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Neuroprognostication of cardiac arrest patients remains a challenge. We evaluated the early prognostic value and optimal time of measuring serum and cerebrospinal fluid (CSF) tau protein levels to predict neurologic outcome in postcardiac arrest patients treated with targeted temperature management (TTM). We also evaluated the cutoff values in predicting poor outcomes. Patients treated with TTM following cardiac arrest, from May 2018 to June 2019, were included in the study. Serum and CSF tau levels were obtained and compared immediately, at 24, 48, and 72 hours after return of spontaneous circulation (ROSC). The area under the receiver-operating characteristic curve (AUROC) and the Delong method were used to identify the cutoff values of serum and CSF tau protein levels in predicting poor outcomes at each interval. Of 38 patients enrolled, 16 experienced poor outcomes. Both serum and CSF tau levels were consistently higher in the poor outcome group than in the good outcome group. The AUROCs of serum and CSF tau protein were not significantly different at each time point. Immediately after ROSC, sensitivities of both serum and CSF tau protein levels were 31.25% at 100% specificity and increased to 86.6% and 73.3%, respectively, at 72 hours. This study demonstrates that serum and CSF tau protein levels could be used as valuable predictors of neurologic outcomes in postcardiac arrest patients treated with TTM. The early optimal time for measuring the serum and CSF tau protein levels was determined to be 72 hours after ROSC.

Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase ubiquitously expressed mainly in the cytoplasm of several tissues. SHP2 modulates diverse cell signaling events that control metabolism, cell growth, differentiation, cell migration, transcription and oncogenic transformation. It interacts with diverse molecules in the cell, and regulates key signaling events including RAS/ERK, PI3K/AKT, JAK/STAT and PD-1 pathways downstream of several receptor tyrosine kinases (RTKs) upon stimulation by growth factors and cytokines. SHP2 acts as both a phosphatase and a scaffold, and plays prominently oncogenic functions but can be tumor suppressor in a context-dependent manner. It typically acts as a positive regulator of RTKs signaling with some inhibitory functions reported as well. SHP2 expression and activity is regulated by such factors as allosteric autoinhibition, microRNAs, ubiquitination and SUMOylation. Dysregulation of SHP2 expression or activity causes many developmental diseases, and hematological and solid tumors. Moreover, upregulated SHP2 expression or activity also decreases sensitivity of cancer cells to anticancer drugs. SHP2 is now considered as a compelling anticancer drug target and several classes of SHP2 inhibitors with different mode of action are developed with some already in clinical trial phases. Moreover, novel SHP2 substrates and functions are rapidly growing both in cell and cancer. In view of this, we comprehensively and thoroughly reviewed literatures about SHP2 regulatory mechanisms, substrates and binding partners, biological functions, roles in human cancers, and different classes of small molecule inhibitors target this oncoprotein in cancer.

Vacuole membrane protein 1 (VMP1) is an endoplasmic reticulum (ER) transmembrane protein that regulates the formation of autophagosomes and lipid droplets. Recent evidence suggests that VMP1 plays a critical role in lipoprotein secretion in zebra fish and cultured cells. However, the pathophysiological roles and mechanisms by which VMP1 regulates lipoprotein secretion and lipid accumulation in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are unknown.Liver-specific and hepatocyte-specific Vmp1 knockout mice as well as Vmp1 knock-in mice were generated by crossing Vmp1Hepatocyte-specific deletion of Vmp1 severely impaired VLDL secretion resulting in massive hepatic steatosis, hepatocyte death, inflammation and fibrosis, which are hallmarks of NASH. Mechanistically, loss of Vmp1 led to decreased hepatic levels of phosphatidylcholine and phosphatidylethanolamine as well as to changes in phospholipid composition. Deletion of Vmp1 in mouse liver also led to the accumulation of neutral lipids in the ER bilayer and impaired mitochondrial beta-oxidation. Overexpression of VMP1 ameliorated steatosis in diet-induced NASH by improving VLDL secretion. Importantly, we also showed that decreased liver VMP1 is associated with NAFLD/NASH in humans.Our results provide novel insights on the role of VMP1 in regulating hepatic phospholipid synthesis and lipoprotein secretion in the pathogenesis of NAFLD/NASH.Non-alcoholic fatty liver disease and its more severe form, non-alcoholic steatohepatitis, are associated with a build-up of fat in the liver (steatosis). However, the exact mechanisms that underly steatosis in patients are not completely understood. Herein, the authors identified that the lack of a protein called VMP1 impairs the secretion and metabolism of fats in the liver and could therefore contribute to the development and progression of non-alcoholic fatty liver disease.

There has been no comparative study on the clinical value of magnetic resonance tumor regression grade (mrTRG)1-2 and ycT0-1N0 for the prediction of ypT0-1N0 after concurrent chemoradiotherapy (CCRT) for rectal cancer. We compared the diagnostic performance between mrTRG1-2 and ycT0-1N0 for predicting ypT0-1N0 as a selection criterion for non-radical management after CCRT in locally advanced rectal cancer.This retrospective study enrolled 291 patients from three referral hospitals between January 2018 and March 2020. The diagnostic performance of ycT0-1N0 and mrTRG1-2 for the prediction of ypT0-1N0 was compared in terms of sensitivity, specificity, positive-predictive value, negative-predictive value, and area under the curve (AUC).Sixty-eight patients (23.4%) achieved ypT0-1N0. Nineteen patients (6.5%) had ycT0-1N0, and 91 patients (31.2%) had mrTRG1-2. For predicting ypT0-1N0, ycT0-1N0 had a sensitivity of 16.2% (95% confidence interval [CI]: 8.36‒27.10) and positive-predictive value of 57.9% (95% CI: 36.57‒76.63), while mrTRG1-2 had a sensitivity of 58.8% (95% CI: 46.23‒70.63) and positive-predictive value of 44.0% (95% CI: 36.46‒51.74). When predicting ypT0-1N0, mrTRG1-2 showed a higher AUC (0.680, 95% CI: 0.604‒0.756) than ycT0-1N0 (0.563, 95% CI: 0.481‒0.645) (P 0.001).mrTRG1-2 might be a better indicator than ycT0-1N0 for the selection of non-radical management of advanced rectal cancer post-CCRT. However, additional diagnostic tools are required for predicting ypT0-1N0 because mrTRG1-2 or yc stage on MRI has insufficient evidence for diagnosing ypT0-1N0.

