Module control of network analysis in psychopathology.

The network approach to characterizing psychopathology departs from traditional latent categorical and dimensional approaches. Causal interplay among symptoms contributed to dynamic psychopathology system. Therefore, analyzing the symptom clusters is critical for understanding mental disorders. Furthermore, despite extensive research studying the topological features of symptom networks, the control relationships between symptoms remain largely unclear. Here, we present a novel systematizing concept, module control, to analyze the control principle of the symptom network at a module level. We introduce Module Control Network (MCN) to identify key modules that regulate the network's behavior. By applying our approach to a multivariate psychological dataset, we discover that non-emotional modules, such as sleep-related and stress-related modules, are the primary controlling modules in the symptom network. Our findings indicate that module control can expose central symptom cluster governing psychopathology network, offering novel insights into the underlying mechanisms of mental disorders and individualized approach to psychological interventions.

Diagnosis and treatment of secondary nephrotic syndrome with rash as the first symptom: a case report.

BACKGROUND: Membranous nephropathy (MN) is a common type of nephrotic syndrome (NS) in adults, accounting for about 20-30% of cases. Although secondary to specific factors, the coexistence of MN and mantle cell lymphoma (MCL) has been scarcely reported in clinical literature. CASE PRESENTATION: A 59-year-old Chinese male was admitted to the hospital with a generalized pruritic rash with bilateral lower extremity edema, which did not improve significantly after symptomatic treatment. He had undergone renal biopsy, and the diagnosis was thought to be secondary MN (SMN), therefore, we did a lymph node biopsy on the patient and found that MN was complicated with MCL. Soon after, the patient was admitted to the hematology department for a BR chemotherapy regimen (composed of bendamustine 90 mg/m2 BSA (body surface area), rituximab 375 mg/m2 BSA and dexamethasone 5 mg), and during the post-treatment follow-up, both his symptoms and renal function improved. CONCLUSIONS: The mechanism underlying the combination of SMN and MCL remains elusive and exceedingly rare, consequently often overlooked in clinical practice. This case serves to offer valuable clinical insights for diagnosis and treatment, while emphasizing the pivotal role of renal pathology in clinical assessment.

Epigenetic molecular underpinnings of brain structural-functional connectivity decoupling in patients with major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is progressively recognized as a stress-related disorder characterized by aberrant brain network dynamics, encompassing both structural and functional domains. Yet, the intricate interplay between these dynamic networks and their molecular underpinnings remains predominantly unexplored. METHODS: Both structural and functional networks were constructed using multimodal neuroimaging data from 183 MDD patients and 300 age- and gender-matched healthy controls (HC). structural-functional connectivity (SC-FC) coupling was evaluated at both the connectome- and nodal-levels. Methylation data of five HPA axis key genes, including NR3C1, FKBP5, CRHBP, CRHR1, and CRHR2, were analyzed using Illumina Infinium Methylation EPIC BeadChip. RESULTS: We observed a significant reduction in SC-FC coupling at the connectome-level in patients with MDD compared to HC. At the nodal level, we found an imbalance in SC-FC coupling, with reduced coupling in cortical regions and increased coupling in subcortical regions. Furthermore, we identified 23 differentially methylated CpG sites on the HPA axis, following adjustment for multiple comparisons and control of age, gender, and medication status. Notably, three CpG sites on NR3C1 (cg01294526, cg19457823, and cg23430507), one CpG site on FKBP5 (cg25563198), one CpG site on CRHR1 (cg26656751), and one CpG site on CRHR2 (cg18351440) exhibited significant associations with SC-FC coupling in MDD patients. CONCLUSIONS: These findings provide valuable insights into the connection between micro-scale epigenetic changes in the HPA axis and SC-FC coupling at macro-scale connectomes. They unveil the mechanisms underlying increased susceptibility to MDD resulting from chronic stress and may suggest potential pharmacological targets within the HPA-axis for MDD treatment.

From Connectivity to Controllability: Unraveling the Brain Biomarkers of Major Depressive Disorder.

