Spectrum and mortality of opportunistic infections among HIV/AIDS patients in southwestern China.

We describe the opportunistic infections (OIs) of HIV/AIDS to understand the spectrum, mortality, and frequency of multiple coinfected OIs among HIV/AIDS patients in southern China, where OIs are severe. We carried out a retrospective cohort study of hospitalized HIV-infected individuals at the Fourth People's Hospital of Nanning, Guangxi, China, from Jan. 2011 to May. 2019. The chi-square test was used to analyze cross-infection; the Kaplan‒Meier analysis was used to compare mortality. A total of 12,612 HIV-infected patients were admitted to this cohort study. Among them, 8982 (71.2%) developed one or more OIs. The overall in-hospital mortality rate was 9.0%. Among the patients, 35.6% coinfected one OI, and 64.4% coinfected more than two OIs simultaneously. Almost half of the patients (60.6%) had CD4 + T-cell counts < 200 cells/µL. Pneumonia (39.8%), tuberculosis (35.3%), and candidiasis (28.8%) were the most common OIs. Coinfected cryptococcal meningitis and dermatitis are the most common combined OIs. The rate of anaemia (17.0%) was highest among those common HIV-associated complications. Multiple OIs are commonly found in hospitalized HIV/AIDS patients in southwestern China, which highlights the need for improved diagnosis and treatment.

Severe anemia, severe leukopenia, and severe thrombocytopenia of amphotericin B deoxycholate-based induction therapy in patients with HIV-associated talaromycosis: a subgroup analysis of a prospective multicenter cohort study.

BACKGROUND: This study's objective was to investigate the predictors for severe anemia, severe leukopenia, and severe thrombocytopenia when amphotericin B deoxycholate-based induction therapy is used in HIV-infected patients with talaromycosis. METHODS: A total of 170 HIV-infected patients with talaromycosis were enrolled from January 1st, 2019, to September 30th, 2020. RESULTS: Approximately 42.9%, 20.6%, and 10.6% of the enrolled patients developed severe anemia, severe leukopenia, and severe thrombocytopenia, respectively. Baseline hemoglobin level < 100 g/L (OR = 5.846, 95% CI: 2.765 ~ 12.363), serum creatinine level > 73.4 µmol/L (OR = 2.573, 95% CI: 1.157 ~ 5.723), AST/ALT ratio > 1.6 (OR = 2.479, 95% CI: 1.167 ~ 5.266), sodium level ≤ 136 mmol/liter (OR = 4.342, 95% CI: 1.747 ~ 10.789), and a dose of amphotericin B deoxycholate > 0.58 mg/kg/d (OR = 2.504, 95% CI:1.066 ~ 5.882) were observed to be independent risk factors associated with the development of severe anemia. Co-infection with tuberculosis (OR = 3.307, 95% CI: 1.050 ~ 10.420), and platelet level (per 10 × 109 /L) (OR = 0.952, 95% CI: 0.911 ~ 0.996) were shown to be independent risk factors associated with the development of severe leukopenia. Platelet level < 100 × 109 /L (OR = 2.935, 95% CI: 1.075 ~ 8.016) was identified as the independent risk factor associated with the development of severe thrombocytopenia. There was no difference in progression to severe anemia, severe leukopenia, and severe thrombocytopenia between the patients with or without fungal clearance at 2 weeks. 10 mg on the first day of amphotericin B deoxycholate was calculated to be independent risk factors associated with the development of severe anemia (OR = 2.621, 95% CI: 1.107 ~ 6.206). The group receiving a starting amphotericin B dose (10 mg, 20 mg, daily) exhibited the highest fungal clearance rate at 96.3%, which was significantly better than the group receiving a starting amphotericin B dose (5 mg, 10 mg, 20 mg, daily) (60.9%) and the group receiving a starting amphotericin B dose (5 mg, 15 mg, and 25 mg, daily) (62.9%). CONCLUSION: The preceding findings reveal risk factors for severe anemia, severe leukopenia, and severe thrombocytopenia. After treatment with Amphotericin B, these severe adverse events are likely unrelated to fungal clearance at 2 weeks. Starting amphotericin B deoxycholate at a dose of 10 mg on the first day may increase the risk of severe anemia but can lead to earlier fungal clearance. TRIAL REGISTRATION: ChiCTR1900021195. Registered 1 February 2019.

