Enhanced DNA repair through droplet formation and p53 oscillations.

Living organisms are constantly exposed to DNA damage, and optimal repair is therefore crucial. A characteristic hallmark of the response is the formation of sub-compartments around the site of damage, known as foci. Following multiple DNA breaks, the transcription factor p53 exhibits oscillations in its nuclear concentration, but how this dynamics can affect the repair remains unknown. Here, we formulate a theory for foci formation through droplet condensation and discover how oscillations in p53, with its specific periodicity and amplitude, optimize the repair process by preventing Ostwald ripening and distributing protein material in space and time. Based on the theory predictions, we reveal experimentally that the oscillatory dynamics of p53 does enhance the repair efficiency. These results connect the dynamical signaling of p53 with the microscopic repair process and create a new paradigm for the interplay of complex dynamics and phase transitions in biology.

Emergence of large-scale cell death through ferroptotic trigger waves.

Large-scale cell death is commonly observed during organismal development and in human pathologies1-5. These cell death events extend over great distances to eliminate large populations of cells, raising the question of how cell death can be coordinated in space and time. One mechanism that enables long-range signal transmission is trigger waves6, but how this mechanism might be used for death events in cell populations remains unclear. Here we demonstrate that ferroptosis, an iron- and lipid-peroxidation-dependent form of cell death, can propagate across human cells over long distances (≥5 mm) at constant speeds (around 5.5 µm min-1) through trigger waves of reactive oxygen species (ROS). Chemical and genetic perturbations indicate a primary role of ROS feedback loops (Fenton reaction, NADPH oxidase signalling and glutathione synthesis) in controlling the progression of ferroptotic trigger waves. We show that introducing ferroptotic stress through suppression of cystine uptake activates these ROS feedback loops, converting cellular redox systems from being monostable to being bistable and thereby priming cell populations to become bistable media over which ROS propagate. Furthermore, we demonstrate that ferroptosis and its propagation accompany the massive, yet spatially restricted, cell death events during muscle remodelling of the embryonic avian limb, substantiating its use as a tissue-sculpting strategy during embryogenesis. Our findings highlight the role of ferroptosis in coordinating global cell death events, providing a paradigm for investigating large-scale cell death in embryonic development and human pathologies.

Aucubin suppresses TLR4/NF-κB signalling to shift macrophages toward M2 phenotype in glucocorticoid-associated osteonecrosis of the femoral head.

In this study, we investigated whether the ability of aucubin to mitigate the pathology of GONFH involves suppression of TLR4/NF-κB signalling and promotion of macrophage polarization to an M2 phenotype. In necrotic bone tissues from GONFH patients, we compared levels of pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages as well as levels of TLR4/NF-κB signalling. In a rat model of GONFH, we examined the effects of aucubin on these parameters. We further explored its mechanism of action in a cell culture model of M1 macrophages. Necrotic bone tissues from GONFH patients contained a significantly increased macrophage M1/M2 ratio, and higher levels of TLR4, MYD88 and NF-κB p65 than bone tissues from patients with hip osteoarthritis. Treating GONFH rats with aucubin mitigated bone necrosis and demineralization as well as destruction of trabecular bone and marrow in a dose-dependent manner, based on micro-computed tomography. These therapeutic effects were associated with a decrease in the overall number of macrophages, decrease in the proportion of M1 macrophages, increase in the proportion of M2 macrophages, and downregulation of TLR4, MYD88 and NF-κB p65. These effects in vivo were confirmed by treating cultures of M1 macrophage-like cells with aucubin. Aucubin mitigates bone pathology in GONFH by suppressing TLR4/NF-κB signalling to shift macrophages from a pro- to anti-inflammatory phenotype.

Fully automated hybrid approach on conventional MRI for triaging clinically significant liver fibrosis: A multi-center cohort study.

