A Prediction Model for Clinical Outcomes of COVID-19 Hospitalized Patients: Construction and Accuracy Assessment.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic spread rapidly with considerable morbidity nationwide since China's liberalization in December 2022. Our work has focused on identifying different predictive factors from the laboratory examination of critically ill patients, and forecasting the unfavorable outcome of critically ill patients with COVID-19 through a combined diagnosis of biological markers. METHODS: We conducted a retrospective study at the Department of First Affiliated Hospital of Wenzhou Medical University, China, from December 24, 2022, to January 10, 2023, where 434 critically ill patients who met the inclusion criteria were involved. Machine analysis was employed to search for the parameters with the highest predictive value to calculate COVID-19 mortality by exploiting 66 typical laboratory results. RESULTS: Combined diagnosis of serum albumin (ALB), lactate dehydrogenase (LDH), direct bilirubin (Dbil), ferritin, pulse oxygen saturation (SpO2), and neutrophil count (NEUT#) was evaluated, and the result with the highest predictive value (NEUT#) was selected as the predictor for COVID-19 mortality with a sensitivity of 89.2% and a specificity of 77.4%. CONCLUSIONS: The increased levels of LDH, Dbil, ferritin, and NEUT#, along with lowered ALB and SpO2 levels are the most decisive variables for forecasting the mortality for COVID-19 according to our machine-learning-based model. The combined diagnosis could be used to improve further diagnostic performance.

Comparison of resting-state spontaneous brain activity between treatment-naive schizophrenia and obsessive-compulsive disorder.

BACKGROUND: Schizophrenia (SZ) and obsessive-compulsive disorder (OCD) share many demographic characteristics and severity of clinical symptoms, genetic risk factors, pathophysiological underpinnings, and brain structure and function. However, the differences in the spontaneous brain activity patterns between the two diseases remain unclear. Here this study aimed to compare the features of intrinsic brain activity in treatment-naive participants with SZ and OCD and to explore the relationship between spontaneous brain activity and the severity of symptoms. METHODS: In this study, 22 treatment-naive participants with SZ, 27 treatment-naive participants with OCD, and sixty healthy controls (HC) underwent a resting-state functional magnetic resonance imaging (fMRI) scan. The amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo) and degree of centrality (DC) were performed to examine the intrinsic brain activity of participants. Additionally, the relationships among spontaneous brain activity, the severity of symptoms, and the duration of illness were explored in SZ and OCD groups. RESULTS: Compared with SZ group and HC group, participants with OCD had significantly higher ALFF in the right angular gyrus and the left middle frontal gyrus/precentral gyrus and significantly lower ALFF in the left superior temporal gyrus/insula/rolandic operculum and the left postcentral gyrus, while there was no significant difference in ALFF between SZ group and HC group. Compared with HC group, lower ALFF in the right supramarginal gyrus/inferior parietal lobule and lower DC in the right lingual gyrus/calcarine fissure and surrounding cortex of the two patient groups, higher ReHo in OCD group and lower ReHo in SZ group in the right angular gyrus/middle occipital gyrus brain region were documented in the present study. DC in SZ group was significantly higher than that in HC group in the right inferior parietal lobule/angular gyrus, while there were no significant DC differences between OCD group and HC group. In addition, ALFF in the left postcentral gyrus were positively correlated with positive subscale score (r = 0.588, P = 0.013) and general psychopathology subscale score (r = 0.488, P = 0.047) respectively on the Positive and Negative Syndrome Scale (PANSS) in SZ group. ALFF in the left superior temporal gyrus/insula/rolandic operculum of participants with OCD were positively correlated with compulsion subscale score (r = 0.463, P = 0.030) on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). The longer the illness duration in SZ group, the smaller the ALFF of the left superior temporal gyrus/insula/rolandic operculum (Rho = 0.-492, P = 0.020). The longer the illness duration in OCD group, the higher the ALFF of the right supramarginal gyrus/inferior parietal lobule (Rho = 0.392, P = 0.043) and the left postcentral gyrus (Rho = 0.385, P = 0.048), and the lower the DC of the right inferior parietal lobule/angular gyrus (Rho = - 0.518, P = 0.006). CONCLUSION: SZ and OCD show some similarities in spontaneous brain activity in parietal and occipital lobes, but exhibit different patterns of spontaneous brain activity in frontal, temporal, parietal, occipital, and insula brain regions, which might imply different underlying neurobiological mechanisms in the two diseases. Compared with OCD, SZ implicates more significant abnormalities in the functional connections among brain regions.

From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion.