Initiating antiretroviral therapy within 2 weeks of anti-Pneumocystis treatment does not increase mortality or AIDS-defining events in patients with HIV-associated moderate to severe Pneumocystis pneumonia: results of a prospective observational multicenter study.

BACKGROUND: The mortality rate remains high among patients with coinfection with Pneumocystis pneumonia (PCP) and HIV. The timing for initiation of antiretroviral therapy (ART) after a diagnosis of moderate to severe PCP remains controversial, however. We therefore designed the present study to determine the optimal timing for ART initiation in AIDS-associated PCP (AIDS/PCP) patients. METHODS: This was a multicenter, observational, prospective clinical trial. Eligible participants were recruited from 14 hospitals in mainland China, and assigned to an Early ART arm (initiation of ART ≤ 14 days after PCP diagnosis) and a Deferred ART arm (initiation of ART > 14 days after PCP diagnosis). The primary outcomes were death and the incidence of AIDS-defining events at week 48. The secondary outcomes were the changes in CD4+ T-cell counts from baseline values at weeks 12, 24, and 48, the virological suppression rate at week 24 and week 48, the rate of development of PCP-associated immune reconstitution inflammatory syndrome (PCP/IRIS), and the rate of adverse events over 48 weeks. RESULTS: The present study was performed using the data of 363 participants, with 169 participants in the Early ART arm, and 194 participants in the Deferred ART arm. Immunological and virological outcomes were found to be similar in both treatment arms. At week 48, there were no significant differences for the incidence of mortality (20 vs. 26, p = 0.860), and AIDS-defining events (17 vs. 26, p = 0.412). Over 48 weeks, the rates of PCP/IRIS (2 vs. 3, p = 1.000), adverse events (70 vs. 72, p = 0.465), and grade 3 or 4 adverse events (28 vs. 34, p = 0.919) did not reach statistical significance. A significant difference observed between two study arms was that 11 participants (55.0%) in the Early ART arm compared to 23 participants (88.5%) in the Deferred ART arm (p = 0.026) succumbed before ART had ever been started. CONCLUSIONS: Early ART initiation results in no increase in mortality, AIDS-defining events, IRIS, adverse events, and immunological or virological outcomes. These results support the early initiation of ART in patients with moderate to severe AIDS/PCP. Clinical trial registration The present trial was registered at Chinese Clinical Trial Registry (ChiCTR1900021195). Registered 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362 .

Directed Brain Network Analysis for Fatigue Driving Based on EEG Source Signals.

Fatigue driving is one of the major factors that leads to traffic accidents. Long-term monotonous driving can easily cause a decrease in the driver's attention and vigilance, manifesting a fatigue effect. This paper proposes a means of revealing the effects of driving fatigue on the brain's information processing abilities, from the aspect of a directed brain network based on electroencephalogram (EEG) source signals. Based on current source density (CSD) data derived from EEG signals using source analysis, a directed brain network for fatigue driving was constructed by using a directed transfer function. As driving time increased, the average clustering coefficient as well as the average path length gradually increased; meanwhile, global efficiency gradually decreased for most rhythms, suggesting that deep driving fatigue enhances the brain's local information integration abilities while weakening its global abilities. Furthermore, causal flow analysis showed electrodes with significant differences between the awake state and the driving fatigue state, which were mainly distributed in several areas of the anterior and posterior regions, especially under the theta rhythm. It was also found that the ability of the anterior regions to receive information from the posterior regions became significantly worse in the driving fatigue state. These findings may provide a theoretical basis for revealing the underlying neural mechanisms of driving fatigue.

Multicentre derivation and validation of a prognostic scoring system for mortality assessment in HIV-infected patients with talaromycosis.