Measurable residual disease (MRD) negativity is a strong prognostic indicator in multiple myeloma (MM). However, the optimal use of MRD in daily clinical practice has been hampered by the limited feasibility of MRD testing. Therefore, we examined the clinical relevance of commercially available MRD modalities based on clonality assays by fragment analysis with IdentiClone® (n = 73 patients) and next-generation sequencing (NGS) with LymphoTrack® (n = 116 patients) in newly diagnosed patients with MM who received autologous stem cell transplantation (ASCT). MRD was assessed at the end of induction (pre-ASCT) and/or at 100 days after ASCT (post-ASCT). MRD could not predict survival when assessed by fragment analysis. However, NGS-based MRD negativity at pre- or post-ASCT was beneficial in terms of progression-free and overall survival. Moreover, NGS-based MRD negativity was independently associated with improved progression-free and overall survival, and MRD-positive patients both pre- and post-ASCT had worst outcome. Indeed, initial adverse prognostic features by high-risk cytogenetics could be mitigated upon achieving MRD negativity by NGS. We demonstrate the feasibility and clinical benefit of achieving MRD negativity by commercially available clonality-based MRD assays in MM and support incorporating NGS, but not fragment analysis, to tailor therapeutic strategies in real-world practice.

Ubiquitin-specific protease 7 (USP7) plays a critical role in multiple signaling pathways, and many recent studies have proved its association with many diseases. The USP7-murine double minute 2-p53 pathway and the relationship between USP7 and the important immune protein PD-L1 in cancer progression and metastasis have been clarified. Recently, USP7 has emerged as a promising and potent therapeutic target for cancer and has attracted both academic and industrial attention.This review focuses on the structure, activity, and applications of USP7 inhibitors in cancer therapy. It also focuses on patents reported since 2014.Recently, USP7 has attracted considerable attention owing to its physiological and pathophysiological roles in cancer progression, and few studies have focused on the development of USP7 inhibitors. Compared with micromolar first-generation USP7 inhibitors, second-generation USP7 inhibitors exhibit higher potency (at nanomolar level for both USP7 and cell inhibitory activities), higher selectivity, and better pharmacokinetic properties, and they largely broaden the range of candidates for further clinical tests. However, there is still a need for a more precise description of compounds with receptors, the structural diversity of these compounds, and screening methods.

Peritoneal metastasis (PM) remains a major obstacle in the treatment of stage IV gastric cancer. This is a dose-escalation study of intraperitoneal (IP) paclitaxel combined with intravenous (IV) fluorouracil, leucovorin, and oxaliplatin (FOLFOX) to determine the recommended phase II dose in gastric cancer patients.Patients with gastric adenocarcinoma and PM were enrolled. The recommended phase II dose of IP paclitaxel was determined using the standard "3 + 3" dose escalation with planned doses ranging from 40 to 100 mg/mAmong the 13 patients, there was no DLT at 40 and 60 mg/mThe biweekly regimen of IP paclitaxel and FOLFOX is safe and the recommended dose of IP paclitaxel for a phase II trial is 60 mg/m

We compared the ability of head computed tomography (HCT) and MRI, respectively, obtained before or after target temperature management to predict neurologic outcomes in out-of-hospital cardiac arrest (OHCA) survivors.This retrospective study included adult comatose OHCA survivors who underwent neuroimaging scans within 6 h (first HCT) or 72-96 h (second HCT and MRI) after the return of spontaneous circulation (ROSC). We calculated the gray-white matter ratio (GWR), hypoxic-ischemic brain injury presence (loss of boundary at the basal ganglia level [LOB at BG], sulcal effacement at the centrum semiovale [SE at CS], and pseudo-SAH sign), and the overall score based on MRI findings (a total score of 21 brain regions individually scored according to the degree of signal abnormality).Overall, 78 patients were included in this analysis, of whom 45 (58%) showed poor outcomes. The second HCT scan showed greater prognostic performance than the first HCT scan for GWR (area under curve 0.92 vs. 0.70), LOB at BG (0.93 vs. 0.65), SE at CS (0.89 vs. 0.64), and pseudo-SAH sign (0.75 vs. 0.51). The overall score on MRI (0.99) showed the highest prognostic performance. However, on the second HCT scan, the combination of GWR and LOB at BG showed prognostic performance (0.96) comparable to the overall score on MRI (P = 0.12); the corresponding sensitivity and specificity values were 85.7% and 100%.Overall score on MRI and the combination of GWR and LOB at BG findings on second HCT scans may help predict poor outcomes in OHCA survivors.

Background aims Despite the great advances in immunosuppressive therapy for severe aplastic anemia (SAA), most patients are not completely cured. Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has been recommended as an alternative treatment in adult SAA patients. However, haplo-HSCT presents a higher incidence of graft failure and graft-versus-host disease (GVHD). The authors designed a combination of haplo-HSCT and umbilical cord-derived mesenchymal stem cells (UC-MSCs) for treatment of SAA in adult patients and evaluated its effects. Methods Adult patients (≥18 years) with SAA (N = 25) were given HLA-haploidentical hematopoietic stem cells (HSCs) combined with UC-MSCs after a conditioning regimen consisting of busulfan, cyclophosphamide, fludarabine and anti-thymocyte globulin and intensive GVHD prophylaxis, including cyclosporine, basiliximab, mycophenolate mofetil and short-term methotrexate. Additionally, the effects of the protocol in adult SSA patients were compared with those observed in juvenile SAA patients (N = 75). Results All patients achieved myeloid engraftment after haplo-HSCT at a median of 16.12 days (range, 11–26). The median time of platelet engraftment was 28.30 days (range, 13–143). The cumulative incidence of grade II acute GVHD (aGVHD) at day +100 was 32.00 ± 0.91%. No one had grade III–IV aGVHD at day +100. The cumulative incidence of total chronic GVHD was 28.00 ± 0.85%. The overall survival was 71.78 ± 9.05% at a median follow-up of 42.08 months (range, 2.67–104). Promisingly, the protocol yielded a similar curative effect in both young and adult SAA patients. Conclusions The authors’ data suggest that co-transplantation of HLA-haploidentical HSCs and UC-MSCs may provide an effective and safe treatment for adult SAA.