Glucose-stimulated insulin secretion from islet ß cells is mediated by KATP channels. However, the role of non-KATP K+ channels in insulin secretion is largely unknown. Here, we show that a non-KATP K+ channel, KCNH6, plays a key role in insulin secretion and glucose hemostasis in humans and mice. KCNH6 p.P235L heterozygous mutation co-separated with diabetes in a four-generation pedigree. Kcnh6 knockout (KO) or Kcnh6 p.P235L knockin (KI) mice had a phenotype characterized by changing from hypoglycemia with hyperinsulinemia to hyperglycemia with insulin deficiency. Islets from the young KO mice had increased intracellular calcium concentration and increased insulin secretion. However, islets from the adult KO mice not only had increased intracellular calcium levels but also had remarkable ER stress and apoptosis, associated with loss of ß cell mass and decreased insulin secretion. Therefore, dysfunction of KCNH6 causes overstimulation of insulin secretion in the short term and ß cell failure in the long term.

ß1 -Adrenoceptor autoantibodies increase the susceptibility to ventricular arrhythmias involving abnormal repolarization in guinea-pigs.

NEW FINDINGS: What is the central question of this study? High titres of autoantibodies against the second extracellular loop of the ß1 -adrenergic receptor (ß1 -AAs) can be detected in the sera of patients with ventricular arrhythmias, but a causal relationship between ß1 -AAs and ventricular arrhythmias has not been established. What is the main finding and its importance? Monoclonal ß1 -AAs (ß1 -AR mAbs) were used in the experiments. We showed that ß1 -AR mAbs increased susceptibility to ventricular arrhythmias and induced repolarization abnormalities. Antibody adsorption of ß1 -AAs will be a potential new therapeutic strategy for ventricular arrhythmias in patients with high titres of ß1 -AAs. High titres of autoantibodies against the second extracellular loop of the ß1 -adrenergic receptor (ß1 -AAs) can be detected in sera from patients with ventricular arrhythmias, but a causal relationship between ß1 -AAs and ventricular arrhythmias has not been established. In this work, ECGs of guinea-pigs and isolated guinea-pig hearts were recorded. Ventricular tachycardia (VT) and ventricular fibrillation (VF) were evoked by programmed electrical stimulation of the left ventricular epicardium of isolated guinea-pig hearts. The monophasic action potential and effective refractory period of the left ventricle were recorded in paced isolated guinea-pig hearts. Furthermore, to increase the specificity, monoclonal autoantibodies against the second extracellular loop of the ß1 -adrenergic receptor (ß1 -AR mAbs) were used in all experiments. The results showed that ß1 -AR mAbs induced premature ventricular contractions in guinea-pigs and isolated guinea-pig hearts. In addition, ß1 -AR mAbs decreased the threshold of VT/VF and prolonged the duration of VT/VF. Furthermore, ß1 -AR mAbs shortened the corrected QT interval and effective refractory period, and prolonged late-phase repolarization of the monophasic action potential (MAPD90-30 ). These changes in electrophysiological parameters might be attributed, at least in part, to the arrhythmogenicity of ß1 -AR mAbs.

Role of BKCa in Stretch-Induced Relaxation of Colonic Smooth Muscle.

Stretch-induced relaxation has not been clearly identified in gastrointestinal tract. The present study is to explore the role of large conductance calcium-activated potassium channels (BKCa) in stretch-induced relaxation of colon. The expression and currents of BKCa were detected and the basal muscle tone and contraction amplitude of colonic smooth muscle strips were measured. The expression of BKCa in colon is higher than other GI segments (P < 0.05). The density of BKCa currents was very high in colonic smooth muscle cells (SMCs). BKCa in rat colonic SMCs were sensitive to stretch. The relaxation response of colonic SM strips to stretch was attenuated by charybdotoxin (ChTX), a nonspecific BKCa blocker (P < 0.05). After blocking enteric nervous activities by tetrodotoxin (TTX), the stretch-induced relaxation did not change (P > 0.05). Still, ChTX and iberiotoxin (IbTX, a specific BKCa blocker) attenuated the relaxation of the colonic muscle strips enduring stretch (P < 0.05). These results suggest stretch-activation of BKCa in SMCs was involved in the stretch-induced relaxation of colon. Our study highlights the role of mechanosensitive ion channels in SMCs in colon motility regulation and their physiological and pathophysiological significance is worth further study.

Comparison of functional magnetic resonance imaging in cerebral activation between normal Uygur and Mandarin participants in semantic identification task.