BACKGROUND: Although the widespread use of modern antiretroviral therapy (ART) has reduced the incidence of talaromycosis in people living with HIV, mortality remains as high as 20% in this population, even after appropriate antifungal treatment. OBJECTIVES: The objective of our study was to develop a risk assessment system for HIV-infected patients with comorbid talaromycosis, in order to provide these patients with appropriate, effective and potentially life-saving interventions at an early stage of their illness. PATIENTS/METHODS: This was a multicentre, retrospective cohort study conducted in China. We built a predictive model based on data from 11 hospitals, and a validated model using the data of 1 hospital located in an endemic area. RESULTS: Forward stepwise multivariate statistical calculations indicated that age, aspartate aminotransferase/alanine transaminase ratio and albumin levels, and BUN levels were valid, independent predictors of the risk of death in HIV-infected patients with talaromycosis. Our developed and validated risk scoring system is effective for the identification of HIV-infected patients with talaromycosis at high risk of death at hospital admission (p < .001; AUC = 0.860). In our study, our risk prediction model provided functional and robust discrimination in the validation cohort (p < .001; AUC = 0.793). CONCLUSION: The prognostic scoring system for mortality assessment developed in the present study is an easy-to-use clinical tool designed to accurately assist clinicians in identifying high-risk patients with talaromycosis.

Brain Complex Network Characteristic Analysis of Fatigue during Simulated Driving Based on Electroencephalogram Signals.

Fatigued driving is one of the major causes of traffic accidents. Frequent repetition of driving behavior for a long time may lead to driver fatigue, which is closely related to the central nervous system. In the present work, we designed a fatigue driving simulation experiment and collected the electroencephalogram (EEG) signals. Complex network theory was introduced to study the evolution of brain dynamics under different rhythms of EEG signals during several periods of the simulated driving. The results show that as the fatigue degree deepened, the functional connectivity and the clustering coefficients increased while the average shortest path length decreased for the delta rhythm. In addition, there was a significant increase of the degree centrality in partial channels on the right side of the brain for the delta rhythm. Therefore, it can be concluded that driving fatigue can cause brain complex network characteristics to change significantly for certain brain regions and certain rhythms. This exploration may provide a theoretical basis for further finding objective and effective indicators to evaluate the degree of driving fatigue and to help avoid fatigue driving.

Effects of topologies on signal propagation in feedforward networks.

We systematically investigate the effects of topologies on signal propagation in feedforward networks (FFNs) based on the FitzHugh-Nagumo neuron model. FFNs with different topological structures are constructed with same number of both in-degrees and out-degrees in each layer and given the same input signal. The propagation of firing patterns and firing rates are found to be affected by the distribution of neuron connections in the FFNs. Synchronous firing patterns emerge in the later layers of FFNs with identical, uniform, and exponential degree distributions, but the number of synchronous spike trains in the output layers of the three topologies obviously differs from one another. The firing rates in the output layers of the three FFNs can be ordered from high to low according to their topological structures as exponential, uniform, and identical distributions, respectively. Interestingly, the sequence of spiking regularity in the output layers of the three FFNs is consistent with the firing rates, but their firing synchronization is in the opposite order. In summary, the node degree is an important factor that can dramatically influence the neuronal network activity.

Intrinsic excitability state of local neuronal population modulates signal propagation in feed-forward neural networks.

Reliable signal propagation across distributed brain areas is an essential requirement for cognitive function, and it has been investigated extensively in computational studies where feed-forward network (FFN) is taken as a generic model. But it is still unclear how distinct local network states, which are intrinsically generated by synaptic interactions within each layer, would affect the ability of FFN to transmit information. Here we investigate the impact of such network states on propagating transient synchrony (synfire) and firing rate by a combination of numerical simulations and analytical approach. Specifically, local network dynamics is attributed to the competition between excitatory and inhibitory neurons within each layer. Our results show that concomitant with different local network states, the performance of signal propagation differs dramatically. For both synfire propagation and firing rate propagation, there exists an optimal local excitability state, respectively, that optimizes the performance of signal propagation. Furthermore, we find that long-range connections strongly change the dependence of spiking activity propagation on local network state and propose that these two factors work jointly to determine information transmission across distributed networks. Finally, a simple mean field approach that bridges response properties of long-range connectivity and local subnetworks is utilized to reveal the underlying mechanism.

Electroencephalographic oscillations of alpha and beta rhythms during phrase-guessing procedure.