Major Depressive Disorder (MDD) is a significant neurological condition associated with aberrations in brain functional networks. Traditional studies have predominantly analyzed these from a network topology perspective. However, given the brain's dynamic and complex nature, exploring its mechanisms from a network control standpoint provides a fresh and insightful framework. This research investigates the integration of network controllability and machine learning to pinpoint essential biomarkers for MDD using functional magnetic resonance imaging (fMRI) data. By employing network controllability methods, we identify crucial brain regions that are instrumental in facilitating transitions between brain states. These regions demonstrate the brain's ability to navigate various functional states, emphasizing the utility of network controllability metrics as potential biomarkers. Furthermore, these metrics elucidate the complex dynamics of MDD and support the development of precision medicine strategies that incorporate machine learning to improve the precision of diagnostics and the efficacy of treatments. This study underscores the value of merging machine learning with network neuroscience to craft personalized interventions that align with the unique pathological profiles of individuals, ultimately enhancing the management and treatment of MDD.

State- and trait-related dysfunctions in bipolar disorder across different mood states: a graph theory study.

BACKGROUND: The interplay between state- and trait-related disruptions in structural networks remains unclear in bipolar disorder (BD), but graph theory can offer insights into global and local network changes. We sought to use diffusion-tensor imaging (DTI) and graph theory approaches to analyze structural topological properties across distinct mood states and identify high-risk individuals by examining state- and trait-related impairments in BD. METHODS: We studied changes in white matter network among patients with BD and healthy controls, exploring relationships with clinical variables. Secondary analysis involved comparing patients with BD with unaffected people at high genetic risk for BD. RESULTS: We included 152 patients with BD, including 52 with depressive BD (DBD), 64 with euthymic BD (EBD) and 36 with manic BD (MBD); we also included 75 healthy controls. Secondary analyses involved 27 unaffected people at high genetic risk for BD. Patients with DBD and MBD exhibited significantly lower global efficiencies than those with EBD and healthy controls, with patients with DBD showing the lowest global efficiencies. In addition, patients with DBD displayed impaired local efficiency and normalized clustering coefficient (γ). At a global level, γ correlated negatively with depression and anxiety. Compared with healthy controls, and across mood states, patients with BD showed abnormal shortest path lengths in the frontolimbic circuit, a trend mirrored among those at high genetic risk for BD. LIMITATIONS: Considerations include medication effects, absence of recorded BD episode counts and the cross-sectional nature of the study. CONCLUSION: Mood-specific whole-brain network metrics could serve as potential biomarkers in BD for transitions between mood states. Moreover, these findings contribute to evidence of trait-related frontolimbic circuit irregularities, shedding light on underlying pathophysiological mechanisms in BD.

Total network controllability analysis discovers explainable drugs for Covid-19 treatment.

BACKGROUND: The active pursuit of network medicine for drug repurposing, particularly for combating Covid-19, has stimulated interest in the concept of structural controllability in cellular networks. We sought to extend this theory, focusing on the defense rather than control of the cell against viral infections. Accordingly, we extended structural controllability to total structural controllability and introduced the concept of control hubs. Perturbing any control hub may render the cell uncontrollable by exogenous stimuli like viral infections, so control hubs are ideal drug targets. RESULTS: We developed an efficient algorithm to identify all control hubs, applying it to a largest homogeneous network of human protein interactions, including interactions between human and SARS-CoV-2 proteins. Our method recognized 65 druggable control hubs with enriched antiviral functions. Utilizing these hubs, we categorized potential drugs into four groups: antiviral and anti-inflammatory agents, drugs acting on the central nervous system, dietary supplements, and compounds enhancing immunity. An exemplification of our approach's effectiveness, Fostamatinib, a drug initially developed for chronic immune thrombocytopenia, is now in clinical trials for treating Covid-19. Preclinical trial data demonstrated that Fostamatinib could reduce mortality rates, ICU stay length, and disease severity in Covid-19 patients. CONCLUSIONS: Our findings confirm the efficacy of our novel strategy that leverages control hubs as drug targets. This approach provides insights into the molecular mechanisms of potential therapeutics for Covid-19, making it a valuable tool for interpretable drug discovery. Our new approach is general and applicable to repurposing drugs for other diseases.

Total network controllability analysis discovers explainable drugs for Covid-19 treatment.

