized by 76E1, will guide epitope-based design of next-generation pan-coronavirus vaccines and antivirals.

Incidence and Risk Factors Associated with Technique Failure in the First Year of Peritoneal Dialysis: A Single Center Retrospective Cohort Study in Southern China.

BACKGROUND: Technique failure is more likely to occur during the first 12 months after peritoneal dialysis (PD) initiation, which is a great challenge encountered in PD patients. The aim of this study was to investigate the incidence and risk factors associated with technique failure within the first year of PD patients in Southern China. METHODS: Incident PD patients who were followed up for at least one year at The First Affiliated Hospital of Sun Yat-sen University from January 1, 2006 to December 31, 2015 were included. Technique failure was defined as transferring to hemodialysis (HD) for more than 30 days or death within the first year after start of PD. A competitive risk regression analysis was used to explore the incidence and risk factors of the technique failure. RESULTS: Overall, 2,290 incident PD patients were included in this study, with a mean age of 48.2 ± 15.7 years, 40.9% female and 25.2% with diabetes. A total of 173 patients (7.5%) had technique failure during the first year of PD. Among them, the patient death account for 62.4% (n = 108) and transferring to HD account for 37.6% (n = 65). The main reasons for death were cardiovascular diseases (n = 32, 29.6%), infection (n = 15, 13.8%) and for conversion to HD were mechanical cause (n = 28, 43.1%), infection cause (n = 22, 33.8%). The risk factors for the technique failure included advanced age (HR 2.78, 95%CI 1.82-4.30), low body mass index (BMI < 18.5 kg/m2: HR 1.77, 95%CI 1.17-2.67), history of congestive heart failure (HR 2.81, 95%CI 1.58-4.98), or time on HD before PD ≤ 3 months (HR 1.49, 95%CI 1.05-2.10), peritonitis (HR 2.02, 95%CI 1.36-3.01);while higher serum albumin (HR 0.93, 95%CI 0.89-0.96) and using employee medical insurance to pay expenses (HR 0.47, 95%CI 0.32-0.69) were associated with reduced risk. CONCLUSIONS: Advanced age, poor nutritional status, history of HD or congestive heart failure, and peritonitis are related factors that increase the risk of technique failure in the first year of PD, while patients' type of medical insurance may also have an influence on early technique failure.