Phrases-guessing is one of the essential reasoning abilities in problem solving for human beings. However, it is still an open question about why individuals perform differently during the same reasoning task. In this study, we utilized a bilingual phrase-guessing task to explore the neural activities under the individually different performances with electroencephalography. Participants who had no knowledge of Greek were required to guess the meaning of a Greek phrase (long or short in length) by making an either-or selection as to which translation-equivalent Chinese word corresponds to Greek word. Names of color were used as experimental stimuli for which two Chinese words denoted the same color with one as a conventional color name and the other as a novel color name. The experiment yielded length of phrases (long vs. short) and novelty of phrases (novel vs. conventional) as variables. The behavioral results revealed significant length-by-novelty interaction on the number of selections. However, neither main effects nor interactive effects were found on response time. Further, the amplitude spectrums of high alpha rhythm, low alpha rhythm, and low beta rhythm during the task were positively associated with the participants' number of selections for a long Greek phrase with a novel and complex Chinese phrase (LNc) and a short Greek phrase with a conventional Chinese phrase (SCo), while negatively correlated with the response time of selections for LNc and SCo. Our findings suggested that the consistency between participants' behavior and electrophysiological oscillations (alpha and beta bands) could be employed as biomarkers for decoding the phrase-guessing procedure.

Characteristics and risk factors for readmission in HIV-infected patients with Talaromyces marneffei infection.

OBJECTIVES: Talaromyces marneffei (T. marneffei) is an opportunistic fungal infection (talaromycosis), which is common in subtropical regions and is a leading cause of death in HIV-1-infected patients. This study aimed to determine the characteristics and risk factors associated with hospital readmissions in HIV patients with T. marneffei infection in order to reduce readmissions. METHODS: We conducted a retrospective study of admitted HIV-infected individuals at the Fourth People's Hospital of Nanning, Guangxi, China, from 2012 to 2019. Kaplan-Meier analyses and Principal component analysis (PCA) were used to evaluate the effects of T. marneffei infection on patient readmissions. Additionally, univariate and multifactorial analyses, as well as Propensity score matching (PSM) were used to analyze the factors associated with patient readmissions. RESULTS: HIV/AIDS patients with T. marneffei-infected had shorter intervals between admissions and longer lengths of stay than non-T. marneffei-infected patients, despite lower readmission rates. Compared with non-T. marneffei-infected patients, the mortality rate for talaromycosis patients was higher at the first admission. Among HIV/AIDS patients with opportunistic infections, the mortality rate was highest for T. marneffei at 16.2%, followed by cryptococcus at 12.5%. However, the readmission rate was highest for cryptococcus infection (37.5%) and lowest for T. marneffei (10.8%). PSM and Logistic regression analysis identified leukopenia and elevated low-density lipoprotein (LDL) as key factors in T.marneffei-infected patients hospital readmissions. CONCLUSIONS: The first admission represents a critical window to intervene in the prognosis of patients with T. marneffei infection. Leukopenia and elevated LDL may be potential risk factors impacting readmissions. Our findings provide scientific evidence to improve the long-term outcomes of HIV patients with T. marneffei infection.

Propagation of spiking regularity and double coherence resonance in feedforward networks.

We investigate the propagation of spiking regularity in noisy feedforward networks (FFNs) based on FitzHugh-Nagumo neuron model systematically. It is found that noise could modulate the transmission of firing rate and spiking regularity. Noise-induced synchronization and synfire-enhanced coherence resonance are also observed when signals propagate in noisy multilayer networks. It is interesting that double coherence resonance (DCR) with the combination of synaptic input correlation and noise intensity is finally attained after the processing layer by layer in FFNs. Furthermore, inhibitory connections also play essential roles in shaping DCR phenomena. Several properties of the neuronal network such as noise intensity, correlation of synaptic inputs, and inhibitory connections can serve as control parameters in modulating both rate coding and the order of temporal coding.

Alteration of regional heterogeneity and functional connectivity for obese undergraduates: evidence from resting-state fMRI.

