This study aimed to develop risk scores based on clinical characteristics at presentation to predict intensive care unit (ICU) admission and mortality in COVID-19 patients. 641 hospitalized patients ...with laboratory-confirmed COVID-19 were selected from 4997 persons under investigation. We performed a retrospective review of medical records of demographics, comorbidities and laboratory tests at the initial presentation. Primary outcomes were ICU admission and death. Logistic regression was used to identify independent clinical variables predicting the two outcomes. The model was validated by splitting the data into 70% for training and 30% for testing. Performance accuracy was evaluated using area under the curve (AUC) of the receiver operating characteristic analysis (ROC). Five significant variables predicting ICU admission were lactate dehydrogenase, procalcitonin, pulse oxygen saturation, smoking history, and lymphocyte count. Seven significant variables predicting mortality were heart failure, procalcitonin, lactate dehydrogenase, chronic obstructive pulmonary disease, pulse oxygen saturation, heart rate, and age. The mortality group uniquely contained cardiopulmonary variables. The risk score model yielded good accuracy with an AUC of 0.74 (95% CI, 0.63-0.85, p = 0.001) for predicting ICU admission and 0.83 (95% CI, 0.73-0.92, p<0.001) for predicting mortality for the testing dataset. This study identified key independent clinical variables that predicted ICU admission and mortality associated with COVID-19. This risk score system may prove useful for frontline physicians in clinical decision-making under time-sensitive and resource-constrained environment.
The efficacy of combining radiation therapy with immune checkpoint inhibitor blockade to treat brain tumors is currently the subject of multiple investigations and holds significant therapeutic ...promise. However, the long-term effects of this combination therapy on the normal brain tissue are unknown. Here, we examined mice that were intracranially implanted with murine glioma cell line and became long-term survivors after treatment with a combination of 10 Gy cranial irradiation (RT) and anti-PD-1 checkpoint blockade (aPD-1). Post-mortem analysis of the cerebral hemisphere contralateral to tumor implantation showed complete abolishment of hippocampal neurogenesis, but neural stem cells were well preserved in subventricular zone. In addition, we observed a drastic reduction in the number of mature oligodendrocytes in the subcortical white matter. Importantly, this observation was evident specifically in the combined (RT + aPD-1) treatment group but not in the single treatment arm of either RT alone or aPD-1 alone. Elimination of microglia with a small molecule inhibitor of colony stimulated factor-1 receptor (PLX5622) prevented the loss of mature oligodendrocytes. These results identify for the first time a unique pattern of normal tissue changes in the brain secondary to combination treatment with radiotherapy and immunotherapy. The results also suggest a role for microglia as key mediators of the adverse treatment effect.
Potassium-solubilizing bacteria are an important microbial group that play a critical role in releasing mineral potassium from potassium-containing minerals, e.g., potassium feldspar. Their ...application may reduce eutrophication caused by overused potassium fertilizers and facilitate plants to utilize environmental potassium. In this study, a high-efficiency potassium-solubilizing bacterium, named NK851, was isolated from the Astragalus sinicus rhizosphere soil. This bacterium can grow in the medium with potassium feldspar as the sole potassium source, releasing 157 mg/L and 222 mg/L potassium after 3 days and 5 days of incubation, respectively. 16S rDNA sequencing and cluster analysis showed that this strain belongs to Priestia megaterium. Genome sequencing further revealed that this strain has a genome length of 5,305,142 bp, encoding 5473 genes. Among them, abundant genes are related to potassium decomposition and utilization, e.g., the genes involved in adherence to mineral potassium, potassium release, and intracellular trafficking. Moreover, the strong potassium-releasing capacity of NK851 is not attributed to the acidic pH but is attributed to the extracellular potassium feldspar-binding proteins, such as the elongation factor TU and the enolase that contains potassium feldspar-binding cavities. This study provides new information for exploration of the bacterium-mediated potassium solubilization mechanisms.
Introduction
Glioblastoma multiforme (GBM) is a deadly brain tumor with a short expected median survival, despite current standard-of-care treatment. We explored the combination of intermediate ...stereotactic dose radiation therapy and immune checkpoint inhibitor therapy as a novel treatment strategy for GBM.
Methods
Glioma xenograft-bearing mice were exposed to high dose brain-directed radiation (10 Gy single exposure) as well as mouse anti-PD-1 antibody. The tumor-bearing animals were randomized to four groups: no treatment, radiation alone, anti-PD-1 alone, and radiation + anti-PD-1. Survival was followed, and tumor growth was monitored using MRI. Immunohistochemistry, gene expression arrays, and flow cytometry were used to characterize the treatment-induced effects. Pharmacologic inhibitors of T-lymphocytes, bone marrow derived macrophages, and microglia were used to assess the respective roles of different immune populations in observed treatment effects.