To evaluate clinical and radiological outcomes including hindfoot alignment after plate vs intramedullary nailing (IMN) for distal tibia fracture and to define radiologic parameters that influence changes in hindfoot alignment.Among 92 patients with distal tibia metaphyseal fractures treated from 2002 to 2015, 39 cases of intramedullary nailing and 53 cases of standard plate osteosynthesis were performed. Union rate and complication rate were compared in both groups. Radiographic measurements including hindfoot angulation, moment arm, calcaneal pitch angle, and Meary angle were evaluated at a minimum of 1-year follow-up. Hindfoot alignment changes after surgery were compared between both groups using student t-test. Correlation and regression were analyzed between fracture alignment parameters and hindfoot alignment.All patients ultimately healed, with an average union period of 26 weeks in both groups. The AOFAS and VAS scores were not significantly different between the two groups. Complications were similar between the two groups. Hindfoot alignment angle, calcaneal pitch, and Meary angle showed no significant differences between the groups. The hindfoot moment arm increased with valgus in the IMN group. A low correlation was detected between angulation at the fracture site in the coronal view and hindfoot alignment (angulation and moment arm) changes (R = 0.38). A significantly high correlation was noted only between transverse rotation and hindfoot alignment changes (R = 0.79).Rotation in the transverse plane notably influenced changes in hindfoot alignment. And this suggests that patients with distal tibia fracture should be closely monitored for hindfoot alignment changes caused by intraoperative transverse rotation regardless of the fixation method.

There are varying definitions of women at high risk of breast cancer across different institutions, and there are reports suggesting that the breast cancer risk assessment tools have not been well integrated into clinical practice. In this study, we tried to investigate the perceived importance of different breast cancer risk factors by physicians in China. A cross-sectional survey involving 386 anonymous physicians was conducted using a 20-item, 5-point Likert scale questionnaire. The Kruskal-Wallis test and post-hoc pairwise comparisons were used to compare the differences in response. Most of the respondents were either breast surgeons/specialists (n=161; 41.7%) or medical oncologists (n=151; 39.1%), and the results showed that the breast cancer risk factors were not perceived as equally important. The weighting of each risk factor also varied depending on the physician's medical specialty, location of practice, and the number of years of clinical experience. This study provides a more updated insight into the perceptions of physicians in China toward the breast cancer risk factors, as well as underlines the potential improvements in breast cancer risk assessment strategies that can be done.

Background: As a FAD (Flavin Adenine Dinucleotide) - dependent histone demethylase discovered in 2004, LSD1 (lysine-specific demethylase 1) was reported to be overexpressed in diverse tumors, regulating target genes transcription associated with cancer development. Hence, LSD1 targeted inhibitors may represent a new insight in anticancer drug discovery. For these reasons, researchers in both the pharmaceutical industry and academia have been actively pursuing LSD1 inhibitors in the quest for new anti-cancer drugs. Objectives: This review summaries patents about LSD1 inhibitors in recent 5 years in the hope of providing a reference for LSD1 researchers to develop new modulators of LSD1 with higher potency and fewer adverse effects. Methods: This review collects LSD1 inhibitors disclosed in patents since 2016. The primary ways of patent searching are Espacenet®, Google Patents, and CNKI. Results: This review covers dozens of patents related to LSD1 inhibitors in recent five years. The compound structures are mainly divided into TCP (Tranylcypromine) derivatives, imidazole derivatives, pyrimidine derivatives, and other natural products and peptides. Meanwhile, the compounds that have entered the clinical phase are also described. Conclusion: Most of the compounds in these patents have been subjected to activity analysis with LSD1 and multi-cell lines, showing good antitumor activity in vitro and in vivo. These patents exhibited the structural diversity of LSD1 inhibitors and the potential of natural products as novel LSD1 inhibitors.

Background: Photobiomodulation (PBM) affects local blood flow regulation through nitric oxide generation, and various studies have reported on its effect on improving cognitive function in neurodegenerative diseases. However, the effect of PBM in the areas of the vertebral arteries (VA) and internal carotid arteries (ICA), which are the major blood-supplying arteries to the brain, has not been previously investigated. Objective: We aimed to determine whether irradiating PBM in the areas of the VA and ICA, which are the major blood-supplying arteries to the brain, improved regional cerebral blood flow (rCBF) and cognitive function. Methods: Fourteen patients with mild cognitive impairments were treated with PBM. Cognitive assessment and single-photon emission computed tomography were implemented at the baseline and at the end of PBM. Results: Regarding rCBF, statistically significant trends were found in the medial prefrontal cortex, lateral prefrontal cortex, anterior cingulate cortex, and occipital lateral cortex. Based on the cognitive assessments, statistically significant trends were found in overall cognitive function, memory, and frontal/executive function. Conclusion: We confirmed the possibility that PBM treatment in the VA and ICA areas could positively affect cognitive function by increasing rCBF. A study with a larger sample size is needed to validate the potential of PBM.

Background Preoperative sarcopenia is associated with a poor long‐term prognosis in patients with gastric cancer (GC). Most GC patients rapidly lose muscle mass after gastrectomy. This retrospective cohort study analysed the effect of postoperative muscle loss and surgery‐induced sarcopenia on the long‐term outcomes of patients with GC. Methods Preoperative and postoperative 1 year abdominal computed tomography scans were available for 1801 GC patients who underwent curative gastrectomy between January 2009 and December 2013 at Seoul National University Bundang Hospital. The patients were categorized into normal, presarcopenia, and sarcopenia groups according to the skeletal muscle index (SMI) measured on computed tomography scans. Patients who were not sarcopenic prior to gastrectomy but became sarcopenic after surgery were defined as the surgery‐induced sarcopenia group. Results There were 1227 men and 574 women included in the study. The mean age of the patients was 59.5 ± 12.3 years. Multivariable Cox‐regression analyses showed that preoperative SMI was not associated with overall survival (OS). However, postoperative sarcopenia was associated with significantly worse OS only in men [hazard ratio (HR), 1.75; 95% confidence interval (CI), 1.08–2.85]. SMI loss was an independent risk factor for OS in the entire cohort and in men (HR, 1.01; 95% CI, 1.00–1.02, for the entire cohort; HR, 1.02; 95% CI, 1.01–1.04, for men). The surgery‐induced sarcopenia group was associated with significantly higher mortality (HR, 1.84; 95% CI, 1.16–2.90, for the cohort; HR, 2.73; 95% CI, 1.54–4.82, for men), although SMI loss and surgery‐induced sarcopenia were not risk factors in women. Similar results were obtained for relapse‐free survival. Conclusions Postoperative muscle mass loss and surgery‐induced sarcopenia are prognostic factors for survival in patients with GC. Impact of postoperative muscle mass loss and surgery‐induced sarcopenia on survival outcomes is dependent on the sex.

