Idiopathic normal pressure hydrocephalus (iNPH) is considered an age-dependent chronic communicating hydrocephalus associated with cerebrospinal fluid (CSF) malabsorption; however, the aetiology of ventricular enlargement in iNPH has not yet been elucidated. There is accumulating evidence that support the hypothesis that various alterations in CSF dynamics contribute to ventricle dilatation in iNPH. This review focuses on CSF dynamics associated with ventriculomegaly and summarises the current literature based on three potential aetiology factors: genetic, environmental and hydrodynamic. The majority of gene mutations that cause communicating hydrocephalus were associated with an abnormal structure or dysfunction of motile cilia on the ventricular ependymal cells. Aging, alcohol consumption, sleep apnoea, diabetes and hypertension are candidates for the risk of developing iNPH, although there is no prospective cohort study to investigate the risk factors for iNPH. Alcohol intake may be associated with the dysfunction of ependymal cilia and sustained high CSF sugar concentration due to uncontrolled diabetes increases the fluid viscosity which in turn increases the shear stress on the ventricular wall surface. Sleep apnoea, diabetes and hypertension are known to be associated with the impairment of CSF and interstitial fluid exchange. Oscillatory shear stress to the ventricle wall surfaces is considerably increased by reciprocating bidirectional CSF movements in iNPH. Increased oscillatory shear stress impedes normal cilia beating, leading to motile cilia shedding from the ependymal cells. At the lack of ciliary protection, the ventricular wall is directly exposed to increased oscillatory shear stress. Additionally, increased oscillatory shear stress may be involved in activating the flow-mediated dilation signalling of the ventricular wall. In conclusion, as the CSF stroke volume at the cerebral aqueduct increases, the oscillatory shear stress increases, promoting motor cilia shedding and loss of ependymal cell coverage. These are considered to be the leading causes of ventricular enlargement in iNPH. Hydrocephalus is characterised by pathological enlargement of the ventricles. Communicating chronic hydrocephalus in adult is synonymous with normal pressure hydrocephalus (NPH) in which the ventricles expand while the intracranial pressure remains within normal range . PatientIn the early 1900s, Cushing proposed the third circulation theory that CSF is secreted by the choroid plexus in the ventricles, flows from the lateral ventricles to the third and fourth ventricles via the foramina of Monro and cerebral aqueduct, moves to the subarachnoid spaces through the foramina of Magendie and Luschka, circulates from the basal cistern to the subarachnoid spaces in the convexity part of the brain, and finally be absorbed into the blood through the arachnoid villi . AlthougCcdc39, Celsr2, Celsr3, Cetn2, Dvls, FoxJ1, Hydin, Mdnah5, Pkd1, Tg737, Daple, Dnah14, Cfap43 and Cwh43 genes, which were related to the structure or function of motile cilia on ependymal cells, have been reported to develop hydrocephalus in animal models [FoxJ1 plays a crucial role in the constant maintenance of motile cilia, and mutation in FoxJ1 causes ciliopathy characterised by foetal hydrocephalus [κB kinase-2 inhibitors [Hydin, a gene that encodes a central pair protein within the axon of motile cilia and expresses ependymal cell layer lining the ventricles, also may induce hydrocephalus when mutated [Mdnah5 is specifically expressed in ependymal cells, and is essential for ultra-structural and functional integrity of ependymal cilia [Pkd1 gene, required for cilia function, and polaris encoded by the Tg737 gene, required for cilia structure, are reported to be crucial mechanosensitive molecules to control fluid flow through primary cilia in endothelial cells [Daple regulates the direction and coordination of motile cilia beating in the ependymal cells, and determines the direction of CSF flow [Daple-deficient mice present communicating hydrocephalus [DAPLE causes autosomal recessive congenital hydrocephalus [DNAH14 results in motile cilia dysfunction was identified in familial cases diagnosed with panventriculomegaly with a wide foramen of Magendie and large cisterna magna (PaVM) that belongs to a subtype of late-onset congenital communicating hydrocephalus [CFAP43, encoding a protein associated with ependymal cilia, was also identified as a cause of familial NPH, and CFAP43 knock-out mice exhibited hydrocephalus due to morphologic abnormality of motile cilia [CWH43 which regulates the membrane targeting of glycosylphosphatidylinositol-anchored proteins were identified in 8 of 53 iNPH patients (15 %), and CWH43 mutant mice exhibited communicating hydrocephalus with gait and balance dysfunction [CWH43 mutant mice appear normal at birth and show no major deficits through middle age, they are considered to be the animal model close to iNPH or late-onset congenital or developmental hydrocephalus. The number of ependymal cilia of CWH43 mutant mice was significantly decreased compared to that of wild type mice, although CWH43 has not been reported to be a gene associated with dysfunction or degeneration of motile cilia and ependymal cells. This review excluded genes that were reported to be associated with cerebral aqueduct stenosis and non-communicating hydrocephalus. These genetic studies provide robust support regarding the importance of ciliary function and offer a commonality among the varied causes of communicating hydrocephalus. However, less is understood on how these gene mutations associated with ciliary dysfunction result in ventricle dilation. Other genes which were reported to cause hydrocephalus in rodents are associated with several inflammatory cytokines. Transgenic mice that overexpressed the transforming growth factor β1 (TGF-β1) die within 3 weeks after developing a severe form of hydrocephalus [hyh mouse, one-third survive longer and exhibit congenital hydrocephalus [Genetic-based pathways offer valuable insights into understanding the underlying mechanisms of communicating hydrocephalus. There has been accumulating evidence which supports the association of ciliary dysfunction lining the ventricle surfaces with congenital hydrocephalus , 34–36. l models . For exacephalus . Hydrocehibitors . Further mutated , 44. Mdnal cilia . Both thal cells , 53. DapCSF flow . Daple-dcephalus , and mutcephalus . Mutatiole cilia . Two delfunction . Becausecephalus . In the cephalus , 57. Hercephalus . TherefoAlcohol abuse during pregnancy is a known risk factor for foetal hydrocephalus , 60. FurIn vivo experiments have shown that the increase in fluid viscosity enhances the dilatation of the vasculature, in parallel with changes in blood viscosity, through the sensitivity of the endothelium to shear stress [Patients with iNPH have a higher comorbidity rate of diabetes, which is more than double, compared with an age-adjusted general population –66; hower stress , 74.A higher frequency of sleep apnoea was reported in iNPH patients in a case-control study . Indeed,In a nested case-control study, hypertension was reported to be a potential risk factor for hydrocephalic ventricular enlargement, which was distinct from ventricular enlargement in iNPH . In rodeCurrent CSF dynamic results suggest that age-related impairment of meningeal lymphatic CSF drainage and glymphatic fluid exchange between CSF and interstitial fluid may contribute to the pathogenesis of iNPH , 82–85. Under normal conditions, the movement of CSF in the cerebral aqueduct is much less than those in the foramen magnum and premedullary cistern , 17 The Oscillation of the shear stress on the vascular endothelial cells has been noted in the pathogenesis of vascular dilation through activation of inflammatory signals , 92–97. in situ hybridisation. Therefore, PTPRQ concentration in the CSF is a good candidate as a CSF biomarker for ventricular enlargement in NPH due to the degeneration of motile cilia on the ependymal cells.Recently, Nakajima et al. reported that iNPH patients had significantly higher concentration of the protein tyrosine phosphatase receptor type Q (PTPRQ) in the lumbar CSF (mean: 619 pg/mL), compared with either healthy control individuals 296 pg/mL), patients with Alzheimer’s disease (365 pg/mL) or Parkinson’s disease (338 pg/mL) . Further96 pg/mL,This review summarises the current literature related to the mechanism of ventricular enlargement in iNPH. Although the aetiology of ventricular enlargement in iNPH has not yet been demonstrated, several reports suggest that the increase oscillatory shear stress on the ventricular wall, shedding of motor cilia and the subsequent loss of ependymal cell coverage may be crucially involved for ventricular enlargement in iNPH Fig. . The cum


Cervical cancer continues to be one of the leading causes of cancer deaths among females in low and middle-income countries. In this study, we aimed to assess the independent prognostic value of clinical and potential prognostic factors in progression-free survival (PFS) in cervical cancer.We conducted a retrospective study on 92 cervical cancer patients treated from 2017 to 2019 at the Zhuhai Hospital of Traditional Chinese and Western Medicine. Tumor characteristics, treatment options, progression-free survival and follow-up information were collected. Kaplan–Meier method was used to assess the PFS.P = 0.002). Kaplan-Meier survival curve analysis showed that cervical cancer patients with initial symptoms age 25–39 had worse survival prognoses (P = 0.020). And the using of uterine manipulator in laparoscopic treatment showed a better prognosis (P < 0.001). A novel discovery of our study was to verify the prognostic values of retrieved lymph nodes count combining with FIGO staging system, which had never been investigated in cervical cancer before. According to the Kaplan-Meier survival curve analysis and receiver operating characteristic (ROC) curve analysis, significant improvements were found after the combination of retrieved lymph nodes count and FIGO stage in predicting PFS for cervical cancer patients .Results showed that the number of retrieved lymph nodes had a statistically significant effect on PFS of cervical cancer patients (Number of retrieved lymph nodes, initial symptoms age, uterine manipulator, and retrieved lymph nodes count combining with FIGO staging system could be potential prognostic factors for cervical cancer patients.The online version contains supplementary material