Obesity was found to be related with the changes of brain functions in human beings. There were several brain areas that were verified to be correlated with the obesity, including the parietal cortex, frontal cortex and so on. However, the cortical regions found from different studies were discrepant due to the different ages, gender distribution and satiation degree of participants. We found that the regional homogeneity of right angular gyrus were smaller in obese undergraduates than that in normal-weight undergraduates. Moreover, functional connectivity of the left middle temporal cortex and the right angular gyrus were found to be smaller in obese group than that in normal-weight group by setting the right angular gyrus as seed region. In addition, multiple regression analysis suggested that the right superior frontal gyrus and left middle temporal gyrus were significantly correlated with their body mass index for normal-weight undergraduates, but no significant correlation was found for obese group. In summary, these findings indicated the functional changes of the cortex in obese undergraduates, which might be significant for providing imaging-based biomarkers for intervention and therapy of obesity.

Growth performance, fatty acid composition, and lipid metabolism are altered in groupers (Epinephelus coioides) by dietary fish oil replacement with palm oil.

In this study, we conducted a 56-d feeding trial to investigate the effects of replacing the fish oil (FO) with palm oil (PO) on the performance, tissue fatty acid (FA) composition, and mRNA levels of genes related to hepatic lipid metabolism in grouper (Epinephelus coioides). Five isolipidic (13% crude lipid) and isonitrogenous (48% CP) diets were formulated by incrementally adding PO to the control diet (25% fish meal and 9% added FO) to replace FO in the control diets. Triplicate groups of 30 groupers (initial weight: 12.6 ± 0.1 g) were fed one of the diets twice daily, to apparent satiety. The replacement of FO with 50% PO revealed maximum growth without affecting the performance and whole-body proximate compositions, and replacing FO with 100% PO revealed a comparable (P > 0.05) growth with that of the control diet, suggesting PO as a suitable alternative to FO. The analysis of FA profiles in the dorsal muscle and liver though reflected the FA profile of the diet, PO substitutions above 50% could compromise (P < 0.05) the FA profile in the liver and flesh of the fish species in comparison with the control diet. Furthermore, the mRNA levels of FAS, G6PD, LPL, PPARΑ, and Δ6FAD genes in the liver had positive linear and/or quadratic responses, but the SCD, HSL, ATGL, FABP, SREBP-1C and ELOVL5 had the opposite trend, with increasing dietary PO inclusion levels, whereas the mRNA level of ACC was not affected by dietary treatments. The optimal level of PO substitution for FO was estimated to be 47.1% of the feed, based on the regression analysis of percent weight gains against dietary PO inclusion levels; however, it might affect the FA profile in the liver and flesh of the fish species, and further study is required to investigate whether the changes in tissue FA composition will affect the welfare and market value over a production cycle of grouper.

Dietary Lactoferrin Supplementation Improves Growth Performance and Intestinal Health of Juvenile Orange-Spotted Groupers (Epinephelus coioides).

A 56-day feeding trial was conducted to investigate the effects of dietary lactoferrin (LF) supplementation on the growth performance and intestinal health of juvenile orange-spotted groupers fed high-soybean-meal (SBM) diets. The control diet (FM) and high-soybean-meal diet (SBM60) were prepared to contain 480 g/kg protein and 110 g/kg fat. Three inclusion levels of 2, 6, and 10 g/kg LF were added into the SBM60 to prepare three diets (recorded as LF2, LF6, and LF10, respectively). The results showed that the supplementation of LF in SBM60 increased the growth rate in a dose-dependent manner. However, the feed utilization, hepatosomatic index, whole-body proximate composition, and the abundance and diversity of intestinal microbiota did not vary across the dietary treatments (p > 0.05). After the dietary intervention with LF, the contents of the intestinal malondialdehyde, endotoxin, and d-lactic acid, as well as the plasma low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and total cholesterol were lower, and the intestinal activities of the glutathione peroxidase, lipase, trypsin, and protease were higher in the LF2-LF10 groups than that in the SBM60 group (p < 0.05). The supplementation of LF in SBM60 increased the muscle layer thickness of the middle and distal intestine and the mucosal fold length of the middle intestine vs. the SBM60 diet (p < 0.05). Furthermore, the supplementation of LF in SBM60 resulted in an up-regulation of the mRNA levels for the IL-10 and TGF-ß1 genes and a down-regulation of the mRNA levels of the IL-1ß, IL-12, IL-8, and TNF-α genes vs. the SBM60 diet (p < 0.05). The above results showed that a dietary LF intervention improves the growth and alleviates soybean meal-induced enteritis in juvenile orange-spotted groupers. The dietary appropriate level of LF was at 5.8 g/kg, through the regression analysis of the percent weight gain against the dietary LF inclusion levels.