To investigate the dietary nutrient intake and the nutritional status of children with Duchenne muscular dystrophy (DMD), and to explore the correlation between them, so as to provide theoretical basis for the formulation of proper nutritional treatment for children with DMD.A total of 223 children aged 2 to 14 years who came to West China Second University Hospital, Sichuan University from July 2017 to April 2021, and who were diagnosed with DMD by genetic testing were enrolled as the subjects of the study. Dietary assessment was conducted with a 3-day 24-hour dietary recall, and serum vitamin D level was measured by chemiluminescence method.Only 33.2% of the children with DMD were found to be of normal nutritional status. The incidences of stunted growth, underweight, overweight and obesity were 13.5%, 14.4%, 14.3% and 8.1%, respectively. Among the children with DMD, those with serum vitamin D deficiency and insufficiency accounted for 9.0% and 89.7%, respectively. According to the dietary recall of the children with MDM, the daily energy ratio of carbohydrate, protein and fat were (47.40±6.64)%, (14.46±2.22)%, and (38.17±5.30)%, respectively. The daily intake of dietary calcium and vitamin D were (433.32±164.39) mg per day and (155.73±89.30) IU per day, respectively. The ratio of daily protein intake to the estimated average requirement for protein (The dietary structure of children with DMD is obviously not suited to their condition and nutritional deficiency coexists with overnutrition among them. Further research needs to be done for developing appropriate nutritional guidance programs and standardized nutritional management measures for children with DMD.

Cholesterol is an essential substance to maintain cell membranes. Low levels of total cholesterol (TC) are associated with poor prognosis in critically ill patients. Cardiac arrest-induced whole-body ischemia and reperfusion injury cause a sepsis-like syndrome. The Cholesterol level in post-cardiac arrest patients may indicate the degree of endotoxemia or inflammation caused by ischemic and reperfusion injury. We aimed to investigate the association of TC levels with neurologic outcome of out-of-hospital cardiac arrest (OHCA) survivors who underwent target temperature management (TTM). This was a retrospective single-center observational study from May 2018 to April 2021 on a cohort of 106 patients. TC levels were determined in samples obtained immediately and at 24, 48, and 72 hours after the return of spontaneous circulation (ROSC). The primary outcome was poor neurologic outcome at 3 months after ROSC. Poor neurologic outcome was defined by cerebral performance categories 3 to 5. Sixty patients had a poor neurologic outcome. TC levels were significantly lower in the poor neurologic outcome group at each time point. The TC levels for predicting poor neurologic outcome had a sensitivity of 80.8%, with 67.6% specificity at 48 hours (TC48) after ROSC. The areas under the curve value of TC48 was 0.771 (0.670-0.853), with a cutoff value of 114 mg/dL. TC level at 48 hours after ROSC was a helpful marker for the 3-month poor neurologic outcome. This might be an easily accessible predictive marker of neurologic outcome in OHCA survivors treated with TTM.

The study aimed to evaluate the macular microvasculature of X-linked retinoschisis (XLRS) and identify correlations between vascular changes, structural changes, and functional outcome.Genetically confirmed XLRS patients and heathy control subjects underwent complete ophthalmic examination, dilated funduscopic examination, optical coherence tomography, and optical coherence tomography angiography. Schisis distribution, outer plexiform layer discontinuation, photoreceptor layer thickness, and photoreceptor outer segment length were reviewed using optical coherence tomography. Vascular flow density and foveal thickness at foveal and parafoveal area were measured using optical coherence tomography angiography.A total of 17 eyes of 9 XLRS patients and 22 eyes of 11 control subjects were examined from July 2018 to August 2020. Flow density in the deep capillary plexus at foveal and parafoveal area decreased in XLRS patients compared with control subjects (P = 0.014 and 0.001, respectively), whereas foveal avascular zone area and perimeter remarkably increased (P = 0.015 and 0.001, respectively). Although outer and total retinal layers were significantly thicker in XLRS, inner retinal layer was thinner with reduced photoreceptor layer thickness and shortened photoreceptor outer segment length (P0.001 and P0.001, respectively). Foveal flow loss in deep capillary plexus, foveal avascular zone enlargement, thinner inner retina and photoreceptor layer thickness, and shortened photoreceptor outer segment length correlated with best-corrected visual acuity.X-linked retinoschisis eyes exhibit decreased flow density in the deep capillary plexus and variable foveal avascular zone with enlarged perimeter. Structural deterioration of the photoreceptor best reflects the degenerative changes, whereas microvascular alteration shows considerable correlation with functional outcome in XLRS.

This randomized controlled trial aimed to investigate the effects of dance therapy using telerehabilitation on trunk control and balance training in patients with stroke and compare them with the effects of conventional treatment.We enrolled 17 patients with subacute or chronic stroke who were randomly assigned to either an experimental or a control group. In addition to conventional physical therapy, the experimental group (n = 9) participated in 40-minute, non-face-to-face, dance-therapy sessions and the control group (n = 8) received conventional physical therapy. The primary outcome measures were the Trunk Impairment Scale (TIS) scores to assess trunk control and balance function between the 2 groups as a measure of change from baseline to after the intervention.We found that the TIS scores of the patients in the experimental group significantly improved (P = .017). The TIS results indicated non-inferiority within a predefined margin for dance therapy using telerehabilitation (difference = -0.86, 95% confidence interval [CI] = -2.21 to 0.50).Dance therapy using telerehabilitation significantly improved the TIS scores in the experimental group and was not inferior to conventional rehabilitation treatment when compared in a non-inferiority test. The remote dance program may therefore have similar effects to those of conventional treatment regarding trunk-control improvement in patients with stroke.