available at 10.1186/s12885-021-08243-3. Globally, cervical cancer is the fourth of the most common cancers among females after breast, colorectal, and lung cancer . In low The prediction of clinical prognostic is the key factor in the therapeutic decision-making process. For cervical cancer, the therapeutic strategy generally depends on the clinical stage, which is established by the FIGO  staging system. The FIGO staging system exposes the extent and aggressiveness of cervical tumor, which is one of the known predictors for survivals. Nevertheless, as the FIGO staging was mainly based on clinical assessment of the anatomic extent, the error rate between the final histopathologic classification and the FIGO staging is about 25% in patients with early stages , 8. HencLymphadenectomy is the standard constituent part of cervical cancer patients treatment , 10. RetTraditional clinical variables, including tumor size, parametrial involvement, and so on, play important roles in the patient prognosis and FIGO staging system . NeverthA total of 100 cervical cancer patients of the Zhuhai Hospital of Traditional Chinese and Western Medicine were followed-up in this study between January 2017 and October 2019. Our daily diagnosis and treatment were in strict accordance with the guideline of the 2017 and 2019 NCCN. Totally, we included 100 cervical cancer patients, in whom 93 patients were cervical cancer of stage I-II, 6 patients were stage III, and the other one patient was cervical cancer stage IVa. According to the guideline, these seven patients were recommended to receive radiotherapy and chemotherapy, and were told that surgical treatment was not recommended. However, these patients insisted and strongly demanded surgical treatment, thus they voluntarily signed up for the surgery and was included in the follow-up plan. The exclusion criteria: according to the guidelines of the NCCN and clinical cervical cancer criteria, patients with previous other tumors receiving chemotherapy as well as radiotherapy and with surgical contraindications that cannot receive surgery were excluded from this study. Among the 100 patients, 7 cases were diagnosed with precancerosis after surgery and one case with relapse were also excluded from following analysis. Finally, there was 92 patients included in the following analysis. Lymph node metastases were diagnosed by pathological examination after lymphadenectomy. This study was approved by the institutional ethics committee and informed consent was obtained from all cervical cancer patients. Follow-up duration was from the date of primary therapy to the date of death or last contact (October 2019).All the patients included in this study received surgical treatment for the first time. Among them, based on the NCCN guidelines and patients’ own decision, 5 patients underwent laparoscopic extensive total hysterectomy and bilateral salpingectomy  and other 87 patients underwent laparoscopic radical hysterectomy, pelvic lymph node dissection and partial para-aortic lymph node dissection. Twenty-four patients were submitted to bilateral salpingo-oophorectomy . The extent of para-aortic lymph node dissection (PALND) transformed from para-aortic lymph node sampling to thorough lymphadenectomy up to the level of the renal vein. Pelvic lymph node dissection (PLND) included dissection of the internal iliac, external iliac, common iliac, and obturator lymph nodes on both sides. Parametrial lymph nodes were removed along with the parametrium. Para-aortic nodes and pelvic lymph nodes were both included in the retrieved lymph nodes count. Surgical techniques will improve over time. At the time of 2017, NCCN guidelines recommend radical total hysterectomy plus bilateral pelvic lymphadenectomy as the preferred surgical option and sentinel lymph node biopsy as an alternative method. Nowadays, sentinel lymph node biopsy is the first choice of surgical method for the patients with tumor less than 2 cm according to the NCCN guidelines [P-value < 0.05 was considered statistically significant. All statistical data were analyzed by using SPSS Statistics 22.0 .Kaplan–Meier method was used to assess the progression-free survival (PFS), and the log-rank test was used to analyze prognostic variables. Receiver operating characteristic (ROC) curve analysis was established to evaluate the prognostic performance of variables. Our study was based on data obtained from 92 cervical cancer patients between January 2017 and October 2019. The clinicopathological characteristics of 92 cervical cancer patients are shown in Table P = 0.020) compared to the initial symptom age 40–75 group  compared to the stage I  compared to the retrieved lymph nodes count 16–30 or 85–105 groups  compared to the group without uterine manipulator  in cervical cancer patients.By generating Kaplan-Meier curves of progression-free survival (PFS), we found that the initial symptom age 25–39 group had significantly worse PFS  compared to the stage I group. In our study, we also found that the squamous cell carcinoma group had significantly longer post-operative bladder catheterization period (P = 0.023) compared to the adenocarcinoma and others group. Particularly, the post-operative bladder catheterization period showed a statistical difference between retrieved lymph nodes count 16–30, 31–85, and 86–105 group (P = 0.013). However, in the comparison of the characteristics of initial symptom age, BMI, HPV, uterine manipulator, obstetrical history and pathological differentiation degree, no significant difference in post-operative bladder catheterization period was observed between the groups .Bladder dysfunction is one of the most usual long-term side effects and complications after radical hysterectomy with the incidence of 8–80%. Our study tried to explore the association between the post-operative bladder catheterization period and potential prognostic factors in cervical cancer by Kruskal-Wallis test. As shown in Table As shown in Fig. P < 0.001), and the Kaplan-Meier plot also showed that Group 1 had higher survival rates than the other groups , and the initial symptom age may be prognostic factor. The relational factors in this result are still unclear. It could not be explained by HPV infection respectively, disease pattern and aggressive characteristics were also potential factor [P = 0.015) compared to the stage II, stage III and stage IV cervical cancer patients [Published researches related to the possible significance of initial symptom age of cervical cancer patient as a prognostic factor are contradictory. In several studies, the prognosis is significantly worse in younger cervical cancer patients , 20. Howl factor . Agreed patients .P < 0.001). Findings of our current study demonstrated that the using of uterine manipulator in laparoscopic treatment showed a better prognosis than patients without uterine manipulator using group. In surgical process of this study, the manipulator was carefully treated and its movements were minimized after placement. The direction should be maintained. The force was controlled as much as possible during the whole surgical process to avoid its violent extrusion of the tumor, which would cause the metastasis of cancer cells. After our observation, if these manipulations above could be achieved, the using of the manipulator could help the surgeon better judging the size of the tumor and surrounding tissue conditions to help patients get better PFS.While being widely adopted, the using of uterine manipulator in laparoscopic treatment represents a controversial issue. Recent studies have demonstrated that laparoscopic surgery was correlated with worse PFS and shorter overall survival than open abdominal approach among cervical cancer patients , 26. UteA novel discovery of our study was to verify the prognostic values of retrieved lymph nodes count combining with the FIGO staging system, which had never been investigated in cervical cancer before. Our study separated cervical cancer patients into four groups according to the retrieved lymph nodes count and the FIGO staging system. Kaplan-Meier survival curve analysis showed that Group 1(stage I disease with retrieved lymph nodes count 31–85) had higher survival rates than the other groups. Receiver operating characteristic (ROC) curve analysis also showed the retrieved lymph nodes count combined with the FIGO stage was better than FIGO staging alone in prognostic prediction for cervical cancer patients. In summary, our study indicates that retrieved lymph nodes count combined with the FIGO stage could be a potential prognostic factor for cervical cancer patients. The combining of retrieved lymph nodes count and FIGO staging system prognostic system would provide added risk stratification, so cervical cancer patients with predicted worse prognosis should receive more aggressive therapeutic regimens.P < 0.05 for all). Based on these results, we raised the possibility that the post-operative bladder catheterization period could be potential indirect acting factor for prognosis of cervical cancer patients. Although it is difficult to demonstrate this hypothesis at present study, further relevant research and verification in the future were expected.To date, there is no reported evidence that the post-operative bladder catheterization period has a direct impact on survival. Intraoperative injury of pelvic floor nerve, ureter and bladder were acknowledged factors that affected the days of catheter removal. The time of catheter removal is related to the scope of the operation. Retrieved lymph nodes count reflects the range of surgical dissection, which was found as prognostic factor in this study. Therefore, this study analyzes correlations between potential prognostic factor and days of catheter removal. As shown in results, in the comparison of tumor stage, retrieved lymph nodes count, and pathological type, significant difference in post-operative bladder catheterization period was observed between the groups  in cervical cancer. Number of retrieved lymph nodes, initial symptoms age, uterine manipulator, and retrieved lymph nodes count combining with FIGO staging system were identified as potential prognostic factors for cervical cancer patients.Additional file 1: Figure S1. Kaplan-Meier curves of PFS in patients with cervical cancer. (a): Number of births; (b): Adjuvant radiotherapy or chemotherapy; (c): P53; (d): Ki-67; (e): ER; (f): PR; (g): BMI; (h): HPV; (i): Pathological type; (j): Pathological differentiation degree. PFS, progression-free survival.