Efficacy and Safety of Voriconazole Versus Amphotericin B Deoxycholate Induction Treatment for HIV-Associated Talaromycosis: A Prospective Multicenter Cohort Study in China.

INTRODUCTION: Current guidelines recommend amphotericin B as the preferred drug for induction therapy; however, amphotericin B is not available in certain settings. Induction therapy with amphotericin B deoxycholate or voriconazole has been shown to be an effective treatment for talaromycosis. However, prospective clinical trials comparing these two antifungal drugs are absent from the literature. METHODS: In this open-labeled, multicenter, prospective controlled trial, we enrolled patients at 15 hospitals in China from 2019 to 2020. Participants received induction treatment with either amphotericin B deoxycholate intravenously at a dose of 0.5 to 0.7 mg per kilogram per day or voriconazole at a dose of 6 mg/kg intravenously twice daily for the first day, followed by 4 mg/kg intravenously twice daily for 3 days, and then voriconazole was given either intravenously (4 mg/kg intravenously twice daily) or orally (200 mg twice daily) for the remaining 10 days. The primary outcome was all-cause mortality during 48 weeks after baseline. Secondary outcomes were mortality at week 2 or week 24, clinical resolution of talaromycosis, and fungal clearance at week 2. A propensity score (PS) matching analysis was performed to control confounding factors. RESULTS: We observed no difference in the risk of death at week 2, at week 24, or at week 48 in either the unmatched cohort or the matched cohort. Both in the unmatched and the matched cohorts, logistic regression analysis revealed a significantly lower odds ratio of clinical resolution (OR 0.450, 95% CI 0.291-0.696, p < 0.001; OR 0.443, 95% CI 0.261-0.752, p = 0.003) and fungal clearance (OR 0.514, 95% CI 0.333-0.793, p = 0.003; OR 0.542, 95% CI 0.318-0.923, p = 0.024) in voriconazole users compared to amphotericin B deoxycholate users over the course of 2 weeks. In the induction therapy without ART subgroup patients in the amphotericin B deoxycholate group showed a significantly higher rate of clinical resolution and fungal clearance than those in the voriconazole group (56.1% vs. 30.4%, 95% CI 13.4-36.5, p = 0.000; 63.8% vs. 40.4%, 95% CI 11.1-34.7, p = 0.000), whereas there was no significant difference in clinical resolution and fungal clearance in the induction therapy combined with ART subgroup. CONCLUSIONS: Induction therapy using voriconazole had a similar efficacy, in terms of all-cause mortality rate, to induction therapy using amphotericin B deoxycholate in HIV-infected patients with talaromycosis over a 48-week observation period. Amphotericin B deoxycholate contributed to earlier fungal clearance and earlier clinical resolution of symptoms in the induction therapy without ART subgroup, whereas amphotericin B deoxycholate use did not contribute to a significant difference in clinical resolution and fungal clearance in the induction therapy combination with ART subgroup. TRIAL REGISTRATION: ChiCTR1900021195. Registered 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362 .

Machine learning-based in-hospital mortality prediction of HIV/AIDS patients with Talaromyces marneffei infection in Guangxi, China.