PURPOSE: This study utilized blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) technology to study the activated cerebral regions in normal participants whose native language was Uyghur or Chinese. METHODS: We collected the fMRI data from 15 Uyghur-speaking volunteers and 15 Mandarin-speaking volunteers when executing the semantic identification task and compared the results of two groups. RESULTS: Statistically significant difference of brain activation was found primarily in the left anterior cingulate gyrus (BA23) and the midline precuneus (P<0.05). When performing the semantic identification task, the Uyghur group exhibited significant activation in these two regions, whereas the Chinese group demonstrated relatively weak activation in these areas. CONCLUSION: The cerebral regions activated by Uyghur and Chinese semantic identification are not identical, the dominant hemisphere for both languages is the left cerebral hemisphere. The left anterior cingulate gyrus might have a language function in Uyghur semantic processing.

Serum peroxiredoxin3 is a useful biomarker for early diagnosis and assessemnt of prognosis of hepatocellular carcinoma in Chinese patients.

BACKGROUND: Recently, peroxiredoxin3 (PRDX3) was identified as a novel molecular marker for the progression of hepatocellular carcinoma (HCC). However, its potential clinical application as a serum marker for the early diagnosis and prognosis of HCC has not been investigated. METHODS: PRDX3, alpha-fetaprotein (AFP), and other biochemical parameters were measured in serum samples from 297 Chinese patients, including 96 with HCC, 98 with liver cirrhosis (LC), and 103 healthy controls (HCs). Correlations between serum PRDX3 expression and clinicopathological variables and the relationship between serum PRDX3 expression and prognosis were analyzed. RESULTS: Serum PRDX3 was significantly higher in HCC patients than in the LC and HC groups. The sensitivity and specificity of serum PRDX3 for the diagnosis of HCC were 85.9% and 75.3%, respectively, at a cutoff of 153.26 ng/mL, and the area under the curve was 0.865. Moreover, serum PRDX3 expression was strongly associated with AFP level, tumor diameter, TNM stage, and portal vein invasion. Kaplan-Meier curve analysis revealed that HCC patients with high serum PRDX3 expression had a shorter median survival time than those with low PRDX3 expression. Moreover, serum PRDX3 expression was an independent risk factor for overall survival. The inverse correlation between serum PRDX3 and patient survival remained significant in patients with early-stage HCC and in those with normal serum AFP levels. CONCLUSIONS: Serum PRDX3 can be used as a noninvasive biomarker for the diagnosis and/or prognosis of HCC.

miR-340 reverses cisplatin resistance of hepatocellular carcinoma cell lines by targeting Nrf2-dependent antioxidant pathway.

Many chemotherapeutic agents have been successfully used to treat hepatocellular carcinoma (HCC); however, the development of chemoresistance in liver cancer cells usually results in a relapse and worsening of prognosis. It has been demonstrated that DNA methylation and histone modification play crucial roles in chemotherapy resistance. Currently, extensive research has shown that there is another potential mechanism of gene expression control, which is mediated through the function of short noncoding RNAs, especially for microRNAs (miRNAs), but little is known about their roles in cancer cell drug resistance. In present study, by taking advantage of miRNA effects on the resistance of human hepatocellular carcinoma cells line to cisplatin, it has been demonstrated that miR-340 were significantly downregulated whereas Nrf2 was upregulated in HepG2/ CDDP (cisplatin) cells, compared with parental HepG2 cells. Bioinformatics analysis and luciferase assays of Nrf2-3'-untranslated region-based reporter constructor indicated that Nrf2 was the direct target gene of miR- 340, miR-340 mimics suppressing Nrf2-dependent antioxidant pathway and enhancing the sensitivity of HepG2/ CDDP cells to cisplatin. Interestingly, transfection with miR-340 mimics combined with miR-340 inhibitors reactivated the Nrf2 related pathway and restored the resistance of HepG2/CDDP cells to CDDP. Collectively, the results first suggested that lower expression of miR-340 is involved in the development of CDDP resistance in hepatocellular carcinoma cell line, at least partly due to regulating Nrf2-dependent antioxidant pathway.

Phytoestrogen α-Zearalanol attenuates homocysteine-induced apoptosis in human umbilical vein endothelial cells.

Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases. The enhanced nitrative stress plays an important role in homocysteine-induced endothelial dysfunction. Previous studies have showed that phytoestrogen α -zearalanol alleviated endothelial injury in ovariectomized hyperhomocysteinemic rats; however, the underlying mechanism remains to be clarified. This study was to investigate the effects of α -zearalanol on homocysteine-induced endothelial apoptosis in vitro and explore the possible role of nitrative stress in these effects. Results showed that homocysteine (500 µ mol/L, 24 h) induced the apoptosis of human umbilical vein endothelial cells (HUVECs) obviously, and this effect was significantly attenuated by pretreatment with α -zearalanol (10(-8)~10(-6) mol/L). Moreover, α -zearalanol downregulated proapoptotic protein Bax, upregulated antiapoptotic proteins Bcl-2 and Bcl-XL, and decreased the expression and activity of caspase-9. These findings demonstrated that α -zearalanol could effectively alleviate homocysteine-induced endothelial apoptosis, and this antiapoptosis effect might be related to the inhibition of the intrinsic pathway. Western blot indicated an enhanced 3-nitrotyrosine expression in HUVECs when challenged with homocysteine, which was attenuated by pretreatment with α -zearalanol. This result implied that inhibition of nitrative stress might play a role in the protective effect of α -zearalanol on endothelial cells. Such discovery may shed a novel light on the antiatherogenic activities of α -zearalanol in hyperhomocysteinemia.

[Responses of tomato leaf photosynthesis to rapid water stress].

By using polyethylene glycol (PEG-6000) solution to regulate the water potential of tomato (Lycopersicon esculentum) rhizosphere to simulate water stress, this paper studied the dynamic changes of net photosynthetic rate, dark respiratory rate and CO2 compensatory concentration of detached tomato leaves in the process of photosynthetic induction. Under 1000 micromol m-2 s-1 of light induction, the time required to reach the maximum net photosynthetic rate of water-stressed tomato leaves was shortened by 1/3, while the stomatal conductance was increased by 1.5 times, as compared to the non-stress control. Also, the light saturation point (LSP) of water-stressed tomato leaves was lowered by 65% to 85%, and the light compensation point (LCP) was increased by 75% to 100%, suggesting that the effective range of light utilized by tomato leaves was reduced. Furthermore, water stress decreased the maximum photosynthetic capacity of tomato leaves by 40%, but increased the dark respiration rate by about 45% . It was suggested that rapid water stress made the stomata of tomato leaves quickly opened, without initial photosynthetic induction stage. In conclusion, water stress could induce the decrease of plant light-energy use efficiency and potential, being the main reason for the decrease of plant productivity, and stomatal regulation could be the main physiological mechanism of tomato plants to adapt to rapid water stress.

[Improved methods for researching isolated carotid sinus baroreceptors automatically controlling for sinus pressure].

OBJECTIVE: To develop a system for automatically controlling carotid sinus pressure in the study on baroreceptors. METHODS: The preparation containing carotid sinus with parts of the connected vessels and carotid sinus nerve (CS-CSN) were isolated and perfused. A critical pressure controlling component (PRE-U, Hoerbiger, Deutschland) dictated by a computer was integrated into the system to clamp the intrasinus pressure. The pressure command and the relevant intrasinus pressure were compared to evaluate the validity of the pressure controlling system. RESULTS: A variety of sinus pressure-controlling patterns, including pulsation, ramp and step pressures, could be achieved accurately by using the system, and the pressure-dependent discharge activities of sinus nerve were confirmed. CONCLUSION: This system for clamping carotid sinus pressure could realize multiple pressure-controlling patterns and is a useful and flexible pressure controlling method that could applied in the study on mechano-electric transduction of baroreceptors.

Superior laryngeal nerve loop: patterns and surgical implications.

This study clarifies the patterns of the superior laryngeal nerve loop (SLN loop), connecting the cervical sympathetic chain (CSC) and the SLN and its branches, so as to provide an anatomic basis for decreasing the risk of injury to the external laryngeal nerve (ELN) during neck surgery. Fifty Chinese adult human cadavers fixed with 4 % formalin were dissected, and their SLN loop patterns were analyzed and summarized. In 98 of 100 sides the CSC anastomosed with the SLN and its branches, forming a looped nerve structure which we called the SLN loop. The SLN loops could be divided into five types: e ( n ), t ( n ), i ( n ), t ( n ) e ( n ), and i ( n ) e ( n ) based on morphological variations. The results demonstrated that e ( n ) was most frequently found in the samples (82/100) followed by t ( n ) (9/100), i ( n ) (3/100), t ( n ) e ( n ) (2/100), and i ( n ) e ( n ) (2/100). Comparing with the previous work, we identified additional 18 subtypes of the SLN loop. The relations of the SLN loop to the surrounding structures were complicated, which brought more challenges to thyroidectomy. Thus, we do not advocate routine identification of ELN/ELN loop during the process of thyroidectomy, especially systematic identification of ELN during operation. However, this study introduces the possibility that nerve injury can be avoided by exposure of the nerve via careful dissection in the region of the superior pole of the thyroid gland to the extent that we can initiate individual ligation of the superior polar vessels, along with the help of neuromonitors, video monitors, and magnifying loupes.