Background The active pursuit of network medicine for drug repurposing, particularly for combating Covid-19, has stimulated interest in the concept of structural control capability in cellular networks. We sought to extend this theory, focusing on the defense rather than control of the cell against viral infections. Accordingly, we extended structural controllability to total structural controllability and introduced the concept of control hubs. Perturbing any control hub may render the cell uncontrollable by exogenous stimuli like viral infections, so control hubs are ideal drug targets. Results We developed an efficient algorithm to identify all control hubs, applying it to the largest homogeneous network of human protein interactions, including interactions between human and SARS-CoV-2 proteins. Our method recognized 65 druggable control hubs with enriched antiviral functions. Utilizing these hubs, we categorized potential drugs into four groups: antiviral and anti-inflammatory agents, drugs acting on the central nervous system, dietary supplements, and compounds enhancing immunity. An exemplification of our approach's effectiveness, Fostamatinib, a drug initially developed for chronic immune thrombocytopenia, is now in clinical trials for treating Covid-19. Preclinical trial data demonstrated that Fostamatinib could reduce mortality rates, ICU stay length, and disease severity in Covid-19 patients. Conclusions Our findings confirm the efficacy of our novel strategy that leverages control hubs as drug targets. This approach provides insights into the molecular mechanisms of potential therapeutics for Covid-19, making it a valuable tool for interpretable drug discovery.

Cancer-keeper genes as therapeutic targets.

Finding cancer-driver genes has been a central theme of cancer research. We took a different perspective; instead of considering normal cells, we focused on cancerous cells and genes that maintained abnormal cell growth, which we named cancer-keeper genes (CKGs). Intervening CKGs may rectify aberrant cell growth, making them potential cancer therapeutic targets. We introduced control-hub genes and developed an efficient algorithm by extending network controllability theory. Control hub are essential for maintaining cancerous states and thus can be taken as CKGs. We applied our CKG-based approach to bladder cancer (BLCA). All genes on the cell-cycle and p53 pathways in BLCA were identified as CKGs, showing their importance in cancer. We discovered that sensitive CKGs - genes easily altered by structural perturbation - were particularly suitable therapeutic targets. Experiments on cell lines and a mouse model confirmed that six sensitive CKGs effectively suppressed cancer cell growth, demonstrating the immense therapeutic potential of CKGs.

Prospective comparison of extracorporeal shock wave lithotripsy and ureteroscopy in distal ureteral stones.

The optimal treatment modality of distal ureteral stones is controversial. Therefore, we conducted a prospective study to evaluate the efficacy, safety, and cost of early second shock wave lithotripsy (SWL) sessions versus ureterorenoscopy (URS) in patients with distal ureteral stones. This prospective study was conducted in a tertiary hospital from June 2020 to April 2022. Patients who underwent SWL or URS for distal ureteral stones were enrolled in this study. The stone-free rate (SFR), secondary treatment rate, complications, and costs were recorded. Propensity-score matching (PSM) analysis was also performed. A total of 1023 patients were included, of whom 68.4% (700) were treated with SWL and 31.6% (323) with URS. Based on PSM, SWL had an equivalent SFR (87.4% vs. 84.9%, P = 0.325) at one month after SWL and secondary treatment rate (10.7% vs.10.8%, P = 0.958) when compared with URS. Complications were rare and comparable between the SWL and URS groups (6.0% vs. 5.9%, P > 0.05), while the incidence of ureteral injuries (i.e., perforations) was higher in the URS group compared with the SWL group (1.3% vs. 0%, P = 0.019). The hospital stay was significantly shorter (1 day vs. 2 days, P < 0.001) and the costs considerably less (2000 RMB vs. 25,030 RMB; P < 0.001) in the SWL group compared with the URS group. This prospective study demonstrated that early second SWL sessions had equivalent efficacy in addition to reduced complication rates and costs compared with URS in patients with distal ureteral stones. Our findings may help guide clinical decision making.

Associations between grain intake and hospitalized nephrolithiasis in Chinese adults: a case-control study.