Establishing reliable noninvasive tools to precisely diagnose clinically significant liver fibrosis (SF, ≥F2) remains an unmet need. We aimed to build a combined radiomics-clinic (CoRC) model for triaging SF and explore the additive value of the CoRC model to transient elastography-based liver stiffness measurement (FibroScan, TE-LSM). This retrospective study recruited 595 patients with biopsy-proven liver fibrosis at two centers between January 2015 and December 2021. At Center 1, the patients before December 2018 were randomly split into training (276) and internal test (118) sets, the remaining were time-independent as a temporal test set (96). Another data set (105) from Center 2 was collected for external testing. Radiomics scores were built with selected features from Deep learning-based (ResUNet) automated whole liver segmentations on MRI (T2FS and delayed enhanced-T1WI). The CoRC model incorporated radiomics scores and relevant clinical variables with logistic regression, comparing routine approaches. Diagnostic performance was evaluated by the area under the receiver operating characteristic curve (AUC). The additive value of the CoRC model to TE-LSM was investigated, considering necroinflammation. The CoRC model achieved AUCs of 0.79 (0.70, 0.86), 0.82 (0.73, 0.89), and 0.81 (0.72-0.91), outperformed FIB-4, APRI (all p < 0.05) in the internal, temporal, and external test sets and maintained the discriminatory power in G0-1 subgroups (AUCs range, 0.85-0.86; all p < 0.05). The AUCs of joint CoRC-LSM model were 0.86 (0.79-0.94), and 0.81 (0.72-0.90) in the internal and temporal sets (p = 0.01). The CoRC model was useful for triaging SF, and may add value to TE-LSM.

Signal enhancement ratio of multi-phase contrast-enhanced MRI: an imaging biomarker for survival in pancreatic adenocarcinoma.

OBJECTIVES: To evaluate signal enhancement ratio (SER) for tissue characterization and prognosis stratification in pancreatic adenocarcinoma (PDAC), with quantitative histopathological analysis (QHA) as the reference standard. METHODS: This retrospective study included 277 PDAC patients who underwent multi-phase contrast-enhanced (CE) MRI and whole-slide imaging (WSI) from three centers (2015-2021). SER is defined as (SIlt - SIpre)/(SIea - SIpre), where SIpre, SIea, and SIlt represent the signal intensity of the tumor in pre-contrast, early-, and late post-contrast images, respectively. Deep-learning algorithms were implemented to quantify the stroma, epithelium, and lumen of PDAC on WSIs. Correlation, regression, and Bland-Altman analyses were utilized to investigate the associations between SER and QHA. The prognostic significance of SER on overall survival (OS) was evaluated using Cox regression analysis and Kaplan-Meier curves. RESULTS: The internal dataset comprised 159 patients, which was further divided into training, validation, and internal test datasets (n = 60, 41, and 58, respectively). Sixty-five and 53 patients were included in two external test datasets. Excluding lumen, SER demonstrated significant correlations with stroma (r = 0.29-0.74, all p < 0.001) and epithelium (r = -0.23 to -0.71, all p < 0.001) across a wide post-injection time window (range, 25-300 s). Bland-Altman analysis revealed a small bias between SER and QHA for quantifying stroma/epithelium in individual training, validation (all within ± 2%), and three test datasets (all within ± 4%). Moreover, SER-predicted low stromal proportion was independently associated with worse OS (HR = 1.84 (1.17-2.91), p = 0.009) in training and validation datasets, which remained significant across three combined test datasets (HR = 1.73 (1.25-2.41), p = 0.001). CONCLUSION: SER of multi-phase CE-MRI allows for tissue characterization and prognosis stratification in PDAC. CLINICAL RELEVANCE STATEMENT: The signal enhancement ratio of multi-phase CE-MRI can serve as a novel imaging biomarker for characterizing tissue composition and holds the potential for improving patient stratification and therapy in PDAC. KEY POINTS: Imaging biomarkers are needed to better characterize tumor tissue in pancreatic adenocarcinoma. Signal enhancement ratio (SER)-predicted stromal/epithelial proportion showed good agreement with histopathology measurements across three distinct centers. Signal enhancement ratio (SER)-predicted stromal proportion was demonstrated to be an independent prognostic factor for OS in PDAC.

Syntheses of Linear Biosynthetic C25-Precursors of Leucosceptroids.

An efficient synthetic approach was developed and applied to the syntheses of four linear biosynthetic C25-precursors of leucosceptroids. The synthesis features a Julia-Kocienski olefination and a late-stage bioinspired photo-oxidation as key steps. The immunosuppressive effects of all synthetic compounds on mouse T cells and macrophage RAW264.7 were determined.

A randomized prospective study comparing the effect of low-volume bowel preparations for colonoscopy preparation in China.