Erythrocytes are oxygen carriers and exposed to redox cycle in oxygenation and deoxygenation of hemoglobin. This indicates that circulating erythrocytes are vulnerable to the oxidative injury occurring under the imbalance of redox homeostasis. In this review article, two topics are presented concerning the human erythrocytes exposed to the oxidative inflammation including septic and sterile conditions. First, we demonstrate rheological derangement of erythrocytes subjected to acute oxidative injury caused by exogenous generators of reactive oxygen species (ROS). Erythrocyte filterability as whole-cell deformability has been estimated by the gravity-based nickel mesh filtration technique in our laboratory and was dramatically impaired in a time-dependent manner after starting exposure to the ROS generators, that is associated with concurrent progression of membrane protein degradation, phospholipid peroxidation, erythrocyte swelling, methemoglobin formation, and oxidative hemolysis. Second, we introduce an impairment of erythrocyte filterability confirmed quantitatively in diabetes mellitus and hypertension of animal models and patients under treatment. Among the cell geometry, internal viscosity, and membrane property as the three major determinants of erythrocyte deformability, erythrocyte membrane alteration is supposed to be the primary cause of this impairment in these lifestyle-related diseases associated with persistent oxidative inflammation. Excessive ROS trigger the inflammatory responses and reduce the erythrocyte membrane fluidity. Oxidative inflammation increasing erythrocyte membrane rigidity underlies the impaired systemic microcirculation, which is observed in diabetic and/or hypertensive patients. On the other hand, elevated internal viscosity caused by sickle hemoglobin polymerization is a primary cause of impaired erythrocyte filterability in sickle cell disease (SCD). However, oxidative inflammation is also involved in the pathophysiology of SCD. The physiologic level of ROS acts as signaling molecules for adaptation to oxidative environment, but the pathological level of ROS induces suicidal erythrocyte death (eryptosis). These findings provide further insight into the ROS-related pathophysiology of many clinical conditions. In contrast, intrinsic antioxidative enzymatic  and non-enzymatic  defense mechanisms scavenge ROS generated in erythrocytes to survive oxidative stress. However, ROS accumulate under pathological conditions out of cellular redox control. Erythrocytes are a primary target of oxidative stress because hemoglobin is an iron-containing protein. Under the cyclic oxygenation and deoxygenation of hemoglobin, heme iron mediates hydroxyl radical generation via iron-catalyzed Fenton reaction as follows (Reactive oxygen species (ROS) such as superoxide anion (O follows :2+) and ferric (Fe3+) states. According to the ROS-induced denaturation of hemoglobin, heme further releases free iron that exerts catalytic actions on various cellular components, and ROS are also generated by degradation of heme  generation as follows  expresses some genes involved in inflammatory pathways and accelerates systemic inflammation . These iCirculating erythrocytes deform to transit through the microcirculation, because the diameter of normal erythrocytes (6–8 μm) is greater than the minimum diameter of capillary network (3–4 μm). Apparent blood viscosity decreases with decreasing microvascular diameter, which is known as the Fahraeus–Lindqvist effect . BecauseP) and flow rate (Q) of erythrocytes suspended in physiological saline with hematocrit adjusted exactly to 3.0% (P-Q relationship fitted by the laminar fluid flow model (P-Q curve). The common features of the microfluidic erythrocyte occlusion and nickel mesh erythrocyte filtration are cost-effectiveness and functional assays of erythrocytes rheology without high-resolution imaging. Considering a small fraction (1–5%) of abnormal erythrocyte subpopulation affecting the whole blood fluid behavior  shows no significant changes during aging . The lea to 3.0% . Very lobehavior , the micbehavior .2+ homeostasis  cell geometry, (2) internal viscosity, and (3) membrane properties of circulating erythrocytes . Biconcaeostasis . Microvaeostasis .ex vivo oxidative injury model. Our laboratory confirmed that erythrocyte deformability is suppressed dramatically by acute oxidative stress generated by 2,2′-azobis(2-amidinopropane) dihydrochloride (AAPH), tertiary-butyl hydroperoxide (tBHP), and superoxide anion (O2•–) produced by hypoxanthine-xanthine oxidase reaction  intracellularly and causes internal oxidation  causing cell dehydration and shrinkage 3COOH; MW = 90.12] are oxidative agents generating alkyl radicals in a time- and dose-dependent manner. AAPH is a representative hydrophilic azo compound, and tBHP is an amphiphilic organic compound. These agents liberate alkyl radicals by thermolysis or photolysis. Extracellular alkyl radical attacks erythrocyte surface membrane leading to the peroxyl radical generation and membrane phospholipid peroxidation. Phospholipid peroxyl radical propagates to the adjacent membrane area reaching the membrane protein of band 3. Hyperoxidized phospholipid bilayer increases non-specific cation permeability, and degradation of membrane proteins of several cation transporters induces Na+ influx and accumulation leading to the osmotic cell swelling in a Ca2+-free medium  to oxidized ferric (Fe3+) state. Methemoglobin was assayed by standard spectrophotometric method (2•–) generated by hypoxanthine-xanthine oxidase reaction (2•–) catalyzed by xanthine oxidase in the hypoxanthine-xanthine oxidase assay  dihydrochloride-treated erythrocytes exhibit dark brown, which is compatible with the formation of methemoglobin due to oxidation of iron in heme from reduced ferrous  at the membrane surface. Oxidative stress activates non-selective cation channels, and massive Ca2+ entry causes the expression of Gardos channels and activates calpain and scramblase  derived from the Maillard reaction contribute to the oxidative inflammation . Acute eHypertension is the main cause of cardiovascular diseases, and oxidative inflammation is deeply involved in the complex pathophysiology of hypertension along with sodium overloading, elevated sympathetic activity, an accelerated renin-angiotensin-aldosterone system that augments oxidative stress leading to endothelial dysfunction, vascular aging and remodeling in hypertensive patients . SpontanSickle cell disease is an autosomal recessive disease affecting millions of people worldwide. This hereditary hemoglobinopathy is caused by a single mutation of the β-globin gene producing abnormal hemoglobin called sickle hemoglobin (HbS). Erythrocyte sickling occurs in the deoxygenated condition by polymerization of HbS . This Hbex vivo human erythrocytes to ROS generators impairs the deformability seriously by chain-reacting auto-oxidation causing methemoglobin formation, membrane phospholipid peroxidation, protein degradation, and subsequent hemolysis. This impairment of circulating erythrocyte deformability in vivo disturbs systemic microcirculation and causes profound tissue hypoxia. Although there is still a gap between the chronic overproduction of ROS under the redox imbalance observed in patients with diabetes, hypertension, SCD, and acute oxidative stress caused by overwhelming ROS generation, the positive feedback amplifying oxidative inflammation is supposed to trigger the eryptosis to avoid intravascular hemolysis and sustain the pathophysiology of aforementioned diseases (via activation of the redox-sensitive nuclear transcriptional factor of NF-κB. Therefore, the concept of reversing the oxidative-inflammatory positive feedback may offer the new therapeutic targets to improve erythrocyte rheology in many clinical conditions.The physiological level of ROS is not only the inevitable byproducts of cellular metabolism but also the signaling molecules enhancing antioxidative defense mechanisms and initiating an inflammatory response to restore the ROS-injured cellular components. As a cellular model of acute oxidative inflammation, exposure of diseases , i.e., rTM had an initial concept of this review article and made manuscript writing. MH was chief of the rheological laboratory, engaged in data acquisition and maintenance of erythrocyte filtration apparatus, and made critique and advice on the manuscript revision. SM was chief of the biochemical laboratory and is involved in the maintenance of the high-performance liquid chromatography separating all the major phospholipids in the erythrocyte membrane. TF was the project leader, applied to the funding, and supervised the team collaboration. All authors approved the manuscript submission to this journal.SM and TF was employed by Institute of Rheological Function of Foods Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The intravenous cocaine self-administration model is widely used to characterize the neurobiology of cocaine seeking. When studies are aimed at understanding relapse to cocaine-seeking, a post-cocaine abstinence period is imposed, followed by “relapse” tests to assess the ability of drug-related stimuli (“primes”) to evoke the resumption of the instrumental response previously made to obtain cocaine. Here, we review the literature on the impact of post-cocaine abstinence procedures on neurobiology, finding that the prelimbic and infralimbic regions of the prefrontal cortex are recruited by extinction training, and are not part of the relapse circuitry when extinction training does not occur. Pairing cocaine infusions with discrete cues recruits the involvement of the NA, which together with the dorsal striatum, is a key part of the relapse circuit regardless of abstinence procedures. Differences in molecular adaptations in the NA core include increased expression of GluN1 and glutamate receptor signaling partners after extinction training. AMPA receptors and glutamate transporters are similarly affected by abstinence and extinction. Glutamate receptor antagonists show efficacy at reducing relapse following extinction and abstinence, with a modest increase in efficacy of compounds that restore glutamate homeostasis after extinction training. Imaging studies in humans reveal cocaine-induced adaptations that are similar to those produced after extinction training. Thus, while instrumental extinction training does not have face validity, its use does not produce adaptations distinct from human cocaine users. Approximately 