Results
We found the combined treatment with high dose radiation and immunotherapy to be highly effective with a 75% complete pathologic response and dramatically improved survival outcomes. We found both CD8+ T-cells and macrophages to be necessary for the full effect of combined therapy, with T lymphocytes appearing to play a role early on and macrophages mediating a later phase of the combined treatment effect. Radiation treatment appeared to trigger macrophage repolarization, increasing M1/M2 ratio.
Conclusions
These findings point to a novel immunologic mechanism underlying the interaction between radiotherapy and immunotherapy. They also provide the basis for clinical investigation of immunogenic dose radiation in combination with immune checkpoint blockade as a potential treatment approach for newly diagnosed high grade gliomas.
The development of efficient fungal vaccines is urgent for preventing life-threatening systemic fungal infections. In this study, we prepared a synthetic, cell-based fungal vaccine for preventing ...systemic fungal infections using synthetic biology techniques. The synthetic cell EmEAP1 was constructed by transforming the Escherichia coli chassis using a de novo synthetic fragment encoding the protein mChEap1 that was composed of the E. coli OmpA peptide, the fluorescence protein mCherry, the Candida albicans adhesin Eap1, and the C-terminally transmembrane region. The EmEAP1 cells highly exposed the mChEap1 on the cell surface under IPTG induction. The fungal vaccine was then prepared by mixing the EmEAP1 cells with aluminum hydroxide gel and CpG. Fluorescence quantification revealed that the fungal vaccine was stable even after 112 days of storage. After immunization in mice, the vaccine resided in the lymph nodes, inducing the recruitment of CD11c+ dendritic cells. Moreover, the vaccine strongly activated the CD4+ T splenocytes and elicited high levels of anti-Eap1 IgG. By the prime-boost immunization, the vaccine prolonged the survival time of the mice infected by the C. albicans cells and attenuated fungal colonization together with inflammation in the kidneys. This study sheds light on the development of synthetic biology-based fungal vaccines for the prevention of life-threatening fungal infections.
Purpose
Abiraterone acetate is a highly variable drug and has been approved for the treatment of patients with metastatic castration-resistant prostate cancer in many countries. This study was ...conducted to compare the pharmacokinetic profile between the test product (abiraterone acetate tablet) and reference product ZYTIGA® (250 mg) mainly.
Methods
To overcome the high intra-subject variability of abiraterone, a two-sequence and four-period crossover study was designed to assess bioequivalence between the two products in 32 healthy male Chinese subjects under fasting conditions. The plasma concentration of abiraterone was analyzed by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) assay and the reference-scaled procedure was used to determine bioequivalence for the pharmacokinetics parameters.
Results
The point estimate of geometric mean ratios with 90% confidence interval (CI) of maximum observed concentration (
C
max
) and the area under the concentration–time curve (AUC
0
t
) for abiraterone in the test and reference products were 100.19% (90% CI 87.05–115.32%) and 105.99% (90% CI 96.34–116.62%), respectively, and were both within the range of 80.00–125.00%. The 95% confidence upper limit bound for
(
Y
¯
T
-
Y
¯
R
)
2
-
θ
S
WR
2
was − 0.1079 for
C
max
and was − 0.0515 for AUC
0
t
.
Conclusions
Bioequivalence was demonstrated between the two abiraterone acetate products. The study also confirmed high intra-subject variability, for abiraterone: coefficient of variation (CV, %) of
C
max
values for the test and reference products were 40.33% and 46.58%, while for AUC
0
t
were 24.02% and 34.16%, respectively.
Trial registration
http://www.chinadrugtrials.org.cn/
: CTR20170997.
P301S transgenic mice are an animal model of tauopathy and Alzheimer’s disease (AD), exhibiting tau pathology and synaptic dysfunction. Cornel iridoid glycoside (CIG) is an active ingredient ...extracted from
Cornus officinalis
, a traditional Chinese herb. In the present study, the purpose was to investigate the effects and mechanisms of CIG on tau pathology and synaptic dysfunction using P301S transgenic mice. The results showed that intragastric administration of CIG for 3.5 months improved cognitive impairments and the survival rate of P301S mice. Electrophysiological recordings and transmission electron microscopy study showed that CIG improved synaptic plasticity and increased the ultrastructure and number of synapse. Moreover, CIG increased the expression levels of
N
-methyl-
D
-aspartate receptors (NMDAR) subunits GluN1, GluN2A, and GluN2B, and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunit GluA1. We inferred that the major mechanism of CIG involving in the regulation of synaptic dysfunctions was inhibiting the activation of Janus kinase-2 (JAK2)/signal transducer and activator of transcription 1 (STAT1) signaling pathway and alleviating STAT1-induced suppression of NMDAR expressions. Based on our findings, we thought CIG might be a promising candidate for the therapy of tauopathy such as AD.
This is a retrospective study.
To demonstrate a modified oblique lumbar interbody fusion (OILF) technique for L1-L5.