AIM: To evaluate the effect of sodium picosulfate/magnesium citrate (SPMC) and 3 L split-dose polyethylene glycol (PEG) with or without dimethicone on bowel preparation before colonoscopy. METHODS: In this multicenter, prospective, randomized, controlled study conducted from April 2021 to December 2021, consecutive adult patients scheduled for colonoscopy were prospectively randomized into four groups: SPMC, SPMC plus dimethicone, 3 L PEG, and 3 L PEG plus dimethicone. Primary endpoint was colon cleansing based on Boston Bowel Preparation Scale (BBPS). Secondary endpoints were bubble score, time to cecal intubation, adenoma detection rate (ADR), patient safety and compliance, and adverse events. RESULTS: We enrolled 223 and 291 patients in SPMC and 3 L PEG group, respectively. The proportion with acceptable bowel cleansing, total BBPS score and cecal intubation time were similar in all four subgroups (p > 0.05). Patient-reported acceptability and tolerability was significantly greater in SPMC than 3 L PEG group (p < 0.001); adverse events were significantly lower in SPMC than latter group (p < 0.001). ADR in both groups was greater than 30%. CONCLUSION: SPMC had significantly higher acceptability and tolerability than 3 L PEG, however, was similar in terms of bowel-cleansing effect and cecal intubation time and hence can be used before colonoscopy preparation.

Unusual immunosuppressive pyridine-containing bisnor- (c23), tetranor- (c21) and pentanor- (c20) sesterterpenoids from Tibetan Leucosceptrum canum.

An unusual pyridine-containing sesterterpenoid, leucosceptrodine (1), and five new nor-leucosceptrane sesterterpenoids, including bisnor- (C23, 2), tetranor- (C21, 3) and pentanor- (C20, 4-6) skeletons, were isolated from the leaves of Tibetan Leucosceptrum canum. Their structures including their absolute configurations were determined by extensive spectroscopic analyses and quantum chemical calculations. A single crystal of one epimer (5) was crystallized from a pair of inseparable epimers, and its structure including its absolute configuration was determined by X-ray crystallographic analysis. The immunosuppressive activities of compounds 1-4 with different potencies were evaluated by inhibiting the secretion of cytokines TNF-α and IL-6 in LPS-induced RAW264.7 macrophages.

Structurally Diverse Alkaloids with Anti-Renal-Fibrosis Activity from the Centipede Scolopendra subspinipes mutilans.

Twelve new alkaloids, scolopenolines A-L (1-7, 9-11, 13, 14), along with six known analogues, were isolated from Scolopendra subspinipes mutilans, identified by analysis of spectroscopic data and quantum chemical and computational methods. Scolopenoline A (1), a unique guanidyl-containing C14 quinoline alkaloid, features a 6/6/5 ring backbone. Scolopenoline B (2) is a novel sulfonyl-containing heterodimer comprising quinoline and tyramine moieties. Scolopenoline G (7) presents a rare C12 quinoline skeleton with a 6/6/5 ring system. Alkaloids 1, 8, 10, and 15-18 display anti-inflammatory activity, while 10 and 16-18 also exhibit anti-renal-fibrosis activity. Drug affinity responsive target stability and RNA-interference assays show that Lamp2 might be a potentially important target protein of 16 for anti-renal-fibrosis activity.

Exploration of the profiles of steroidal saponins from Rhizoma Paridis and their metabolites in rats by UPLC-Q-TOF-MS/MS.

INTRODUCTION: Steroidal saponins characterised by intricate chemical structures are the main active components of a well-known traditional Chinese medicine (TCM) Rhizoma Paridis. The metabolic profiles of steroidal saponins in vivo remain largely unexplored, despite their renowned antitumor, immunostimulating, and haemostatic activity. OBJECTIVE: To perform a comprehensive analysis of the chemical constituents of Rhizoma Paridis total saponins (RPTS) and their metabolites in rats after oral administration. METHOD: The chemical constituents of RPTS and their metabolites were analysed using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS). RESULTS: A reliable UPLC-Q-TOF-MS/MS method was established, and a total of 142 compounds were identified in RPTS. Specifically, diosgenin-type saponins showed the diagnostic ions at m/z 415.32, 397.31, 283.25, 271.21, and 253.20, whereas pennogenin-type saponins exhibited the diagnostic ions at m/z 413.31, 395.30, and 251.20. Based on the characteristic fragments and standard substances, 15 specific metabolites were further identified in the faeces, urine, plasma, and bile of rats. The metabolic pathways of RPTS, including phase I reactions (de-glycosylation and oxidation) and phase II reactions (glucuronidation), were explored and summarised, and the enrichment of metabolites was characterised by multivariate statistical analysis. CONCLUSION: The intricate RPTS could be transformed into relatively simple metabolites in rats through de-glycosylation, which provides a reference for further metabolic studies and screening of active ingredients for TCM.