25 million Americans report use of illicit drugs, including cocaine . Cocaine use disorder (CUD) has one of the highest potentials for abuse and chronic relapse. The risk for relapse persists even after months to years of cocaine abstinence . To date, effective pharmacotherapies to reduce relapse remain elusive. Progress toward this goal requires understanding of the neurobiological mechanisms underlying relapse. Animal models of relapse are critical for determining such mechanisms.The rodent model most commonly used to study relapse is the intravenous self-administration (IVSA) model. Rodents are trained to self-administer cocaine in an operant chamber, wherein an operant response  results in the delivery of IV cocaine. Some, but not all, studies utilize cocaine-paired discrete cues such as a stimulus light and/or tone. After weeks of IVSA, rodents are put through a cocaine-free period which typically involves either simple drug abstinence in the home cage or extinction training. Extinction training involves extinguishing the association of instrumental responses and/or drug-paired cues with drug delivery. Some studies extinguish only the lever-drug association by conducting instrumental extinction in a context distinct from the self-administration chamber. Others extinguish the drug-paired cues, but not the instrumental response. The most common type of extinction used in cocaine reinstatement studies is instrumental extinction in the IVSA context. “Voluntary abstinence” models, where rodents are given a choice between drug and another reinforcer such as palatable food, have been used for methamphetamine and opioid studies, but have yet to be employed for cocaine studies . A punisSuch experimental models of drug relapse are used to screen translational compounds for the treatment of relapse, as well as to identify the neurocircuitry and molecular neuroadaptations underlying such relapse. Thus, it is necessary to use animal models with the highest possible degree of clinical translation. In recent years, attention has been given to the fine details of IVSA-based relapse models, finding that parameters such as length of daily cocaine IVSA access, intermittency of access (vs. continuous cocaine access), and polysubstance use  influence the neurobiology of cocaine seeking ,4,5,6,7.activation of the vmPFC (and its projections to the NA shell) decreases cued-primed reinstatement after 21–28 days of extinction from both short (2 h/day) and extended (6 h/day) access to cocaine self-administration ABP688 find decreased mGlu5 availability in the striatum [As summarized in striatum ,77. ThisDue to reported effects of post-cocaine regimen on glutamatergic protein expression, many drugs targeting the glutamate system have been tested for their ability to attenuate relapse after both extinction training and abstinence. For example, the mGlu5 NAM MTEP attenuates context-primed relapse after abstinence as well as cue-primed relapse after extinction both when given systemically and when infused into the NA core ,48,79. NN-acetylcysteine (60 mg/kg) attenuates cue-primed reinstatement after extinction, it does not reduce context-primed relapse after abstinence [Two drugs that target glutamate homeostasis, the antibiotic ceftriaxone and N-acetylcysteine, have been tested in both extinction and abstinence models. Ceftriaxone attenuates cue-primed reinstatement after extinction and abstinence and context-primed relapse after abstinence ,47,70. Cstinence . Thus, cCeftriaxone has also been tested for its ability to attenuate cued relapse after Pavlovian extinction (cue extinction therapy) of discrete cocaine-paired cues. In this study, the Pavlovian extinction sessions occurred in a context distinct from the self-administration context . The combination of ceftriaxone and cue extinction failed to additively or synergistically reduce cued relapse. This is consistent with two randomized controlled studies in humans with CUD showing that another compound which targets the glutamate system, D-cycloserine, had no effect or a worsening effect on cocaine cue reactivity ,83. It sThese results indicate that learning about cue-cocaine relationships and extinguishing the instrumental response made to obtain drug alter the neurobiology observed in late abstinence from cocaine. Extinction training recruits PFC regions to mediate later relapse. However, these conclusions are based on the work of inactivation studies, and at least one study administering specific GluN2b antagonist into the dmPFC finds a role for this brain region in mediating relapse after abstinence. Future work using more pathway-specific manipulations may find a role for this brain region in mediating relapse after abstinence. In support of this idea, the PFC-NA core pathway is strengthened in abstinence  and glutThere are also differences in expression of the NMDA receptor subunit GluN1 and in surface expression of mGlu5 after extinction compared to abstinence. The differences in mGlu5 expression do not lead to an inability of intra-NA core MTEP to attenuate reinstatement of cocaine seeking after extinction . This isN-acetylcysteine does not reduce ongoing self-administration [What about the construct and criterion validity of extinction and abstinence models? Regarding the protein expression data presented here, only mGlu5 can be visualized in the human brain with the use of radioligands and PET. Akin to what is observed in rodents, striatal mGlu5 availability is decreased in humans with CUD. GluN1 expression is increased following extinction from cocaine in rodents and in human cocaine overdose victims . In termstration  and furtThe field could be advanced by a better understanding of what individuals with CUD experience during drug abstinence. This involves characterizing the context of drug-taking and abstinence. While it has widely been assumed that humans do not undergo abstinence in the same context in which drug-taking occurred, our recent interviews with cocaine users reveal that many use cocaine in their personal automobiles and places of residence. This would indicate that a population of users extinguish their drug-taking context. Whether the discrete drug-paired cues  are also being extinguished is unclear. However, others have found that use occurs outside the home . Pure ab


Endovascular thrombectomy (EVT) has changed the landscape of acute stroke therapy and has become the standard of care for selected patients presenting with anterior circulation large-vessel occlusion (LVO) stroke. Despite successful reperfusion, many patients with LVO stroke do not regain functional independence. Particularly, patients presenting with extremes of blood pressure (BP) or hemodynamic variability are found to have a worse clinical recovery, suggesting blood pressure optimization as a potential neuroprotective strategy. Current guidelines acknowledge the lack of randomized trials to evaluate the optimal hemodynamic management during the immediate post-stroke period. Following reperfusion, lower blood pressure targets may be warranted to prevent reperfusion injury and promote penumbral recovery, but adequate BP targets adjusted to individual patient factors such as degree of reperfusion, infarct size, and overall hemodynamic status remain undefined. This narrative review outlines the physiological mechanisms of BP control after EVT and summarizes key observational studies and clinical trials evaluating post-EVT BP targets. It also discusses novel treatment strategies and areas of future research that could aid in the determination of the optimal post-EVT blood pressure. Large vessel occlusions (LVO) account for approximately one third of ischemic strokes but contribute to more than half of all stroke-related mortality and severe disability –3. Over This narrative review aims to describe the physiological mechanisms of how BP influences outcome after EVT, provide an overview of observational studies, and discuss completed and ongoing clinical trials of BP management after EVT. We will also discuss recent advances in personalized blood pressure management approaches and suggest potential areas of future research.CBF = ABP/CVR  depends on the pressure gradient between the cerebral arteries and veins. The cerebral arterial pressure is equivalent to the systemic arterial blood pressure (ABP), while the cerebral venous pressure is equivalent to the intracranial pressure (ICP) , 10. Cer ABP/CVR , 13.Following vessel occlusion, there is a reduction in CBF to the dependent vascular territory. Below a critical threshold of ~10 ml/100 g brain tissue/min, disruption of ion homeostasis and membrane depolarization lead to a loss of neuronal electrical activity , 15. UnlIschemia-induced vasoparalysis in the penumbra leads to loss of intrinsic autoregulatory function , 20. TheTargeted BP therapies aim to maintain BP below or above a fixed threshold. However, BP is one of the most dynamic physiologic variables with significant changes during the early phase after LVO stroke. Sustained increases in BP variability (BPV) may reflect alterations in the mechanisms responsible for cardiovascular homeostasis and represent a potentially modifiable contributor to end-organ damage and poor neurological recovery after LVO stroke –30. AlthCurrent guidelines by the American Heart Association released in 2019 recommend maintaining a BP goal of ≤ 180/105 for the first 24 h after mechanical thrombectomy . These gSeveral studies have suggested that the optimal BP target may depend on the degree of recanalization , 39, 40.Whether the association between lower post-EVT BP and better functional outcome in patients with successful recanalization is causal or just a reflection of other stroke-related factors, such as better collaterals, remains unclear. However, physiological consideration and the results mentioned above have led many stroke centers to adopt a tiered approach to BP management after thrombectomy stratified by reperfusion status. An online survey regarding BP management post EVT performed across StrokeNet sites in the United States found that most institutions (39%) used a target SBP of 120–139 mmHg on recanalized patients and permissive hypertension on non-recanalized patients . HoweverSeveral observational studies have investigated the effect of differing BP treatment protocols after thrombectomy on radiographic and clinical outcomes. Goyal et al. separated patients into three groups based on post-EVT achieved SBPs of <140, <160, and <180 mmHg. Actual BP targets varied and