Introduction: nephrolithiasis is one of the most common urological disorders. Grains are essential staple foods worldwide. This study aimed to investigate the associations between whole grains and refined grains intake, and hospitalized nephrolithiasis in a Chinese population. Methods: the patients and healthy participants were enrolled in the Shenyang sub-cohort of Tianjin Chronic Low-Grade Systemic Inflammation and Health Cohort Study. After selecting and matching by age (±one year) and sex using a 1 : 2 ratio, a total of 666 participants (222 patients and 444 healthy controls) were included. Whole grains and refined grains intake was measured using a validated self-administered food frequency questionnaire. Multivariate conditional logistic regression analysis was used to evaluate the associations between whole grains and refined grains intake with hospitalized nephrolithiasis. Results: after multivariable adjustments, a higher intake of whole grains was inversely associated with hospitalized nephrolithiasis. Compared to participants with the lowest tertile of whole grains intake, the adjusted odds ratio (OR) and 95% confidence interval (CI) of hospitalized nephrolithiasis for participants in the highest tertile was 0.58 (0.26, 0.81) (P for trend = 0.020). In contrast, a higher intake of refined grains was positively associated with nephrolithiasis. Compared to participants with the lowest tertile of refined grains intake, the adjusted OR (95% CI) of hospitalized nephrolithiasis for participants in the highest tertile was 3.75 (1.48, 9.52) (P for trend = 0.006). The results were consistent in both genders. Conclusion: the consumption of whole grains was found to be negatively associated with hospitalized nephrolithiasis, while the consumption of refined grains was positively associated with hospitalized nephrolithiasis. Therefore, a substitution of whole grains for refined grains consumption may assist in hospitalized nephrolithiasis prevention.

hKLK alleviates myocardial fibrosis in mice with viral myocarditis.

Myocardial fibrosis is the most serious complication of viral myocarditis (VMC). This study aimed to investigate the therapeutic benefits and underlying mechanisms of lentivirus-mediated human tissue kallikrein gene transfer in myocardial fibrosis in VMC mice. We established VMC mouse model via intraperitoneal injection with Coxsackie B3 virus. The effect was then assessed after treatment with vehicle, the empty lentiviral vectors (EZ.null), and the vectors expressing hKLK1 (EZ.hKLK1) via tail vein injection for 30 days, respectively. The results showed that administering EZ.hKLK1 successfully induced hKLK1 overexpression in mouse heart. Compared with EZ.null treatment, EZ.hKLK1 administration significantly reduced the heart/weight ratio, improved cardiac function, and ameliorated myocardial inflammation in VMC mice, suggesting that hKLK1 overexpression alleviates VMC in mice. EZ.hKLK1 administration also significantly abrogated the increased myocardial collagen content, type I/III collagen ratio, TGF-ß1 mRNA and protein expression in VMC mice, suggesting that hKLK1 overexpression reduces collagen accumulation and blunts TGF-ß1 signaling in the hearts of VMC mice. In conclusion, our results suggest that hKLK1 alleviates myocardial fibrosis in VMC mice, possibly by downregulating TGF-ß1 expression.

Development and validation of a predictive model for major complications after extracorporeal shockwave lithotripsy in patients with ureteral stones: based on a large prospective cohort.

The risk factors of complications after SWL are not well characterized. Therefore, based on a large prospective cohort, we aimed to develop and validate a nomogram for predicting major complications after extracorporeal shockwave lithotripsy (SWL) in patients with ureteral stones. The development cohort included 1522 patients with ureteral stones who underwent SWL between June 2020 and August 2021 in our hospital. Five hundred and fifty-three patients with ureteral stones participated in the validation cohort from September 2020 to April 2022. The data were prospectively recorded. Backward stepwise selection was applied using the likelihood ratio test with Akaike's information criterion as the stopping rule. The efficacy of this predictive model was assessed concerning its clinical usefulness, calibration, and discrimination. Finally, 7.2% (110/1522) of patients in the development cohort and 8.7% (48/553) of those in the validation cohort suffered from major complications. We identified five predictive factors for major complications: age, gender, stone size, Hounsfield unit of stone, and hydronephrosis. This model showed good discrimination with an area under the receiver operating characteristic curves of 0.885 (0.872-0.940) and good calibration (P = 0.139). The decision curve analysis showed that the model was clinically valuable. In this large prospective cohort, we found that older age, female gender, higher Hounsfield unit, size, and grade of hydronephrosis were risk predictors of major complications after SWL. This nomogram will be helpful in preoperative risk stratification to provide individualized treatment recommendations for each patient. Furthermore, early identification and appropriate management of high-risk patients may decrease postoperative morbidity.

Age effects of Moso bamboo on leaf isoprene emission characteristics.