The modified technique splits anterior portion of psoas belly to access the ...oblique corridor (OC) anteroinferior to psoas, minimizing psoas manipulation and retraction and avoiding nerve injury while offering excellent microscopic visualization. Psoas weakness and neurovascular complication rates in patients treated with traditional OLIF (T-OLIF) or anteroinferior psoas OLIF (AP-OLIF) were retrospectively reviewed. Clinical outcomes were also reviewed.
A total of 162 cases treated with T-OLIF (
= 73) and AP-OLIF (
= 89) for degenerative lumbar disease were included. The mean operative time and blood loss were less with AP-OLIF (
< 0.01). Approach related complications were 14 (19.1%) with T-OLIF and 4 (4.5%) with AP-OLIF. Postoperative visual analog scale (VAS) and Oswestry Disability Index (ODI) scores improved in both T-OIF and AP-OIF groups (
< 0.01).
The modified OLIF technique (AP-OLIF) is characterized by an easy exposure of the lumbar spine under direct microscopic vision, resulting in less psoas weakness and neurovascular injury.
To characterize the temporal characteristics of clinical variables with time lock to mortality and build a predictive model of mortality associated with COVID-19 using clinical variables.
...Retrospective cohort study of the temporal characteristics of clinical variables with time lock to mortality.
Stony Brook University Hospital (New York) and Tongji Hospital.
Patients with confirmed positive for severe acute respiratory syndrome coronavirus-2 using polymerase chain reaction testing. Patients from the Stony Brook University Hospital data were used for training (80%,
= 1,002) and testing (20%,
= 250), and 375 patients from the Tongji Hospital (Wuhan, China) data were used for testing.
None.
Longitudinal clinical variables were analyzed as a function of days from outcome with time-lock-to-day of death (non-survivors) or discharge (survivors). A predictive model using the significant earliest predictors was constructed. Performance was evaluated using receiver operating characteristics area under the curve (AUC). The predictive model found lactate dehydrogenase, lymphocytes, procalcitonin, D-dimer, C-reactive protein, respiratory rate, and white-blood cells to be early predictors of mortality. The AUC for the zero to 9 days prior to outcome were: 0.99, 0.96, 0.94, 0.90, 0.82, 0.75, 0.73, 0.77, 0.79, and 0.73, respectively (Stony Brook Hospital), and 1.0, 0.86, 0.88, 0.96, 0.91, 0.62, 0.67, 0.50, 0.63, and 0.57, respectively (Tongji Hospital). In comparison, prediction performance using hospital admission data was poor (AUC = 0.59). Temporal fluctuations of most clinical variables, indicative of physiological and biochemical instability, were markedly higher in non-survivors compared to survivors (
< 0.001).
This study identified several clinical markers that demonstrated a temporal progression associated with mortality. These variables accurately predicted death within a few days prior to outcome, which provides objective indication that closer monitoring and interventions may be needed to prevent deterioration.
Severe traumatic brain injury (sTBI) often results in disorders of consciousness. Patients emerging from coma frequently exhibit aberrant behaviors such as agitation. These non-purposeful combative ...behaviors can interfere with medical care. Interestingly, agitation is associated with arousal and is often among the first signs of neurological recovery. A better understanding of these behaviors may shed light on the mechanisms driving the return of consciousness in sTBI patients. This study aims to investigate the association between posttraumatic agitation and the recovery of consciousness.
A retrospective chart review was conducted in 530 adult patients (29.1% female) admitted to Stony Brook University Hospital between January 2011 and December 2019 with a diagnosis of sTBI and Glasgow Coma Scale (GCS) ≤8. Agitation was defined as a Richmond Agitation Sedation Scale (RASS) > +1, or any documentation of equivalently combative and violent behaviors in daily clinical notes. The ability to follow verbal commands was used to define the recovery of consciousness and was assessed daily.
Of 530 total sTBI patients, 308 (58.1%) survived. Agitation was present in 169 of all patients and 162 (52.6%) of surviving patients. A total of 273 patients followed commands, and 159 of them developed agitation. Forty patients developed agitation on hospital arrival whereas 119 developed agitation later during their hospital course. Presence of in-hospital agitation positively correlated with command-following (
= 0.315,
< 0.001). The time to develop agitation and time to follow commands showed positive correlation (
= 0.485,
< 0.001). These two events occurred within 3 days in 54 (44.6%) patients, within 7 days in 81 (67.8%) patients, and within 14 days in 96 (80.2%) patients. In 71 (59.7%) patients, agitation developed before command-following; in 36 (30.2%) patients, agitation developed after command-following; in 12 (10.1%) patients, agitation developed on the same day as command-following.
Posttraumatic agitation in comatose patients following sTBI is temporally associated with the recovery of consciousness. This behavior indicates the potential for recovery of higher neurological functioning. Further studies are required to identify neural correlates of posttraumatic agitation and recovery of consciousness after sTBI.
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