depended on the treating physician's preference and the patient's clinical status. The investigators found that achieving an SBP goal of <160 mmHg during the first 24 h post-EVT was associated with lower odds of mortality than permissive hypertension . This stBesides BP targets, BPV has emerged as an important aspect of post-EVT hemodynamic management. Studies found that BPV is elevated in patients with larger strokes and associated with higher rates of death and disability in stroke patients that did not undergo EVT , 45. Furpost-hoc analysis of the BEST study, patients were stratified by recanalization status , and high BPV was associated with poor outcomes for patients with TICI 3 exclusively  was a prospective, randomized, multicenter, controlled, open-label trial aimed to evaluate if BP control with a goal of 100–129 mmHg could reduce the incidence of sICH and improve functional outcomes compared to a goal of 130–185 mmHg in successfully recanalized post-EVT patients . A totalSeveral ongoing prospective randomized control trials are further evaluating the impact of BP after successful EVT. The Blood pressure After Endovascular Stroke Therapy  is a phase 2 clinical trial that randomly assigns patients with TICI 2b-3 to BP targets of ≤140, ≤160, and ≤180 mmHg. These BPs will be maintained for 24-h post-EVT, and the outcomes measures will be final infarct volume at 36-h and 3-month mRS. The Outcome in patients Treated with Intraarterial Thrombectomy- Optimal Blood Pressure Control  is a clinical trial evaluating the impact of SBP targets <140 vs. <180 mmHg on 36-h sICH, 90-day mRS, and mortality on patients with successful reperfusion after EVT. Similarly, the Second Enhanced Control of Hypertension and Thrombectomy Stroke Study  trial will assign patients to an SBP target of <120 vs. 140–180 mmHg during the first 72 h after EVT to evaluate the effect on 90-day mRS. Finally, the Invasive Control of Blood Pressure in Acute Ischemic Stroke After Endovascular Therapy on Clinical Outcomes  trial will compare SBP targets of <140 and <120 mmHg on 90-day sICH and mRS. All ongoing clinical trials will evaluate patients with successful EVT with TICI 2b-3, which is achieved in over 80% of patients with modern EVT techniques. The results of these trials will provide much-needed high-quality evidence and inform blood pressure management after thrombectomy. A summary of completed and ongoing prospective studies can be found in Despite the consistent findings of better outcomes with lower post-thrombectomy BP, reducing BP to the same fixed target may be an oversimplification of the complex physiology. The neutral results of the BP TARGET trial suggest that stratification by reperfusion status may be inadequate for the heterogenous EVT patient population. A one-size-fits-all approach does not account for individual patient factors such a collateral status, infarct size, or history of hypertension. For example, a patient with chronic hypertension may have a rightward shifted autoregulatory curve , and aggBesides maintaining BP below a fixed, predetermined value, there is a strong rationale for a more personalized BP management. We recently compared fixed vs. personalized autoregulation-oriented BP thresholds after EVT . Near-inAnother easily implementable and generalizable approach to personalized BP management is currently being tested in the Effect of Individualized vs. Standard Blood Pressure Management during Mechanical Thrombectomy for Anterior Ischemic Stroke Trial . The study will compare maintaining the BP within 10% of the first MAP measured in the angiography suite vs. a fixed blood pressure goal of 140–180 mmHg. Selecting BP targets based on an individual patients' baseline BP could represent a valid method to incorporate patient-specific factors without the need for advanced monitoring. A similar approach could potentially also be implemented in the post-EVT setting.post-hoc analyses of these trials will be necessary to assess if stroke or patient characteristics have any effect on outcome.Management of hemodynamics in the post-EVT patient is complex and requires careful BP control to ensure adequate CBF to supply the ischemic penumbra while avoiding reperfusion injury. Several clinical trials are underway to evaluate different fixed BP thresholds after EVT with successful recanalization. These studies will provide insight and guidance on the optimal post-EVT BP target. Still, future Patients with high SBP trajectories during the first 24 h after mechanical thrombectomy are at increased risk of an unfavorable outcome. Future research should focus on the early identification of patients with high-risk trajectories that are most likely to benefit from intense post-EVT BP management. Autoregulation-guided blood pressure management may present an elegant alternative over the classical approach of maintaining blood pressure below a fixed, predetermined value. Clinical trials are needed to test autoregulation-based treatment strategies, including tailored pharmacologic blood pressure augmentation and lowering therapies based on patients' real-time autoregulatory status. Parallel lines of inquiry have begun in Europe targeting autoregulation in traumatic brain injury, further suggesting that this approach is timely and feasible in a multicenter clinical trial.Other approaches to post-EVT BP management include the reduction of potentially harmful BP fluctuations. There is ample evidence showing that higher BPV is associated with worse functional outcomes and increased ICH risk. Although it is unclear if this is causative or an epiphenomenon related to the stroke itself, studies aiming to decrease BPV should be pursued , 51, 53.Cerebral perfusion optimization in the immediate post-EVT period is a research priority in acute stroke. Current research is focused on elucidating the best hemodynamic biomarker for defining and monitoring the ideal BP target after stroke. Results from ongoing and future clinical trials will be critical to reduce reperfusion injury and maximize neurological recovery for all stroke patients undergoing endovascular therapy.NP conceived the review. TP drafted the manuscript. SO-G, AH, and NP made critical revisions to the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The COVID-19 pandemic has led to disruptions in elective and outpatient procedures. Guidance from the Centers for Medicare and Medicaid Services provided a framework for gradual reopening of outpatient clinical operations. As the infrastructure to restart endoscopy has been more clearly described, patient concerns regarding viral transmission during the procedure have been identified. Moreover, the efficacy of the measures in preventing transmission have not been clearly delineated.We identified patients with pandemic-related procedure cancellations from 3/16/2020 to 4/20/2020. Patients were stratified into tier groups (1–4) by urgency. Procedures were performed using our hospital risk mitigation strategies to minimize transmission risk. Patients who subsequently developed symptoms or tested for COVID-19 were recorded.Among patients requiring emergent procedures, 57.14% could be scheduled at their originally intended interval. COVID-19 concerns represented the most common rescheduling barrier. No patients who underwent post-procedure testing were positive for COVID-19. No cases of endoscopy staff transmission were identified.Non-COVID-19 related patient care during the pandemic is a challenging process that evolved with the spread of infection, requiring dynamic monitoring and protocol optimization. We describe our successful model for reopening endoscopy suites using a tier-based system for safe reintroduction of elective procedures while minimizing transmission to patients and staff. Important barriers included financial and transmission concerns that need to be addressed to enable the return to pre-pandemic utilization of elective endoscopic procedures. Since the first documented case of COVID-19 in the United States (US) on January 21, 2020, many hospitals have had to enact strict measures to prevent further spread of the virus among the population. The pandemic has led to widespread disruptions in the performance of elective and outpatient procedures. Endoscopic procedures were especially affected by these disruptions due to high rates of aerosolization of the virus by upper endoscopy, viral shedding in the stool, and potential contamination of endoscopy suite surfaces with viable virus up to 72 h after initial contact , 1413, 1Suspending non-urgent endoscopic procedures has serious clinical and financial implications. Approximately 18 million endoscopic procedures are performed annually in the US with an estimated annual healthcare cost of $32.4 billion , 17. TheWith the progression of the COVID-19 pandemic, multiple best practice guidelines have emerged regarding pre-procedure, peri-procedure, and post-procedure risk mitigation strategies. One particular study analyzed the consensus of effectiveness of these strategies among multi-national large endoscopy departments using a modified Delphi method . Many ofTo conclude, our tiered approach for rescheduling while following strict risk mitigation strategies allowed for successfully resuming outpatient endoscopic procedures keeping patients as well as endoscopy staff safe and protected from COVID-19 transmission. Patients who opted to proceed with their procedures were successfully accommodated with 15 min additional time allotted to room cleaning and turnover per case. Additionally, our mitigation measures resulted in no transmission of COVID-19 cases that could be traced back to exposure during endoscopy. Future studies regarding procedural transmission of COVID-19 in the asymptomatic population may further allay patient fears. However, the financial impact of this pandemic will continue to be a stubborn remnant from this novel virus, delaying patient care and impacting utilization of endoscopy in the future.By implementing a tiered approach to reschedule patients undergoing elective endoscopy during the height of the COVID-19 pandemic with strict risk mitigation strategies, our institution was able to safely restart outpatient endoscopy to minimize delays in endoscopic diagnosis and patient care. All patients deemed higher risk that were willing to undergo endoscopy were accommodated for. The main barrier to rescheduling was public perception of safety. The risk mitigation measures taken allowed for zero transmission of COVID-19 among patients and staff members.