Five anti-inflammatory compounds from the resins of Liquidambar orientalis.

Five undescribed compounds, including a triterpenoid (1), three phenylpropanoids [(±)-2 and 4], and an aromatic compound (3), as well as six known analogues (5-10), were isolated from the resins of Liquidambar orientalis Mill. Their structures, including absolute configurations, were determined by using spectroscopic and computational methods, and the five new compounds displayed anti-inflammatory activities in LPS-induced RAW264.7 cells.

New triterpenoids from the aerial parts of the Uygur medicine Salvia deserta.

Phytochemical investigation on the aerial parts of Salvia deserta led to the isolation of eight new pentacyclic triterpenoids including three oleanane- (1 - 3) and five ursane-type (4 - 8) triterpenoids, whose structures were elucidated based on extensive spectroscopic analysis and quantum chemical calculation. Weak immunosuppressive potency was observed for compounds 1, 2, and 4 - 8 via inhibiting the secretion of cytokines TNF-α and IL-6 in LPS-induced macrophages RAW264.7 at 20 µM. In addition, compounds 1, 2, and 4 - 6 exhibited moderate protective activity on t-BHP-induced oxidative injury in HepG2 cells.

[Risk factors for ketoacidosis in children/adolescents with type 1 diabetes mellitus and establishment of a predictive model]. / 儿童青少年1åž‹ç³–å°¿ç— æ‚£å„¿å‘ç”Ÿé ®ç—‡é ¸ä¸­æ¯’çš„å±é™©å› ç´ åˆ†æžåŠé¢„æµ‹æ¨¡åž‹çš„å»ºç«‹.

OBJECTIVES: To investigate the risk factors for diabetic ketoacidosis (DKA) in children/adolescents with type 1 diabetes mellitus (T1DM) and to establish a model for predicting the risk of DKA. METHODS: A retrospective analysis was performed on 217 children/adolescents with T1DM who were admitted to General Hospital of Ningxia Medical University from January 2018 to December 2021. Among the 217 children/adolescents,169 cases with DKA were included as the DKA group and 48 cases without DKA were included as the non-DKA group. The risk factors for DKA in the children/adolescents with T1DM were analyzed, and a nomogram model was established for predicting the risk of DKA in children/adolescents with T1DM. RESULTS: For the 217 children/adolescents with T1DM, the incidence rate of DKA was 77.9% (169/217). The multivariate logistic regression analysis showed that high levels of random blood glucose, hemoglobin A1c (HbA1c), blood ketone body, and triglyceride on admission were closely associated with the development of DKA in the children/adolescents with T1DM (OR=1.156, 3.2031015, 20.131, and 9.519 respectively; P<0.05). The nomogram prediction model had a C-statistic of 0.95, with a mean absolute error of 0.004 between the risk of DKA predicted by the nomogram model and the actual risk of DKA, indicating that the model had a good overall prediction ability. CONCLUSIONS: High levels of random blood glucose, HbA1c, blood ketone body, and triglyceride on admission are closely associated with the development of DKA in children/adolescents with T1DM, and targeted intervention measures should be developed to reduce the risk of DKA.

Predicting Microvascular Invasion in Hepatocellular Carcinoma Using CT-based Radiomics Model.

Background Prediction of microvascular invasion (MVI) may help determine treatment strategies for hepatocellular carcinoma (HCC). Purpose To develop a radiomics approach for predicting MVI status based on preoperative multiphase CT images and to identify MVI-associated differentially expressed genes. Materials and Methods Patients with pathologically proven HCC from May 2012 to September 2020 were retrospectively included from four medical centers. Radiomics features were extracted from tumors and peritumor regions on preoperative registration or subtraction CT images. In the training set, these features were used to build five radiomics models via logistic regression after feature reduction. The models were tested using internal and external test sets against a pathologic reference standard to calculate area under the receiver operating characteristic curve (AUC). The optimal AUC radiomics model and clinical-radiologic characteristics were combined to build the hybrid model. The log-rank test was used in the outcome cohort (Kunming center) to analyze early recurrence-free survival and overall survival based on high versus low model-derived score. RNA sequencing data from The Cancer Image Archive were used for gene expression analysis. Results A total of 773 patients (median age, 59 years; IQR, 49-64 years; 633 men) were divided into the training set (n = 334), internal test set (n = 142), external test set (n = 141), outcome cohort (n = 121), and RNA sequencing analysis set (n = 35). The AUCs from the radiomics and hybrid models, respectively, were 0.76 and 0.86 for the internal test set and 0.72 and 0.84 for the external test set. Early recurrence-free survival (P < .01) and overall survival (P < .007) can be categorized using the hybrid model. Differentially expressed genes in patients with findings positive for MVI were involved in glucose metabolism. Conclusion The hybrid model showed the best performance in prediction of MVI. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Summers in this issue.