Background Acute postoperative pain is a common complication of inguinal hernia repair. Pain management using local application of anesthetic agents over the skin surrounding the surgical incision may reduce the requirement for other pain medications. Targeted topical analgesics such as 5% lidocaine patches have been known to improve acute and chronic pain. However, the clinical effect of lidocaine patches on postoperative pain after inguinal hernia repair has not been studied, especially in patients undergoing surgery at day surgery units. Methods/design This is a single-center, prospective, double-blind, randomized, controlled clinical trial. Participants with unilateral inguinal hernia will be randomized to the lidocaine patch group or the placebo patch group. Based on the randomized allocation sequence, either lidocaine patches or placebo patches will be attached near each participant’s surgical wound after open hernia repair under general anesthesia. Participants will be asked to follow up at our outpatient clinic on the first postoperative day and at 1 week after surgery. The primary outcome is pain intensity, which will be measured using the visual analog scale (VAS) at the time of discharge from the day surgery unit. The secondary outcomes are VAS score at 24 h and 1 week after surgery. We will collect and analyze the participants’ clinical data (amount of intraoperative opioid use, time to recovery, and pain intensity at 30 min after surgery) and demographic characteristics (age, sex, body weight, and height). Discussion This trial may not only provide evidence on the efficacy of a 5% lidocaine patch for acute postoperative pain management after unilateral inguinal hernia repair, but also demonstrate the efficacy and safety of the patch for post-discharge pain management. Trial registration ClinicalTrials.gov NCT04754451. Registered on February 10, 2021.

Introduction Although skin grafts are widely used in reconstruction of large skin defect and complex wounds, many factors lead to suboptimal graft take. Negative-pressure wound therapy (NPWT) reportedly increases the graft take rates when added to skin grafting, but a summary analysis of the data of randomized controlled trials has yet to be performed. We conducted this systematic review and meta-analysis of randomized controlled trials to compare the effectiveness and safety of NPWT and non-NPWT for patients with skin grafts. Methods We searched PubMed, Embase, Cochrane Library, and CNKI for relevant trials based on predetermined eligibility criteria from database establishment to February 2020. Two reviewers screened citations and extracted data independently. The quality of the included studies was evaluated according to the Cochrane Handbook, whereas statistical heterogeneity was assessed using chi-square tests and I2 statistics. Review Manager 5.3 was used for statistical analysis. Results Ten randomized controlled trials with 488 patients who underwent NPWT or non-NPWT were included. Compared with non-NPWT, NPWT yielded an improved the percentage of graft take, a reduction in days from grafting to discharge, with lower relative risk of re-operation, and no increased relative risk of adverse event. Further, the subgroup analysis showed an improved the percentage of graft take in negative pressure of 80 mmHg, and no improved the percentage of graft take in negative pressure of 125 mmHg. Conclusion NPWT is more effective than non-NPWT for the integration of skin grafts, and the negative pressure of 80 mmHg can be recommended. Data on adverse events and negative pressure are, however, limited. A better understanding of complications after NPWT and the ideal negative pressure for the integration of skin grafts is imperative.

To observe the safety of donor NK cell infusions in the settings of hematopoietic stem cell transplantation and after consolidation chemotherapy in elderly patients with acute myeloid leukemia (AML).Forty patients with AML were included, in which 21 patients aged over 60 years were at the stage of complete remission (CR) and 19 patients that received allogeneic hematopoietic stem cell transplantation (allo-HSCT). Mononucleated cells were isolated from peripheral blood from the donors (for allo-HSCT) or healthy immediate family members (elderly AML). The cells were seeded into the flasks pre-coated with NK cell specific activators, and expanded in media containing recombinant human IL-15 and IL-2 for 14 days. The cells were transfused intravenously after the identification of quality control. Trypan blue exclusion test was used for the determination of cell viability and counting. Flow cytometry analysis was performed to assess the surface antigenic profile. Seventy-eight infusions of the cell products were received by the elderly patients with AML after consolidation chemotherapy, 11 infusions were received by the patients during allo-HSCT and 32 infusions 3 moths after transplantation. The safety of cell therapy, body temperature, blood pressure and other indexes were observe during and 48 hours after cell transfusion. Meanwhile, the occurrence and severity of acute graft-versus-host disease (GVHD) were documented.Flow cytometry analysis showed that the proportion of NK cells (CD3NK cell products with a high-purity could be obtained by ex vivo expansion with this protocol. The transfusion of these expanded cells is generally safe in the elderly patients with AML that have received chemotherapy or patients that received hematopoietic stem cell transplantation.NK细胞预防移植复发及治疗老年白血病临床安全性观察.观察急性髓性白血病（AML）患者异基因造血干细胞移植（allo-HSCT）时、移植后及老年AML患者巩固化疗后，供者NK细胞输注的安全性。.入组40例AML患者，其中年龄60岁AML完全缓解（CR）患者21 例，allo-HSCT患者19例。采集健康直系亲属或供者外周血，密度梯度离心法分离单个核细胞，将细胞接种于NK细胞激活剂包被的培养瓶中，以重组人IL-15及IL-2细胞因子组合，优势扩增人NK细胞14 d。质检合格后进行静脉输注。台盼蓝拒染法计数细胞总数和活力，流式细胞术分析免疫细胞表型。AML患者巩固化疗后接受NK细胞输注，共78次；allo-HSCT患者移植时输注NK细胞11次，移植后3个月内输注NK细胞共32次。输注期间及之后48 h，记录患者体温、血压等，以观察细胞治疗的急性毒性，并记录急性移植物抗宿主病（GVHD）发生情况。.免疫表型分析显示，细胞扩增前外周血中NK细胞（CD3-CD56+）占单个核细胞的比例为（14.10±4.22）%（n=121），培养14 d后CD3-CD56+ 细胞比例为（87.29±8.75）%（n=121），NK细胞增殖倍数为 753.47±140.13倍（n=121）。NK细胞输注量为每次（7.58± 2.50）×10采用该体系可获得高纯度的NK细胞，用于白血病造血干细胞移植及老年AML患者，细胞输注是安全的。.