Many tuberculosis (TB) patients incur catastrophic costs. Active case finding (ACF) may have socio-protective properties that could contribute to the WHO End TB Strategy target of zero TB-affected families suffering catastrophic costs, but available evidence remains limited. This study measured catastrophic cost incurrence and socioeconomic impact of an episode of TB and compared those socioeconomic burdens in patients detected by ACF versus passive case finding (PCF).This cross-sectional study fielded a longitudinal adaptation of the WHO TB patient cost survey alongside an ACF intervention from March 2018 to March 2019. The study was conducted in six intervention (ACF) districts and six comparison (PCF) districts of Ho Chi Minh City, Viet Nam. Fifty-two TB patients detected through ACF and 46 TB patients in the PCF cohort were surveyed within two weeks of treatment initiation, at the end of the intensive phase of treatment, and after treatment concluded. The survey measured income, direct and indirect costs, and socioeconomic impact based on which we calculated catastrophic cost as the primary outcome. Local currency was converted into US$ using the average exchange rates reported by OANDA for the study period . We fitted logistic regressions for comparisons between the ACF and PCF cohorts as the primary exposures and used generalized estimating equations to adjust for autocorrelation.p = 0.033), but incurred lower median pre-treatment costs  and lower median total costs . Fewer ACF patients incurred catastrophic costs (15 % vs. 30 %) and had lower odds of catastrophic cost , especially during the intensive phase . ACF patient experienced less social exclusion , but more often resorted to financial coping mechanisms .ACF patients were poorer than PCF patients (multidimensional poverty ratio: 16 % vs. 7 %; ACF can be effective in reaching vulnerable populations and mitigating the socioeconomic burden of TB, and can contribute to achieving the WHO End TB Strategy goals. Nevertheless, as TB remains a catastrophic life event, social protection efforts must extend beyond ACF.The online version contains supplementary material available at 10.1186/s12913-021-06984-2. Tuberculosis (TB) disproportionally affects the poorest segments of society . EconomiDespite recent rapid economic development, Viet Nam remains a high TB burden country. There were 170,000 incident cases and 11,400 TB-related mortalities in 2019 . This crWith a treatment coverage rate of 60 %, there remains a pool of undetected TB and sustained transmission in the community . Active This study aimed to assess the socioeconomic impact and socio-protective potential of ACF by obtaining a longitudinal measure of the financial burden of DS-TB treatment and comparing costs in patients detected through active versus passive case finding.This cross-sectional study fielded a longitudinal cost survey from March 2018 to March 2019 alongside an intervention. The intervention consisted of ACF among household and close contacts, and persons living in presumptive hotspots, boarding homes and urban slums implemented by community health workers (CHW). All household contacts and other targeted persons with symptoms suggestive of TB were referred for chest x-ray screening and sputum testing by rapid molecular assay or smear microscopy. The CHWs supported patients to initiate and adhere to treatment. Patients in the PCF districts received routine care as per national treatment guidelines. The intervention is described in detail elsewhere .The study took place in 12 districts of Ho Chi Minh City (HCMC), Viet Nam ; digital data were checked against the paper surveys to ensure data entry accuracy. All costs were collected in Viet Nam Dong (VNĐ) and converted to US dollars (US$) using the average 2018–2019 exchange rates reported by OANDA for the study period (VNĐ1 = US$0.0000436) . We presented participant demographic, clinical and socioeconomic characteristics. We employed an adapted multidimensional poverty index for TB (MPI-TB) using the Alkire-Foster method to profile a participant’s socioeconomic status –27. The For each treatment period, we collected monthly personal and household income and estimated direct medical, direct non-medical and indirect costs incurred. Direct medical costs included medications, diagnostic tests, consultations and hospitalization fees. Direct non-medical costs included spend on transportation and food. Indirect cost consisted of income loss, which was self-reported by the patient. For those patients who could not provide this information, we calculated income loss by using the self-reported number of working hours/days lost multiplied by the hourly (US$0.90) or daily (US$7.00) minimum wage for Region 1 in Viet Nam . IndirecWe reported the frequency of financial coping mechanisms used, loss of employment, reduction in work hours, lower wage levels or the transfer to a lower paying position or job. We estimated ratios of catastrophic costs and poverty headcount. To estimate catastrophic cost, we applied the WHO definition  of totalChi-square and Fisher’s exact tests were used to determine statistical differences in proportions of categorical variables. Wilcoxon rank-sum tests were used to compare median costs between the ACF and PCF cohorts. We excluded missing data and reported denominators that deviated from the total sample size. Univariate and multivariate logistic models were fitted to measure the association between catastrophic costs incurrence and ACF/PCF cohort alongside other demographic and socioeconomic patient characteristics. Differences in socioeconomic impact and catastrophic costs in individual treatment periods were analyzed by fitting univariate population-averaged logistic regression models using generalized estimation equation methods with working correlation structures based on Quasi-likelihood Information Criteria. Hypothesis tests were two-sided. P-values below 0.05 were considered statistically significant. Data analysis was performed in Stata v15 .Approvals were granted by the Liverpool School of Tropical Medicine Research Ethics Committee (17–019) and Pham Ngoc Thach Provincial TB Hospital Institutional Review Board (430/HDDD-PNT). The implementation of the interventions was approved by the HCMC People’s Committee . The NTP approved use of programmatic treatment data. All protocols were carried out in accordance with relevant guidelines and regulations. Before the interview, we provided a written participant information sheet, a verbal explanations of the study and an opportunity to ask questions to ensure all participants were aware of the study. All participants provided informed written consent. All data were anonymized prior to analysis.One-hundred invited individuals agreed to participate in the survey, but two did not complete the final interview. Thus, the final study sample consisted of 98 participants, 46 PCF and 52 ACF, for a total of 294 survey encounters. Most patients were male (62/98 = 63 %) Table . ACF patThere were fewer new TB patients in the ACF cohort  and fewer pre-treatment hospitalizations  than among PCF patients. ACF patients reported fewer visits to health facilities before initiating treatment (262 vs. 366) with a significantly higher share of ACF patients accessing NTP services compared PCF patients . Conversely, the rate of health-seeking in non-NTP public healthcare facilities  and private healthcare providers  was significantly lower in ACF patients.Prior to TB treatment, the monthly median personal income was significantly lower in the ACF cohort compared to the PCF cohort in the pre-treatment  and continuation phase  , and significantly lower indirect costs  and income loss .Fewer ACF patients incurred catastrophic costs than PCF patients 15 % vs. 30 %) and ACF patients had significantly lower odds of catastrophic cost  . However, patients in the ACF cohort also had a significantly higher risk of resorting to financial coping mechanisms during the continuation phase .We found that ACF significantly reduced catastrophic cost incurrence. Specifically, the study showed a lower proportion and odds of households experiencing catastrophic cost in the ACF cohort compared to the PCF cohort. This was potentially due the higher unemployment and income loss in the PCF cohort, which subsequently amplified the socio-protective effects of ACF. This is concordant with findings from other settings , 31.Compared to the country  and regiOne critical yet underemphasized benefit of ACF is the ability to reach more marginalized populations and increase equity in TB care , 37. OurIt may be that the ACF cohort was unable to afford other alternatives, and therefore were receptive to the CHW’s referral to the NTP. This is also supported by our finding that ACF did not significantly reduce the time between symptom onset and treatment initiation, i.e., diagnostic delays, as observed in other settings . ParticuThe reduction in health facility visits resulting from CHW referrals to the NTP optimized the patient pathway and likely helped to reduce costs among ACF patients. A systematic review of TB-related patient costs in sub-Saharan Africa shows that policies and programs improving access to healthcare has the potential to reduce pre-treatment costs, though the optimal modality for reducing costs to patients remains unknown . ACF patIt is important to note that within our study sample, the PCF cohort reported significantly higher pre-treatment individual and household incomes. However, once TB was diagnosed and treatment commenced we observed no significant differences between the PCF and ACF cohorts. This either suggests that TB had a greater impoverishing effect on PCF patients or could also mean that better socioeconomic conditions afforded the freedom to forego income-generating activities. This is supported by the higher rates of formal employment among PCF patients, who were more likely to benefit from statutory job protections, such as paid sick leave and protection from unlawful termination .Through the longitudinal design of our study, we were able to observe a near-full recovery of household income loss and employment in both cohorts during the continuation phase. The recovery was likely a consequence of TB patients returning to work to recover from the loss in productivity experienced during the illness, whether it was related to directly observed treatment, TB-related disability or statutory leave during the intensive phase. A similar longitudinal survey conducted among ACF and PCF TB patients in Nepal did not show any income recovery during treatment. This discordance was possibly a result of Viet Nam’s stronger economy, which offered more