OBJECTIVE: Talaromycosis is a serious regional disease endemic in Southeast Asia. In China, Talaromyces marneffei (T. marneffei) infections is mainly concentrated in the southern region, especially in Guangxi, and cause considerable in-hospital mortality in HIV-infected individuals. Currently, the factors that influence in-hospital death of HIV/AIDS patients with T. marneffei infection are not completely clear. Existing machine learning techniques can be used to develop a predictive model to identify relevant prognostic factors to predict death and appears to be essential to reducing in-hospital mortality. METHODS: We prospectively enrolled HIV/AIDS patients with talaromycosis in the Fourth People's Hospital of Nanning, Guangxi, from January 2012 to June 2019. Clinical features were selected and used to train four different machine learning models (logistic regression, XGBoost, KNN, and SVM) to predict the treatment outcome of hospitalized patients, and 30% internal validation was used to evaluate the performance of models. Machine learning model performance was assessed according to a range of learning metrics, including area under the receiver operating characteristic curve (AUC). The SHapley Additive exPlanations (SHAP) tool was used to explain the model. RESULTS: A total of 1927 HIV/AIDS patients with T. marneffei infection were included. The average in-hospital mortality rate was 13.3% (256/1927) from 2012 to 2019. The most common complications/coinfections were pneumonia (68.9%), followed by oral candida (47.5%), and tuberculosis (40.6%). Deceased patients showed higher CD4/CD8 ratios, aspartate aminotransferase (AST) levels, creatinine levels, urea levels, uric acid (UA) levels, lactate dehydrogenase (LDH) levels, total bilirubin levels, creatine kinase levels, white blood-cell counts (WBC) counts, neutrophil counts, procaicltonin levels and C-reactive protein (CRP) levels and lower CD3+ T-cell count, CD8+ T-cell count, and lymphocyte counts, platelet (PLT), high-density lipoprotein cholesterol (HDL), hemoglobin (Hb) levels than those of surviving patients. The predictive XGBoost model exhibited 0.71 sensitivity, 0.99 specificity, and 0.97 AUC in the training dataset, and our outcome prediction model provided robust discrimination in the testing dataset, showing an AUC of 0.90 with 0.69 sensitivity and 0.96 specificity. The other three models were ruled out due to poor performance. Septic shock and respiratory failure were the most important predictive features, followed by uric acid, urea, platelets, and the AST/ALT ratios. CONCLUSION: The XGBoost machine learning model is a good predictor in the hospitalization outcome of HIV/AIDS patients with T. marneffei infection. The model may have potential application in mortality prediction and high-risk factor identification in the talaromycosis population.

No Statistically Apparent Difference in Antifungal Effectiveness Observed Among Trimethoprim/Sulfamethoxazole Plus Clindamycin or Caspofungin, and Trimethoprim/Sulfamethoxazole Monotherapy in HIV-Infected Patients with Moderate to Severe Pneumocystis Pneumonia: Results of an Observational Multicenter Cohort Study.

INTRODUCTION: Pneumocystis pneumonia is a common opportunistic infection in patients with HIV/AIDS, and is a leading cause of death in this population. Early selection of effective treatment is therefore critical to reduce mortality. We conducted a clinical trial to compare the effectiveness and safety of three different antifungal treatment regimens in HIV-infected patients with moderate to severe PCP. METHODS: Our study was a multicenter, observational prospective clinical trial. We recruited 320 HIV-infected patients with moderate to severe PCP, and stratified these subjects into a trimethoprim/sulfamethoxazole (TMP-SMX) monotherapy group, a TMP-SMX plus clindamycin group, and a TMP-SMX plus caspofungin group. Patients were invited to participate in 12 weeks of follow-up. Outcomes included the difference in overall mortality and the proportion of overall positive response to treatment in the three groups at weeks 4 and 12, the difference in treatment duration, and the proportion of adverse events among the three groups during the study period. RESULTS: The probability of survival not statistically different among three treatment groups. Mortality in the TMP-SMX monotherapy group (group 1) was 15/115 (13.04%) vs. 20/83 (24.10%) in the TMP-SMX plus clindamycin group (group 2) vs. 24/107 (22.43%) in the TMP-SMX plus caspofungin group (group 3) at week 12 (p = 0.092). The overall positive response rate to treatment in the three groups was 24.14%, 34.94%, and 38.32%, respectively, at week 4, and 33.91%, 38.55%, and 44.86%, respectively, at week 12. No significant difference in the overall positive response rate to treatment at either week 4 or week 12 was noted (p = 0.061, p = 0.246). Rates of changes to therapy were 6.50% (8/123) in group 1, 3.40% (3/87) in group 2, and 2.70% (3/110) in group 3, and did not differ significantly among the three groups (p = 0.376). There were also no significant differences in adverse events among the three treatment groups of patients with moderate to severe PCP. CONCLUSIONS: Our results indicate that there are no significant statistical differences among the three studied treatment regimens in terms of antifungal effectiveness in HIV-infected patients with moderate to severe PCP. TMP-SMX monotherapy is a convenient, cheap, and effective therapeutic drug regimen to treat HIV-infected patients with moderate to severe PCP, and is an appropriate treatment strategy in resource-limited settings. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov , ID: ChiCTR1900021195. Registered on February 1, 2019.