Application of Intestinal Barrier Molecules in the Diagnosis of Acute Cellular Rejection After Intestinal Transplantation.

Diagnosing acute rejection after intestinal transplantation currently heavily relies on histopathological analysis of graft biopsies. However, the invasive risks associated with ileoscopic examination and the inaccessibility for biopsy after ileostomy closure hinder real-time detection of rejection responses. Molecules comprising the intestinal barrier have been identified as physiological and molecular biomarkers for various bowel conditions and systemic diseases. To investigate the potential of barrier function-related molecules in diagnosing rejection after intestinal transplantation, plasma samples were collected longitudinally from transplant recipients. The samples were categorized into "indeterminate for rejection (IND)" and "acute rejection (AR)" groups based on clinical diagnoses at each time point. The longitudinal association between plasma levels of these barrier function-related molecules and acute rejection was analyzed using the generalized estimating equations (GEE) method. Logistic GEE models revealed that plasma levels of claudin-3, occludin, sIgA, and zonulin were independent variables correlated with the clinical diagnosis of acute rejection. The subsequent prediction model demonstrated moderate ability in discriminating between IND and AR samples, with a sensitivity of 76.0%, specificity of 89.2%, and accuracy of 84.6%. In conclusion, monitoring plasma levels of claudin-3, occludin, sIgA, and zonulin shows great potential in aiding the diagnosis of acute rejection after intestinal transplantation.

Discovery of Unusual Sesterterpenoids from Colquhounia coccinea var. mollis and Their Metabolic Implications.

Three unusual sesterterpenoids featuring unprecedented rearranged colquhounane (C25) and tetranorcolquhounane (C21) frameworks, colquhounoids E (1) and F (3) and norcolquhounoid F (2), were isolated from a Lamiaceae medicinal plant Colquhounia coccinea var. mollis. Their structures were elucidated by spectroscopic analysis and quantum chemical calculations. A biomimetic inspired regioselective cyclopropane cleavage was achieved under acidic conditions. The immunosuppressive activities of these new sesterterpenoids were also evaluated.

Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency.

Aromatic L-amino acid decarboxylase deficiency results in decreased neurotransmitter levels and severe motor dysfunction. Twenty-six patients without head control received bilateral intraputaminal infusions of a recombinant adeno-associated virus type 2 vector containing the human aromatic L-amino acid decarboxylase gene (eladocagene exuparvovec) and have completed 1-year evaluations. Rapid improvements in motor and cognitive function occurred within 12 months after gene therapy and were sustained during follow-up for >5 years. An increase in dopamine production was demonstrated by positron emission tomography and neurotransmitter analysis. Patient symptoms (mood, sweating, temperature, and oculogyric crises), patient growth, and patient caretaker quality of life improved. Although improvements were observed in all treated participants, younger age was associated with greater improvement. There were no treatment-associated brain injuries, and most adverse events were related to underlying disease. Post-surgery complications such as cerebrospinal fluid leakage were managed with standard of care. Most patients experienced mild to moderate dyskinesia that resolved in a few months. These observations suggest that eladocagene exuparvovec treatment for aromatic L-amino acid decarboxylase deficiency provides durable and meaningful benefits with a favorable safety profile.

Changes in blood pressure, oxygen saturation, hemoglobin concentration, and heart rate among low-altitude migrants living at high altitude (5380 m) for 360 days.