Isoprene is a highly reactive volatile organic compound that significantly affects atmospheric oxidant capacity, regional air quality, and climate change. Moso bamboo (Phyllostachys edulis), a species widely distributed in tropical and subtropical regions, particularly in China, is a strong isoprene emitter with great potential for carbon sequestration. Carbon sequestration is negatively correlated with culm age; however, the effect of this correlation on isoprene emissions remains unknown. In this study, we investigated the photosynthetic and isoprene emission characteristics of Moso bamboo at different culm ages. The results showed that the age effect on isoprene emission was different from that on photosynthesis; the net photosynthesis rate (Pn) was the highest in young, followed by mature, and then old bamboo, whereas the isoprene emission rate (Iso) was the highest in young, followed by old, and then mature bamboo. Moreover, the percentage of carbon loss as isoprene emission (C-loss) during photosynthesis of old bamboo was 35% higher than that of mature bamboo under standard conditions (leaf temperature: 30°C; light intensity: 1000 µmol m-2 s-1). Therefore, we strongly recommend considering the culm age when establishing an isoprene emission model of Moso bamboo. Additionally, because the Iso and C-loss of old bamboo were higher than those of mature bamboo, we suggest that attention should be paid to the management of bamboo age structure and timely felling of aged bamboo to reduce environmental risk.

Spontaneous Chirality Induction in the Assembly of a Single Layer 2D Network with Switchable Pores.

Although two-dimensional (2D) chiral sheet structures are attractive because of their unique chemical and physical properties, single layer 2D chiral network structures with switchable pore interior remain elusive. Here we report spontaneous chirality induction in a single layer 2D network structure formed from the self-assembly of tetrapod azobenzene molecules. The chirality induction arises from multiple sublayers slipped in a preferred direction in which the sublayer consists of unidentical molecular arrangements in the in-plane a and b directions, breaking both the plane of symmetry and inversion symmetry. The protruded azobenzene units in the pore interior can be selectively isomerized upon UV irradiation, resulting in a reversible deformation of the chiral pores while maintaining the 2D frameworks. The chiral network can thus selectively entrap one enantiomer from a racemic solution with near perfect enantioselectivity, and then release it upon UV irradiation.

Development and validation of a predictive model for stone-free failure after extracorporeal shockwave lithotripsy in patients with ureteral stone in a large prospective cohort.

PURPOSE: To develop and validate a nomogram for predicting stone-free failure after shock wave lithotripsy (SWL) guided by ultrasound in patients with ureteral stones. METHODS: The development cohort consisted of 1698 patients who underwent SWL guided by ultrasound at our center from June 2020 through August 2021. Multivariate unconditional logistic regression analysis was used for building a predictive nomogram with regression coefficients. An independent validation cohort consisted of 712 consecutive patients from September 2020 through April 2021. The performance of the predictive model was assessed in regard to discrimination, calibration, and clinical usefulness. RESULTS: Predictors of stone-free failure included distal stone location (odds ratio = 1.540, P < 0.001), larger stone size (odds ratio = 1.722, P < 0.001), higher stone density (odds ratio = 1.722, P < 0.001), larger skin to stone distance (SSD) (odds ratio = 1.058, P < 0.001), and higher grade of hydronephrosis (odds ratio = 1.755, P = 0.010). For the validation cohort, the model showed good discrimination with an area under the receiver operating characteristic curve of 0.925 (95% confidence interval, 0.898, 0.953) and good calibration (unreliability test, P = 0.412). Decision curve analysis demonstrated that the model was also clinically useful. CONCLUSIONS: This study demonstrated that stone location, stone size, stone density, SSD, and hydronephrosis grade were significant predictors of stone-free failure after SWL guided by ultrasound in patients with ureteral stones. This may guide clinical practice.

NetMoST: A network-based machine learning approach for subtyping schizophrenia using polygenic SNP allele biomarkers.