To investigate the clinical characteristics, etiology, therapy and outcome of hyperthyroidism after allogeneic hematopoietic stem cell transplantation (HSCT).The clinical data of 7 patients who experienced hyperthyroidism were retrospectively analyzed in our hospital.These 7 patients (5 males, 2 females) suffered hyperthyroidism after HSCT. All patients did not apply the pretreatment regimen containing total body irradiation (TBI). The median age was 25 years old, only one child. Six patients underwent haploidentical HSCT except one patient after unrelated HSCT. The median time of hyperthyroidism occurrence was 20 months. Two patients experienced chronic graft versus host disease (GVHD) when hyperthyroidism occurred and were treated successfully with glucocorticoid, however one patient suffered hypothyroidism 3 months later and needed long-term oral levothyroxine maintenance. One patient developed hypothyroidism post treatment ofHyperthyroidism is a rare complication after HSCT but may affect healthy and lead to lower quality of life. Routine thyroid function monitoring should be recommended after HSCT. Treatment of hyperthyroidism should be given according to the pathogeny.异基因造血干细胞移植术后并发甲状腺功能亢进的临床分析.探讨异基因造血干细胞移植术后并发甲状腺功能亢进的临床特点、发病机制、治疗及预后情况.回顾性分析中国人民解放军空军特色医学中心7例异基因造血干细胞移植术后并发甲状腺功能亢进患者的临床资料.7例患者中，男5例，女2例，中位年龄为25（7-32）岁，儿童1例，其余6例为成人，急性白血病3例，慢性粒细胞白血病1例，骨髓增生异常综合征1例，重型再生障碍性贫血2例。6例患者接受单倍体相合造血干细胞移植，1例接受无关供者全相合造血干细胞移植。所有患者均未应用含全身照射（TBI）的预处理方案，发生甲状腺功能亢进中位时间为20（9-25）个月。2例患者在诊断甲亢时合并慢性移植物抗宿主病，经激素及抗排异治疗后，甲亢得到控制，但其中1例在3个月后出现甲状腺功能减退症状，需要长期口服左甲状腺素维持。1例应用异基因造血干细胞移植术后甲状腺功能亢进是少见并发症，但严重影响患者生活质量，移植后长期存活患者需定期监测甲状腺功能，治疗上需根据引起甲状腺功能亢进的原因进行.

To analyze the clinical characteristics of SAA patients with post-transplantation lymphoproliferative disease (PTLD) after allogeneic hematopoietic stem cell transplantation, and to improve diagnosis and treatment of PTLD.The clinical data of 192 patients with SAA patients who underwent HSCT in a single center from September 2010 to September 2017 were analyzed retrospectively. All patients were received antithymocyte globulin（ATG） conditioning regimen and mesenchymal stem cell(MSC) infusion.Among 192 cases, PTLD occurred in 14 cases, the incidence was 7.29％， 9 of them were diagnosed by pathology， and 5 were diagnosed clinically. EBV infection occurred with a median time of 72（35-168） days, Viral load higher than 1×10The incidence of PTLD after HSCT with SAA who used ATG and MSC in conditioning regimen closely relates to EBV infection, age of patients≤12 years, HLA-mismatch in URD-HSCT, grade II to IV GVHD. Rituximab combined with RIS may reduce the incidence of PTLD, combined EBV-CTL and chemotherapy may be the useful and most important treatment for PTLD.重型再生障碍性贫血患者造血干细胞移植治疗后淋巴组织增殖性疾病的临床分析.分析重型再生障碍性贫血(SAA)患者造血干细胞移植（HSCT）后淋巴组织增殖性疾病(PTLD)的临床特征,以提高对PTLD的诊疗水平.回顾分析2010年9月至2017年9月在单中心行HSCT的192例SAA患者的临床资料，分析PTLD的有效预警和治疗方法。本组患者预处理方案中均含有ATG并接受间充质干细胞（MSC）输注.192例SAA患者HSCT移植后有14例并发了EBV+ PTLD，总体发生率为7.29%，其中临床诊断5例，病理诊断9例，移植后PTLD发生中位时间72(35-168)d,所有PTLD均发生了EBV感染，且EBV高载量大于1×10SAA患者接受预处理含有ATG和MSC的HSCT后PTLD发生与EBV高拷贝密切相关，年龄≤12岁儿童、非血缘HSCT中供者为HLA不全相合的移植及合并有II度以上aGVHD者移植后PTLD高发； RIS/RTX抢先治疗有效，疗效不佳患者及时应用CTL及联合化疗是控制病情有效及重要方法.

To analyze the prognostic factors of haplo-HSCT combined with MSC in the treatment of SAA.127 SAA patients who had undergone haplo-HSCT with co-infusion of MSC in our center from January 2014 to August 2019 were analyzed retrospectively. Median age was 11 (1-37) years, and median follow-up time was 39.8 (1-74) months.The median time for neutrophil and platelet engraftment was 14 d and 18 d respectively. The cumulative incidences of grade III-IV aGVHD was 4.4%±1.9% at day +100. The 2-year cumulative incidence of extensive cGVHD was 8.3%± 2.7%. The estimated 3-year OS was 86.1%±3.1%. Univariate analysis showed that high-dose CD34In the haplo-HSCT of SAA, the prognosis of children patients is better than that of adults patients. More CD34单倍体造血干细胞移植联合间充质干细胞治疗重型再生障碍性贫血.分析单倍体造血干细胞移植（haplo-HSCT）联合间充质干细胞治疗重型再生障碍性贫血（SAA）预后的影响因素.回顾性分析2014年1月至2019年8月在空军特色医学中心接受haplo-HSCT联合间充质干细胞输注治疗的SAA患者共127例，中位年龄11（1-37）岁，中位随访时间为39.8（1-74）个月.粒系和血小板的平均植入时间分别为14和18 d。+100 d III-IV度急性移植物抗宿主病（aGVHD）的累积发生率为4.4%±1.9%，2年广泛性慢性移植物抗宿主病（cGVHD）的累积发生率为8.3%±2.7%，3年总体生存（OS）为86.1%±3.1%。单因素分析结果显示：高剂量的CD34在SAA的haplo-HSCT中，儿童患者的预后明显优于成人，输注较多的CD34

Cancer immunotherapy is a rapidly developing and effective method for the treatment of a variety of malignancies in recent years. As a significant immune checkpoint, programmed cell death 1 ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) play the most significant role in cancer immune escape and cancer immunotherapy. Though PD-L1 have become an important target for drug development and there have been various approved drugs and clinic trials targeting it, and various clinical response rate and adverse reactions prevent many patients from benefiting from it. In recent years, combination trials have become the main direction of PD-1/PD-L1 antibodies development. Here, we summarized PD-L1 biofunctions and key roles in various cancers along with the development of PD-L1 inhibitors. The regulators that are involved in controlling PD-L1 expression including post-translational modification, mRNA level regulation as well as degradation and exosome secretory pathway of PD-L1 were focused. This systematic summary may provide comprehensive understanding of different regulations on PD-L1 as well as a broad prospect for the search of the important regulator of PD-L1. The regulatory factors of PD-L1 can be potential targets for immunotherapy and increase strategies of immunotherapy in combination.