employment options after the completion of TB treatment, a greater ability for TB patients to re-enter the job market, and to recover from the deleterious socioeconomic impact of TB.The socioeconomic burden throughout individual treatment phases requires further investigation, but our findings that the burden was highest during the intensive phase may inform and optimize social protection mechanisms. As attention to social protection schemes, such as cash transfers, is increasing,  it may bOur study was subject to recall and social desirability bias. We believe the longitudinal design of the survey and audit of receipts mitigated the impact of these limitations, but also required a concerted effort to remind patients of the period in question when assessing costs, as well as time and income losses. Focusing solely on HCMC biased our data towards a higher socioeconomic class and limited the generalizability of our findings in the national and international context. As the study was conducted under programmatic conditions, patient follow-up was periodically affected by supply chain and program irregularities. Through close collaboration with the provincial and national TB control programs, we tried to minimize the impact of these irregularities.ACF can be effective in reaching vulnerable populations and mitigating the socioeconomic burden of TB. Programs should consider ACF a key strategy to support TB-affected families and achieve the WHO End TB Strategy goals. Nevertheless, as TB remains a catastrophic life event, social protection efforts must extend beyond ACF. Given resource limitations, it may be possible to focus these efforts on TB patients in the intensive phase of treatment so that more TB–affected families can receive support.Additional file 1:


To explore an effective algorithm based on artificial neural network to pick correctly the minority of pregnant women with SLE suffering fetal loss outcomes from the majority with live birth and train a well behaved model as a clinical decision assistant.We integrated the thoughts of comparative and focused study into the artificial neural network and presented an effective algorithm aiming at imbalanced learning in small dataset.We collected 469 non-trivial pregnant patients with SLE, where 420 had live-birth outcomes and the other 49 patients ended in fetal loss. A well trained imbalanced-learning model had a high sensitivity of 19/21 (The misprediction of the two patients was explainable. Algorithm improvements in artificial neural network framework enhanced the identification in imbalanced learning problems and the external validation increased the reliability of algorithm.The well-trained model was fully qualified to assist healthcare providers to make timely and accurate decisions.The online version contains supplementary material available at 10.1186/s12911-021-01486-x. Systemic lupus erythematosus (SLE) is a multi-systemic autoimmune disease, affecting predominantly women of childbearing age . The preThe pregnancy of SLE patients is regarded as high-risk events due to high incidence of obstetric complication  and SLE flare, which results in adverse maternal and fetal outcomes . Recentlument}%) –5. Fetalument}%) . Predictument}%) . The sevArtificial neural network (ANN) –11, a maWith scarce clinical samples and imbalanced pregnant outcomes of pregnant SLE patients, conventional algorithms including ANNs, can not identify the minority of pregnant women with SLE suffering fetal loss outcomes . Such imAn alternate approach to imbalanced learning is the tree-based ensemble methodology which integrates several classifier modules to aggregate their predictions. Ensemble methodologies, such as bagging-based, boosting-based, gradient tree boosting algorithms and extreme gradient boosting (XGBoost) have good performances in some specific situations –33. In tInclusion Criteria: Pregnant patients with SLE who had established archives and labored in Ren Ji Hospital from September 2011 to June 2018; no limitation to age and gestational weeks; SLE classification diagnostic criteria were according to the 1997 American College of Rheumatology (ACR) revised SLE classification criteria .Exclusion criteria: Multiple gestation or abortions due to personal reasons were excluded.469 pregnant women with SLE who met the above criteria had been included in this study. Among them, 49 cases had fetal loss, and the remaining 420 cases had live births, with a fetal loss rate of  samples , random A retrospective collection of pregnant SLE patients with an electronic medical records (EHR) was performed in the Department of Obstetrics and Gynecology, Ren Ji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from September 2011 to June 2018.Live birth: the birth of a living baby .Spontaneous abortion: spontaneous termination of a pregnancy before 28 weeks of gestation .Therapeutic abortion: abortion for therapeutic reasons as the pregnancy might threat maternal health, such as a life-threatening SLE flare or other severe obstetric complications Stillbirth or intrauterine fetal deaths: any baby born without signs of life after 28 weeks of gestation Fetal loss: defined as all pregnancies that did not end with live birth , includiPre-gestational SLE status—Remission stage: a patient takes a low dose of or has stopped prednisone treatment without clinical manifestations of SLE activity for more than 6 months prior to conception Pre-gestational SLE status—Active stage: a patient presents clinical manifestations of SLE activity. Disease activity was evaluated according to the SLE Disease Activity Index 2000 (SLEDAI-2K) Pre-gestational SLE status—Initial onset: a new onset or diagnosis of SLE during pregnancyNephritis: proteinuria Cutaneous lesion: including malar rash, discoid rash, photosensitivity, oral ulcersHematological disorder: including hemolytic anemia with elevated reticulocytes, leukopenia Arthritis: nonerosive arthritis Serositis: pleural effusion, pericarditisSLE clinical manifestations: including nephritis, cutaneous lesion, hematological disorder, arthritis, serositis Nephritisx. No data were missing except some in 24-hour-urinary protein level and we filled them in a reasonable way.SLE-affected pregnant patients with a live birth outcomes were regarded as negatives and ones with fetal loss outcomes were positives. 29 medical indices from patients’ data  represented the number of fetal loss samples (labeled positive) in the ith batch. In consideration of divisibility, we set the batch size as 13 in this paper.In our work, we integrated such thoughts of comparative and focused study , 35, 48 Aiming at finding fetal loss patients to the greatest extent, we set sensitivity, which measures the percentage of pregnant patients with fetal loss who are correctly identified, as the most significant evaluation index. Accuracy is also an important index computing the correct prediction percentage all over samples. Specificity is the extent to which actual negatives are correctly identified as such. Some other metrics like F1-score, Precision Recall Area Under Curve (PR-AUC) and Matthews correlation coefficient (MCC) are also used as the evaluation indices.Stochastic optimization algorithm, concretely speaking stochastic gradient descent, is used to train the neural network with randomly initialized weights. In the phase of parameter establishment, to overcome the contingency and generalize the results, we trained about 120 neural networks with both random initialization of weights and randomly-selected samples. For each network, random 234 out of 338 samples were put in the training set and the remaining 104 ones, not used for training, were tested and predicted in the calculation of evaluation indices . Some networks, which were not convergent in the training process or performed totally wrong test results, were excluded and then we averaged the remaining indices to determine network parameters.Given optimal parameters , we trained thousands of neural networks in the phase of classified prediction and picked the one with a high sensitivity and comprehensive consideration of accuracy and specificity.In ANN, each neuron in the hidden layer conducts a nonlinear function on the input and learns some knowledge by mapping from medical indices to predictive categories. Redundant neurons lead to an over-fitting while insufficient ones give an incomplete expression. In order to establish the number of artificial neurons in the hidden layer, we selected sensitivity as the key indicator. Given In the previous literature, cost-sensitive learning was used to modify the cost of misclassification in the decision process . We made5-Δ Fig. b.lr based on the label of this sample:The seminal work of dealing with imbalanced data made cost-sensitive modifications of the back-propagation learning algorithm in the ANN framework  and the entclass1pt{minimaFigure Subsequently, we established the number of artificial neurons in the hidden layer in Fig. Given the optimal network parameters, we trained thousands of neural networks . Training is stopped to avoid overfitting when the sum squared error on the validation set has begun to rise. We then picked one with high performance  using DMwR package in R [XGBoost and AdaBoost were firstly implemented in R using xgboost and JOUSBoost package.  We then performed the SMOTE algorithm with nine combinations of the parameters  had a 13-year SLE history and her assessment before pregnancy showed a remission stage of illness. During the gestation, her state of illness kept quiescent in clinical manifestation and laboratory test, but she suffered preterm premature rupture of membranes (PPROM) at The other misdiagnosed patient  of the hospital and were not included in this study. Moreover, the black-box nature of the algorithm  makes itAdditional file 1: Video 1. Trade-off between sensitivity and specificity with dynamically varying Δ from -20% to 25%