Subtyping neuropsychiatric disorders like schizophrenia is essential for improving the diagnosis and treatment of complex diseases. Subtyping schizophrenia is challenging because it is polygenic and genetically heterogeneous, rendering the standard symptom-based diagnosis often unreliable and unrepeatable. We developed a novel network-based machine-learning approach, netMoST, to subtyping psychiatric disorders. NetMoST identifies polygenic risk SNP-allele modules from genome-wide genotyping data as polygenic haplotype biomarkers (PHBs) for disease subtyping. We applied netMoST to subtype a cohort of schizophrenia subjects into three distinct biotypes with differentiable genetic, neuroimaging and functional characteristics. The PHBs of the first biotype (36.9% of all patients) were related to neurodevelopment and cognition, the PHBs of the second biotype (28.4%) were enriched for neuroimmune functions, and the PHBs of the third biotype (34.7%) were associated with the transport of calcium ions and neurotransmitters. Neuroimaging patterns provided additional support to the new biotypes, with unique regional homogeneity (ReHo) patterns observed in the brains of each biotype compared with healthy controls. Our findings demonstrated netMoST's capability for uncovering novel biotypes of complex diseases such as schizophrenia. The results also showed the power of exploring polygenic allelic patterns that transcend the conventional GWAS approaches.

Development and Validation of a Nomogram for Predicting Blood Pressure Change Failure in Patients with Pheochromocytoma and Concomitant Hypertension after Adrenalectomy.

(1) Background: Pheochromocytoma is a common cause of secondary hypertension, which is considered curable; nevertheless, some patients still suffer from hypertension after adrenalectomy. Therefore, we developed and validated a nomogram for predicting blood pressure change failure in patients with pheochromocytoma and concomitant hypertension after adrenalectomy. (2) Methods: The development cohort of this study consisted of 259 patients with pheochromocytoma who underwent adrenalectomy at our center between 1 January 2007 and 31 December 2018. Each patient's clinicopathologic data were recorded. LASSO (the least absolute shrinkage and selection operator) regression was used to reduce and select the features of the data. Furthermore, we used multivariate logistic regression analysis to develop the prediction model. An independent cohort of 110 consecutive patients from 1 January 2019 to 31 December 2021 was used for validation. The performance of this nomogram was assessed with regard to discrimination, calibration, and clinical usefulness. (3) Results: 40.9% and 46.4% of patients experienced blood pressure change failure in the development and validation cohorts of this study, respectively. We found that older patients with a longer duration of hypertension and concomitant cardiovascular events were more likely to suffer from blood pressure change failure. In the validation cohort, the model manifested great discrimination with an AUROC (area under the receiver operating characteristic) of 0.996 (p < 0.001) and good calibration (unreliability test, p = 0.359). Decision curve analysis demonstrated that the model was clinically useful. (4) Conclusions: This study presented a reliable nomogram that facilitated individualized preoperative prediction of blood pressure change failure after adrenalectomy in patients with pheochromocytoma, which may help decision-making in perioperative treatment and follow-up strategies.

Prospective comparison of extracorporeal shock wave lithotripsy versus flexible ureterorenoscopy in patients with non-lower pole kidney stones under the COVID-19 pandemic.

Both shock wave lithotripsy (SWL) and flexible ureterorenoscopy (F-URS) are recommended as the first choice for non-lower pole kidney stones. Therefore, we conducted a prospective study to evaluate the efficacy, safety, and cost of SWL versus F-URS in patients with solitary non-lower pole kidney stones ≤ 20 mm under the COVID-19 pandemic. This prospective study was conducted in a tertiary hospital from June 2020 to April 2022. Patients who underwent lithotripsy (SWL or F-URS) for non-lower pole kidney stones were enrolled in this study. The stone-free rate (SFR), retreatment rate, complications, and cost were recorded. Propensity score-matched (PSM) analysis was performed. A total of 699 patients were finally included, of which 81.3% (568) were treated with SWL and 18.7% (131) underwent F-URS. After PSM, SWL showed equivalent SFR (87.9% vs. 91.1%, P = 0.323), retreatment rate (8.6% vs. 4.8%, P = 0.169), and adjunctive procedure (2.6% vs. 4.9%, P = 0.385) compared with F-URS. Complications were scarce and also comparable between SWL and F-URS (6.0% vs 7.7%, P > 0.05), while the incidence of ureteral perforation was higher in the F-URS group compared with the SWL group (1.5% vs 0%, P = 0.008). The hospital stay was significantly shorter (1 day vs 2 days, P < 0.001), and the cost was considerably less (1200 vs 30,083, P < 0.001) in the SWL group compared with the F-URS group. This prospective cohort demonstrated that SWL had equivalent efficacy with more safety and cost benefits than F-URS in treating patients with solitary non-lower pole kidney stones ≤ 20 mm. During the COVID-19 pandemic, SWL may have benefits in preserving hospital resources and limiting opportunity for virus transmission, compared to URS. These findings may guide clinical practice.