Background: The link between neuromyelitis optica spectrum disorder (NMOSD) and cardiovascular disease is currently unclear. Objective: To determine the acute myocardial infarction (MI) risk in patients with MS and NMOSD. Methods: This study analyzed the Korean National Health Insurance Service database between January 2010 and December 2017. The included patients comprised 1503/1675 adults with MS/NMOSD who had not experienced ischemic heart disease or ischemic stroke at the index date. Matched controls were selected based on age, sex, and the presence of hypertension, diabetes mellitus (DM), and dyslipidemia. Results: The risks of developing MI were 2.61 (hazard ratio (HR), 95% confidence interval (CI) 1.73–3.95) and 1.95 (95% CI = 1.18–3.22) times higher in MS and NMOSD compared with the control populations. Patients with NMOSD had a similar MI risk compared with patients with MS, after adjusting for age, sex, income, hypertension, DM, and dyslipidemia (HR = 0.59, 95% CI = 0.34–1.02, p = 0.059). Among each patient group, the MI risk did not differ significantly with age (20–39, 40–64 or ⩾65 years), sex, or the presence of hypertension, DM, or dyslipidemia. Conclusion: The MI risk increased in MS and NMOSD and seemed to be comparable between NMOSD and MS.

Background/Purpose: Transplant recipients are vulnerable to life-threatening community-acquired respiratory viruses (CA-RVs) infection (CA-RVI). Even if non-transplant critically ill patients in intensive care unit (ICU) have serious CA-RVI, comparison between these groups remains unclear. We aimed to evaluate clinical characteristics and mortality of CA-RVI except seasonal influenza A/B in transplant recipients and non-transplant critically ill patients in ICU. Methods: We collected 37,777 CA-RVs multiplex real-time reverse transcription-polymerase chain reaction test results of individuals aged ≥18 years from November 2012 to November 2017. The CA-RVs tests included adenovirus, coronavirus 229E/NL63/OC43, human bocavirus, human metapneumovirus, parainfluenza virus 1/2/3, rhinovirus, and respiratory syncytial virus A/B. Results: We found 286 CA-RVI cases, including 85 solid organ transplantation recipients (G1), 61 hematopoietic stem cell transplantation recipients (G2), and 140 non-transplant critically ill patients in ICU (G3), excluding those with repeated isolation within 30 days. Adenovirus positive rate and infection cases were most prominent in G2 (p

Background Indocyanine green (ICG) is a multifunctional dye used in tumor localization, tissue perfusion, and lymph node (LN) mapping during fluorescence-guided laparoscopic colorectal surgery. Purpose This study aimed to establish the optimal protocol for preoperative endoscopic submucosal ICG injection to perform fluorescence lymph node mapping (FLNM), along with undisturbed fluorescent tumor localization and ICG angiography during a single surgery. Methods Colorectal cancer patients (n = 192) were enrolled from May 2017 to December 2019. Colonoscopic submucosal ICG injection was performed 12 to 18 h before surgery. ICG injection protocols were modified based on the total injected ICG (mg) and tattooing site number. The concentrations of ICG were gradually decreased from the standard dose (2.5 mg/ml) to the minimum dose (0.2 mg/ml). Successful FLNM (FLNM-s) was defined as distinct fluorescent LNs observed under NIR camera. The patient’s age, sex, body mass index (BMI), stage, cancer location, obstruction, and laboratory findings were compared between the FLNM-s and failed FLNM (FLNM-f) groups to identify clinical and pathological factors that affect FLNM. Results In the ICG dose section of 0.5 to 1 mg, the success rate was highest within all functions including FLNM, fluorescent tumor localization, and ICG angiography. FLNM-s was related to ICG dose (0.5–1 mg), multiple submucosal injections, location of cancer, camera light source, and lower BMI. In the multivariate analysis, camera light source, non-obesity, and multiple injections were independent factors for FLNM-s). The mean total number of harvested LNs was significantly higher in the FLNM-s group than that in the FLNM-f group (p p = 0.859). Conclusions Preoperative, endoscopic submucosal ICG injection with dose range 0.5 to 1 mg would be optimal protocol for multifunctional ICG applications during fluorescence-guided laparoscopic colorectal surgery.

Histone deacetylases (HDACs) are essential for maintaining homeostasis by catalyzing histone deacetylation. Aberrant expression of HDACs is associated with various human diseases. Although HDAC inhibitors are used as effective chemotherapeutic agents in clinical practice, their applications remain limited due to associated side effects induced by weak isoform selectivity. HDAC6 displays unique structure and cellular localization as well as diverse substrates and exhibits a wider range of biological functions than other isoforms. HDAC6 inhibitors have been effectively used to treat cancers, neurodegenerative diseases, and autoimmune disorders without exerting significant toxic effects. Progress has been made in defining the crystal structures of HDAC6 catalytic domains which has influenced the structure-based drug design of HDAC6 inhibitors. This review summarizes recent literature on HDAC6 inhibitors with particular reference to structural specificity and functional diversity. It may provide up-to-date guidance for the development of HDAC6 inhibitors and perspectives for optimization of therapeutic applications.

Accurate, sensitive and rapid nucleic acid tests are important to implement timely treatment measures and control the spread of disease. Herein, we developed a novel portable platform for highly sensitive and specific detection of nucleic acids by integrating an entropy-driven amplification strategy into lateral flow assay (LFA) biosensor. We find that introducing an entropy-driven amplification strategy yields bright intensities on the test line of LFA stirp, which results in improved sensitivity for targeted nucleic acid detection. The developed LFA biosensor showed good reproducibility, specificity and sensitivity for target DNA and H1N1-RNA detection with a low detection limit of 1.43 pM and 2.02 pM, respectively. Its practical potential was also verified by detecting the target nucleic acid in human serum. More importantly, the design of an entropy-driven amplification strategy in this portable platform retained the convenient, rapid and low-cost characterizations of LFA biosensor due to the compact amplification principle and the elimination of enzyme use. Thus, we believe that this assay biosensor will certainly report its own position in the timely detection of nucleic acid, especially when the medical environment and resources are fewer.

© 2020 Elsevier Ltd. All rights reserved., Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.