The accurate segregation of chromosomes is essential for the survival of organisms and cells. Mistakes can lead to aneuploidy, tumorigenesis and congenital birth defects. The spindle assembly checkpoint ensures that chromosomes properly align on the spindle, with sister chromatids attached to microtubules from opposite poles. Here, we review how tension is used to identify and selectively destabilize incorrect attachments, and thus serves as a trigger of the spindle assembly checkpoint to ensure fidelity in chromosome segregation. Tension is generated on properly attached chromosomes as sister chromatids are pulled in opposing directions but resisted by centromeric cohesin. We discuss the role of the Aurora B kinase in tension-sensing and explore the current models for translating mechanical force into Aurora B-mediated biochemical signals that regulate correction of chromosome attachments to the spindle. Organisms package their genetic material into chromosomes; faithful segregation of these structures through cell division is critical as mistakes can lead to disease, infertility and congenital defects ,2. EukarThe accuracy of chromosome segregation is protected by the spindle assembly checkpoint (SAC) which monitors kinetochore-microtubule attachments and activates in response to errors. The SAC delays anaphase until all chromosomes are bi-oriented on the spindle . The cheDrosophila kinetochore microtubules exerting 12–62 pN of force each and thus their kinetochores experiencing 144–764 pN of tension [Chromosomes that are correctly attached to the spindle experience mechanical pulling forces that generate tension across the sister chromatids A. Bi-ori tension . Budding tension .The tension force generated on correctly attached sister chromatids stabilizes and increases kinetochore-microtubule attachments ,32,33. NHistorically, mechanistic explanations of the SAC activation by mis-attached chromosomes have fallen into two competing camps: one stating that unattached kinetochores trigger the SAC, and the other pointing to lack of tension on kinetochores. The tension model was originally based on Nicklas’ manipulation of force on chromosomes. In addition to demonstrating that tension stabilized attachments, Nicklas also showed that exerting tension on incorrectly attached chromosomes induced metaphase-arrested cells to enter anaphase . In contStudies in budding yeast have provided a simplified approach to tension vs attachment. With a single microtubule attaching per kinetochore, budding yeast have binary attachment status that eliminates the complication of multiple microtubules attachments per kinetochore . TensionRecent studies have also supported tension-independent pathways regulating SAC activation. Borealin, a member of the Chromosome Passenger Complex involved in Aurora B localization, was shown to regulate SAC activity independent of tension. Disruption of a microtubule-binding domain in Borealin resulted in increased attachment errors, disrupted SAC signaling, and decreased phosphorylation of incorrect attachments regardless of tension state . In otheDistinguishing between tension and attachment in SAC activation and error correction is complicated by their inter-relationship. As described above, the two have a positive feedback relationship wherein tension stabilizes and promotes attachment, leading to increased attachments ,31,32. ATension regulates the SAC and the correction of erroneous attachments, but the location of tension-sensing is still unclear. When sister chromatids are correctly attached to opposite poles, both kinetochores ,59,60 anDrosophila S2 cells display reduced inter-kinetochore stretch but not intra-kinetochore stretch; the cells did not activate the checkpoint [Kinetochores have been shown to elongate under tension and this intra-kinetochore stretch is the other proposed site of tension-sensing ,59,73,74The Aurora B kinase is the critical regulator of tension-based response to chromosome attachments. Originally identified in a budding yeast screen to identify genes involved in the regulation of chromosome segregation, Aurora B (Ipl1 in yeast) was responsible for changes in ploidy . WithoutDrosophila meiosis, point mutations in the IN-Box cause increased segregation errors, including early separation of sister chromatids in meiosis I [Aurora B is regulated and localized on chromosomes via the chromosome passenger complex (CPC) consisting of three non-enzymatic subunits: Borealin, Survivin and INCENP . Borealieiosis I .Localization of Aurora B and the CPC is critical for proper chromosome segregation. During prometaphase and metaphase, the CPC localizes at the inner centromere, then relocates to the spindle midzone in anaphase  where itC. elegans [Aurora B targets multiple proteins for phosphorylation in response to erroneous attachments including kinetochore proteins, CPC members, and spindle checkpoint components. Phosphorylation of outer kinetochore proteins in the KMN network  triggers a release of microtubule attachment ,44. The  elegans . Phospho elegans ,106,107  elegans . Aurora  elegans . Phospho elegans . While n elegans ,111. Pho elegans .C.elegans and HeLa cells have also shown that Aurora B phosphorylation of the C-terminus of INCENP stimulates greater kinase activity, resulting in a positive feedback loop that reinforces kinase activity at kinetochores [Aurora B has also been shown to phosphorylate CPC members: INCENP and itself. Phosphorylation of INCENP by Aurora B affects its ability to bind microtubules, which impairs its migration to the spindle midzone in anaphase ,113. Stutochores ,115. Aurtochores , its mittochores  and accutochores .Xenopus immunodepletion assays showed that Aurora B also controls the localization of checkpoint proteins Mps1, Bub1 and Bub3, which inhibits downstream SAC signaling and complex formation [Aurora B promotes the activation and maintenance of the SAC signaling. Inhibition of Aurora B through ZM447439 drug treatment prevented the kinetochore localization of SAC proteins BubR1, Mad2, and CENP-E . Additioormation . More reormation  as well ormation .Many models have been proposed to explain the Aurora B-based translation of mechanical tension into biochemical signaling, and they generally group into three categories: (1) spatial separation models, where Aurora B is physically separated from its targets by tension, (2) tension-sensitive activation models, where the activity of Aurora B is modulated by another protein in response to tension, and (3) kinetochore localization models, where a subpopulation of Aurora B localizes on kinetochores in early mitosis when tension is low, and (4) a new model in which the downstream effects of Aurora B phosphorylation are differentiated by tension rather initial sensing by the kinase.Spatial separation models are based on the localization of Aurora B within the inner centromere where it is proposed that the kinase remains constitutively active after initial activation . Under lRecent studies have yielded two variations of the spatial separation model: the dog leash model and the centromere gradient model . The dogAn alternative spatial separation model is based on a gradient of Aurora B where kinase activity is high near the inner centromere B. When tIn contrast to spatial separation models where an active Aurora B kinase cannot reach its targets, tension-sensitive models posit that the activity of Aurora B is regulated by tension. This regulation can occur via a “tensiometer”, a spring-like protein that alters Aurora B activity, or via inhibitory proteins that counteract Aurora B. Several proteins have been proposed to act as a spring regulator including INCENP  due to iAurora B regulation in response to tension has also been proposed through balance of inhibitory activities. Protein phosphatases PP1 and PP2A localize to the outer kinetochore , with PPRecent studies on Aurora B localization has revealed three distinct pools of the kinase ,101,102.A new model has been proposed based on kinetochore-localized Aurora B in which the kinase is directly recruited to kinetochores where it phosphorylates targets until it is displaced by tension, either through conformational change of binding sites or by active eviction . RemainiThe models outlined above are based on the premise that Aurora B is responsive to tension, either through changing localization  or altering kinase activity (tension-sensitive models). A recent study by Chen et al. proposes an entirely different mechanism; rather than differential Aurora B action based on tension, the authors propose a model in which the downstream effect of Aurora B phosphorylation is different depending on the tension-state of the attachment . Aurora Active Aurora B was transiently targeted to specific kinetochores using an optogenetics approach. The outer kinetochore protein Spc25 and the Aurora B- activating domain of INCENP were tagged with light-sensitive dimerizing domains; when activated, a photo-caged ligand was released and the two domains transiently heterodimerized . This apThis study demonstrates that the biochemical response to phosphorylation depends on the mechanical tension-state of the attachment. Kinetochores typically exhibit a catch-bond interaction with microtubules, where tension stabilizes the interaction and increases the disassociation time ,36. ChenDecades of research has yielded great advancements in the understanding of chromosome segregation. The proper attachment of chromosomes to the mitotic spindle and the ability to correct errors is critical for an organism’s viability. The role of tension has been firmly established as a mechanism to distinguish between correct and incorrect attachments. The Aurora B kinase is the main effector of tension-based corrections, and several models exist to explain how it senses tension. Spatial separation of the kinase from its targets or tension-based regulation of kinase activity are two firmly established models, but recent studies have yielded two new models. A kinetochore localization model posits that a subpopulation of Aurora B located on kinetochores is responsible for tension-based error correction , and a mA critical consideration for all of these models is that they need not be mutually exclusive, and in fact, a combination of models could address many outstanding questions. While Chen et al. clearly demonstrated that phosphorylation response is tension-dependent , this doThese models provide exciting insights into the translation of mechanical tension force into Aurora B-mediated biochemical signals and offer guidance in future experimentation to distinguish between the different mechanisms. Future experimentation will need to address several outstanding questions, including the activity and localization of Aurora B under tension. One major distinguishing feature between spatial separation-based models and tension-sensitive activation models is the activity status of Aurora B under tension. Previous studies have probed Aurora B activity under tension using phospho-sensors tethered to inner and outer kinetochore proteins and concluded that the kinase is active under tension ,57. HoweFuture investigations of tension sensing mechanisms will need to address the role of chromosome oscillation in error correction. While not discussed in this review, oscillatory movements of chromosomes on the metaphase spindle are correlated with correction of attachment errors in both mitosis and meiosis (see  for a re