Prolonged Intermittent Renal Replacement Therapy Combined with Hemoperfusion Can Improve Early Recovery of Moderate and Severe Acute Pancreatitis, Especially in Patients with Acute Kidney Injury.

INTRODUCTION: The aim of this study was to investigate the efficacy of prolonged intermittent renal replacement therapy (PIRRT) plus hemoperfusion (HP) in treating moderately severe acute pancreatitis (MSAP) and severe acute pancreatitis (SAP). METHODS: A total of 105 MSAP and SAP patients were enrolled. Sixty of them received routine internal medical therapy (control group), and 45 received PIRRT and HP in addition to routine internal medical therapy (PIRRT + HP group). The vital signs, laboratory results, and the Acute Physiology and Chronic Health Evaluation II (APACHE II) score were compared between the two groups before treatment and on the 3rd and 7th days of treatment. RESULTS: No deaths or treatment-related serious adverse reactions occurred in both groups. After 3 and 7 days of treatment, the APACHE II score decreased more significantly in the PIRRT + HP group than in the control group (3 days: 5.47 [±3.30] vs. 7.53 [±3.89], p = 0.005. 7 days: 4.82 [±3.49] vs. 6.87 [±3.54], p = 0.004). After 3 days of treatment, the inflammatory combination parameters systemic immune-inflammation index (SII) and neutrophil-to-lymphocyte ratio (NLR) in the PIRRT + HP group decreased more significantly than those in the control group (SII: 1,239.00 [737.80-1,769.00] vs. 2,013.00 [1,260.00-3,167.00], p = 0.001. NLR: 8.78 [±4.52] vs. 11.88 [±7.30], p = 0.009). After 7 days of treatment, SII, NLR, and hypersensitive C-reactive protein decreased significantly compared with baseline, but no statistical differences between the two groups were observed. AST in both groups remained stable with treatment. There was no significant difference in baseline creatinine between the two groups of AKI patients, but after 3 and 7 days of treatment, the proportion of acute kidney injury (AKI) patients in the PIRRT + HP group whose creatinine decreased by 50% from baseline or fell to the normal range was significantly higher than that in the control group (p < 0.05). CONCLUSION: PIRRT + HP therapy could not only improve the general conditions, as measured by APACHE II score, but also reduce the inflammatory cascade of patients with acute pancreatitis. For MSAP and SAP patients complicated with AKI, this therapy may accelerate the recovery of renal function.

Total controllability analysis discovers explainable drugs for Covid-19 treatment.

Network medicine has been pursued for Covid-19 drug repurposing. One such approach adopts structural controllability, a theory for controlling a network (the cell). Motivated to protect the cell from viral infections, we extended this theory to total controllability and introduced a new concept of control hubs. Perturbation to any control hub renders the cell uncontrollable by exogenous stimuli, e.g., viral infections, so control hubs are ideal drug targets. We developed an efficient algorithm for finding all control hubs and applied it to the largest homogenous human protein-protein interaction network. Our new method outperforms several popular gene-selection methods, including that based on structural controllability. The final 65 druggable control hubs are enriched with functions of cell proliferation, regulation of apoptosis, and responses to cellular stress and nutrient levels, revealing critical pathways induced by SARS-CoV-2. These druggable control hubs led to drugs in 4 major categories: antiviral and anti-inflammatory agents, drugs on central nerve systems, and dietary supplements and hormones that boost immunity. Their functions also provided deep insights into the therapeutic mechanisms of the drugs for Covid-19 therapy, making the new approach an explainable drug repurposing method. A remarkable example is Fostamatinib that has been shown to lower mortality, shorten the length of ICU stay, and reduce disease severity of hospitalized Covid-19 patients. The drug targets 10 control hubs, 9 of which are kinases that play key roles in cell differentiation and programmed death. One such kinase is RIPK1 that directly interacts with viral protein nsp12, the RdRp of the virus. The study produced many control hubs that were not targets of existing drugs but were enriched with proteins on membranes and the NF-$\kappa$B pathway, so are excellent candidate targets for new drugs.