BACKGROUND: This article aimed to study the adjustment and adaptation of resting systolic blood pressure (SBP), diastolic blood pressure (DPB), oxygen saturation (SpO2 ), hemoglobin concentration ([Hb]), and heart rate (HR) in low-altitude migrants during a 1-year stay at high altitude. MATERIALS AND METHODS: Our study enrolled 35 young migrants who were exposed to a hypoxia environment at 5380 m altitude on the Qinghai Tibetan Plateau between June 21, 2017, and June 16, 2018. We set 14-time points (the 1st-10th, 20th, 30th, 180th, and 360th day after arriving at 5380 m) for obtaining the measurements of resting SBP, DBP, HR, SpO2, and [Hb] and compared them with the control values recorded prior to migration. Variables with continuous data were summarized as means (SD). One-way repeated measures ANOVA without assuming sphericity was carried out to test whether the mean values (SBP, DBP, HR, SpO2 , and [Hb]) on different days were different significantly. Furthermore, Dunnett's multiple comparisons test was carried out to determine the time points whose values were significantly different from the control values. RESULTS: SBP and DBP were continually increasing within d1-3 and peaked on the 3rd day, then steadily declined from d3 to d30. SBP fell back to the control values on d10 (p > 0.05), and DBP fell back to the control values on d20 (p > 0.05). A significant decline occurred on d180 (p < 0.05). Both SBP and DBP were lower than the control values on d180 (p < 0.05), and this trend was maintained to d360. There were similar characteristics of HR and BP in the time course at HA. HR on d1-3 was increasing (p < 0.05) compared to the control values, after which it fell back to the control values on d180 (p > 0.05), and this trend was maintained to d360. SpO2 was the lowest on d1 and lower than the control value throughout the study at HA (p < 0.05). [Hb] increased after long-term exposure (180 and 360 days) to HA (p < 0.05). CONCLUSIONS: Our study continuously monitored lowlanders at 5380 m in Tibet, and is perhaps the only longitudinal study of migrants conducted at an altitude above 5000 m during a 1-year period. Our study provides new information on the adjustment and adaptation of [Hb], SpO2 , SBP, DBP, and HR in high-altitude plateau migrants during a 360-day stay at an altitude of 5380 m.

Broad Impacts of Coronavirus Disease 2019 (COVID-19) Pandemic on Acute Respiratory Infections in China: An Observational Study.

BACKGROUND: To combat the coronavirus disease 2019 (COVID-19) pandemic, nonpharmaceutical interventions (NPIs) were implemented worldwide, which impacted a broad spectrum of acute respiratory infections (ARIs). METHODS: Etiologically diagnostic data from 142 559 cases with ARIs, who were tested for 8 viral pathogens (influenza virus [IFV], respiratory syncytial virus [RSV], human parainfluenza virus [HPIV], human adenovirus [HAdV], human metapneumovirus [HMPV], human coronavirus [HCoV], human bocavirus [HBoV], and human rhinovirus [HRV]) between 2012 and 2021, were analyzed to assess the changes in respiratory infections in China during the first COVID-19 pandemic year compared with pre-pandemic years. RESULTS: Test-positive rates of all respiratory viruses decreased during 2020, compared to the average levels during 2012-2019, with changes ranging from -17.2% for RSV to -87.6% for IFV. Sharp decreases mostly occurred between February and August when massive NPIs remained active, although HRV rebounded to the historical level during the summer. While IFV and HMPV were consistently suppressed year-round, RSV, HPIV, HCoV, HRV, and HBoV resurged and went beyond historical levels during September 2020-January 2021, after NPIs were largely relaxed and schools reopened. Resurgence was more prominent among children <18 years and in northern China. These observations remain valid after accounting for seasonality and long-term trend of each virus. CONCLUSIONS: Activities of respiratory viral infections were reduced substantially in the early phases of the COVID-19 pandemic, and massive NPIs were likely the main driver. Lifting of NPIs can lead to resurgence of viral infections, particularly in children.

Cerebellar deep brain stimulation for movement disorders.

Deep brain stimulation (DBS) conventionally target at basal ganglia or thalamic structures, modulating nodal points in the cortico-basal ganglia circuit, in order to effectively treat various movement disorders, including Parkinson's disease, tremor and dystonia (especially mobile type dystonia). However, there are still some other movement disorders, such as dystonia (especially fixed type dystonia), ataxia and freezing of gait, which are not responding well to the current DBS therapy. Cerebellum, similar to basal ganglia, also plays a critical role in the pathophysiology of movement disorders. Deep cerebellar structures, such as dentate nucleus or superior cerebellar peduncle, are noticed for their potential role as treatment targets in movement disorders in recent years. With increasing evidences of animal DBS experiments, recent clinical human subject studies reported that some movement disorders patients not responding to DBS with conventional targets, may benefit significantly from cerebellar DBS. These pioneer study results are invaluable for understanding the clinical use of cerebellar DBS for treatment of movement disorders. We review the recent data of cerebellar DBS performed by different groups and summarize the indications, surgical targets, programming details and outcomes in these clinical reports. We then synthesize the current pathophysiological study of cerebellum on different movement disorders and discuss the potential mechanism of action of cerebellar DBS. In addition to basal ganglia, it is important to study new DBS targets in the cerebellum for more comprehensive treatment of movement disorders.