HIV-associated talaromycosis: Does timing of antiretroviral therapy matter?

OBJECTIVES: No current academic data is available with respect to the optimal timing to initiate antiretroviral therapy (ART) in HIV-positive patients with talaromycosis. Our study aimed to evaluate the optimal timing of ART initiation for patients presenting with AIDS-related talaromycosis. METHODS: In this prospective, randomized, open-label multicenter trial, 228 patients from 15 hospitals in China were randomly assigned to an early ART group (initiation of ART within 2 weeks after randomization) and a deferred ART group (initiation of ART 2 weeks after randomization). The primary endpoint was all-cause mortality during the 48 weeks after randomization. RESULTS: We observed a significant difference in mortality between the early ART group and the deferred ART group (2.2% vs. 8.9%, 95%CI: -0.15 to 14.05, p = 0.049). The composite outcome of AIDS-defining events or death in the early ART group was found to be lower than that in the deferred ART group (3.3% vs. 14.9%; 95%CI: 2.93 to 19.23, p = 0.008). CONCLUSIONS: The prognosis of HIV-infected patients with talaromycosis in the early ART group was more favorable than that of patients in the deferred ART group. These results demonstrate that early ART initiation should be considered in HIV-infected patients with talaromycosis .

Implications of the accumulation of CXCR5+ NK cells in lymph nodes of HIV-1 infected patients.

BACKGROUND: B cell follicles are immune-privileged sites where intensive HIV-1 replication and latency occur, preventing a permanent cure. Recent study showed that CXCR5+ NK cells in B cell follicles can inhibit SIV replication in African green monkeys, but this has not been reported in HIV-1 infected patients. METHODS: Lymphocytes and tissue sections of lymph node were collected from 11 HIV-1 positive antiretroviral therapy (ART)-naive and 19 HIV-1 negative donors. We performed immunofluorescence and RNA-scope to detect the location of CXCR5+ NK cells and its relationship with HIV-1 RNA, and performed flow cytometry and RNA-seq to analyze the frequency, phenotypic and functional characteristics of CXCR5+ NK cells. The CXCL13 expression were detected by immunohistochemistry. FINDINGS: CXCR5+ NK cells, which accumulated in LNs from HIV-1 infected individuals, expressed high levels of activating receptors such as NKG2D and NKp44. CXCR5+ NK cells had upregulated expression of CD107a and ß-chemokines, which were partially impaired in HIV-1 infection. Importantly, the frequency of CXCR5+NK cells was inversely related to the HIV-1 viral burden in LNs. In addition, CXCL13-the ligand of CXCR5-was upregulated in HIV-1 infected individuals and positively correlated with the frequency of CXCR5+ NK cells. INTERPRETATION: During chronic HIV-1 infection, CXCR5+ NK cells accumulated in lymph node, exhibit altered immune characteristics and underlying anti-HIV-1 effect, which may be an effective target for a functional cure of HIV-1.

Vibrational resonance in feedforward network.

This paper investigates vibrational resonance in multi-layer feedforward network (FFN) based on FitzHugh-Nagumo (FHN) neuron model. High-frequency stimuli can improve the input-output linearity of firing rates, especially for the inputs with low firing rate. For FFN network, it is found that high-frequency disturbances play important roles in enhancing the propagation of weak signal through layers. Synfire-enhanced phenomenon of signal propagation is also observed in multi-layers network, when the signal transmission is affected by high-frequency disturbances. Network connections are found to be important for the propagation of weak signal. Besides that, the characteristics of high-frequency stimuli such as heterogeneity and frequency can also modulate the propagation of neural code through layers.