An applied anatomical study on the recurrent laryngeal nerve and inferior thyroid artery.

PURPOSE: The aim of this study was to provide some important information about the morphology and topography of the recurrent laryngeal nerve (RLN) and inferior thyroid artery (ITA), which significantly helps localize and protect the RLN in neck surgery, especially in thyroid surgery. METHODS: Eighty adult cadavers (160 sides) fixed with formalin were dissected, analyzed and measured. RESULTS: (1) 87.5% of the RLNs gave off multiple branches like a tree; the incidence of the RLN loop, connecting one branch to another was 3.125%; in 9.375%, one branch of RLN combined with cervical sympathetic chain (CSC) or superior laryngeal nerve (SLN). (2) A double RLN appeared in four sides, a non-recurrent inferior laryngeal nerve appeared in two cases. (3) In two cases, the RLN communicated with both of the SLN and the CSC near thyroid gland. (4) Most of the ITAs was derived from thyrocervical trunk, and divided into two or three branches before entering the thyroid gland. (5) Three ITAs gave off esophageal branch, one ITA gave off tracheal branch, one right ITA originated abnormally. (6) On the left side, the RLN was behind the ITA in 86.25% of the cases, in front of the artery in 7.5%, the nerve was between artery branches in 2.5%, the artery was between nerve branches in 1.25%, and was among the combined in 2.5%. On the right side, the RLN was in front of the artery in 75.0%, behind the artery in 10.0%, among the branches of the artery in 5.0%, 10.0% the branches of both nerves and artery were interlaced that the relationship between the branches of the nerve and the artery was uncertain. CONCLUSIONS: Because of the variability of the RLN and ITA and the complicated relationship between them, it is necessary to dissect and recognize the RLN to avoid mistaking, ignoring, and misligating of the nerve before ligating the ITA.

[Arrhythmia triggered by stretching rabbit left ventricles and the block effect of streptomysin].

AIM: To observe the effect of stretching left ventricles in the end of action potential on rabbit cardiac activity, and to investigate its possible mechanisms. METHODS: Stretch (120 mmHg, 50 ms) was applied in the end of action potential by the pressure-clamp technique to observe if there would be any changes in rabbit cardiac activity and streptomycin (500 micromol/L) was used to identify the mechanism. RESULTS: Stretch in the end of action potential caused arrhythmia (P < 0.05) and streptomycin blocked the above effect (P < 0.05). CONCLUSION: Streptomycin could block the effect of stretching left ventricles in the end of action potential on rabbit cardiac activity, which indicates that stretch-activated ion channels involve it.

A ventricular pressure-clamping system for the study of mechano-electrical feedback.

It is necessary to control the mechanical stimuli precisely in the studies of cardiac mechano-electrical feedback (MEF). In the present study a ventricular pressure-clamping system has been developed, which can be applied to isolated-perfused rabbit hearts. Controlled by a computer, this system not only can make the left ventricle follow a command defining the same pressure wave as that during a beating cycle under physiological condition, but also deliver mechanical stimuli with a proper waveform to the ventricle at a particular time phase. This system integrates multiple functions, including perfusing, pacing, recording of electrocardiogram and monophasic action potentials, and clamping and measuring of ventricular pressures in isolated-perfused hearts. Thus, it is a distinct system for investigating the phenomena and mechanisms of cardiac MEF at organ level.

[Allogenic transplantation studies on human fetal pancreatic nestin positive cells].

Human fetal pancreatic nestin positive cells cultured in vitro could self assemble to form islet-like cell clusters(ICC). They are multipotential and are capable of generating insulin-producing cells. To investigate their biological character and physiological function in vivo, ICCs were implanted into NOD-Scid mice subcapsularly. The results showed that: (1) Neovascularizations were observed in implant sites. (2) Blood glucose levels of diabetic mice were reduced markedly after implantation of ICCs. (3) ICCs in non-diabetic mice proliferated abnormally and infiltrated into renal parenchyma with many cell structures formed.

[Isolation, culture and biological character studies on human fetal pancreatic nestin positive cells].

Pancreatic nestin positive cells are multipotential stem cells which may play an important role in the development of pancreas. Here we isolated nestin positive cells from human fetal pancreases and then examined its biological characters in vitro. The results showed that: (1) Nestin positive cells expressed high level transcript of ABCG2/BCRP1 which was the molecular determination of stem cells, and they differed from pancreatic ductal epithelium cells both in morphology and in growth behavior. (2) Upon confluence, these cells self assemble to form islet like cell clusters (ICCs). (3) During differentiation, nestin positive cells in ICCs expressed markers of different cell lineages which meant that they were multipotential, and they could generate insulin-producing cells after inducement.