Aim We presented the cut-off value of a diffusion-weighted image (DWI) scoring system to predict poor neurologic outcome using DWI taken 72−96 h after out-of-hospital cardiac arrest (OHCA) patients underwent target temperature management (TTM). Methods This was a prospective single-centre observational study, conducted from March 2018 to April 2020 in OHCA patients after TTM. Neurological status was assessed 6 months after return of spontaneous circulation (ROSC) using the Glasgow-Pittsburgh cerebral performance categories (CPC) scale. CPC of 1–2 demonstrated good neurologic outcomes whilst a CPC of 3–5 was related to poor neurologic outcomes. The receiver operating characteristic curves and DeLong method were used to evaluate the cut-off value of the DWI scoring system to predict poor neurologic outcome. Results The good and poor neurologic outcome groups consisted of 38 (54.3%) and 32 (45.7%) patients, respectively. The area under the receiver operating characteristic curve (AUROC) of the overall, cortex, deep grey nuclei, and cortex plus deep grey nuclei scores, white matter, brainstem, and cerebellum measured 72−96 h after ROSC were 0.96, 0.96, 0.97, 0.96, 0.95, 0.95, and 0.93 respectively. For 100.0% specificity to predict poor neurologic outcome, the overall scores of the DWI scoring system measured 72−96 h after ROSC with a cut-off value of 52 had a sensitivity of 81.3% (95% CI: 63.6–92.8). Conclusion This study demonstrated that the DWI scoring systems measured between 72 and 96 h after ROSC were valuable tools to predict poor neurologic outcome in post-OHCA patients treated with TTM.

NADPH oxidases (NOXs) are comprised of different isoforms, NOX1 to 5 and Duox1 and 2, and they trigger diabetic nephropathy (DN) in the patients with diabetes mellitus. Recently, it was shown that, compared to the other isoforms, the expression of NOX5 was increased in the patients with DN and, NOX5 has been suggested to be important in the development of therapeutic agents. The effect of pan-NOX inhibition by APX-115 has also been investigated in type 2 diabetic mice. However, since NOX5 is absent in mice, we evaluated the effect of pan-NOX inhibition by APX-115 in Nox5 transgenic mouse. Wild type and renal podocyte specific NOX5 transgenic mice (NOX5 pod+) were fed with high-fat diet (60% kcal fat) and treated with APX-115 (60 mg/kg) by oral gavage for 14 weeks. APX-115 significantly improved pancreatic beta cell function by decreased fasting blood glucose levels and increased insulin levels. Further, the total serum cholesterol, triglycerides, and urinary albumin/creatinine levels were also significantly decreased by APX-115 treatment. Increased NOX5 mRNA expressions, increased desmin levels, and reduced podocin protein expressions in the kidney of NOX5 pod + mice were also significantly restored to normal levels by APX-115 treatment. Moreover, APX-115 inhibited the expression of inflammation-related proteins such as TRAF6. Collectively, these data suggest that APX-115 might be a promising therapeutic agent for the treatment of DN because of its pan-NOX inhibitory activity, including its NOX5 inhibitory activity, and also owing to its anti-inflammatory effect.

To investigate the factors associated with visual improvement in response to oral carbonic anhydrase inhibitors (CAIs) and the occurrence of microvascular changes in patients with retinitis pigmentosa-associated cystoid macular edema (RP-CME).This retrospective cohort study included 59 eyes from 39 patients with RP-CME who underwent at least 3 months of oral CAI treatment. The eyes were divided into responding and nonresponding groups based on optical coherence tomography (OCT) criteria (resolution of cyst and reduction of foveal or parafoveal volume). All eyes were assessed before and after treatment using OCT and OCT angiography.Thirty-three eyes (55.9%) demonstrated a positive response to treatment, and 26 eyes (44.1%) did not. Compared with nonresponding eyes, responding eyes had a significantly higher frequency of multilayer CME than CME limited to the inner nuclear layer ( P = 0.016). Subgroup analysis within the responding group revealed that improvements in visual acuity were more likely in eyes with fovea-involving CME and a higher baseline external limiting membrane and ellipsoid zone width. Microvascular parameters showed no significant changes after treatment.Eyes with CME extending to the outer nuclear layer or central fovea, and higher initial photoreceptor integrity may be prognostic factors associated with structural and functional improvements after carbonic anhydrase inhibitors treatment. Early treatment of multilayer CME with foveal involvement seems to be crucial in preventing irreversible photoreceptor damage.

Background Histone lysine-specific demethylase 1 (LSD1) expression has been shown to be significantly elevated in gastric cancer (GC) and may be associated with the proliferation and metastasis of GC. It has been reported that LSD1 repressed tumor immunity through programmed cell death 1 ligand 1 (PD-L1) in melanoma and breast cancer. The role of LSD1 in the immune microenvironment of GC is unknown. Methods Expression LSD1 and PD-L1 in GC patients was analyzed by immunohistochemical (IHC) and Western blotting. Exosomes were isolated from the culture medium of GC cells using an ultracentrifugation method and characterized by transmission electronic microscopy (TEM), nanoparticle tracking analysis (NTA), sucrose gradient centrifugation, and Western blotting. The role of exosomal PD-L1 in T-cell dysfunction was assessed by flow cytometry, T-cell killing and enzyme-linked immunosorbent assay (ELISA). Results Through in vivo exploration, mouse forestomach carcinoma (MFC) cells with LSD1 knockout (KO) showed significantly slow growth in 615 mice than T-cell-deficient BALB/c nude mice. Meanwhile, in GC specimens, expression of LSD1 was negatively correlated with that of CD8 and positively correlated with that of PD-L1. Further study showed that LSD1 inhibited the response of T cells in the microenvironment of GC by inducing the accumulation of PD-L1 in exosomes, while the membrane PD-L1 stayed constant in GC cells. Using exosomes as vehicles, LSD1 also obstructed T-cell response of other cancer cells while LSD1 deletion rescued T-cell function. It was found that while relying on the existence of LSD1 in donor cells, exosomes can regulate MFC cells proliferation with distinct roles depending on exosomal PD-L1-mediated T-cell immunity in vivo. Conclusion LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in GC; this finding indicates a new mechanism with which LSD1 may regulate cancer immunity in GC and provides a new target for immunotherapy against GC.

ObjectiveTo evaluate whether eculizumab helps patients with anti–acetylcholine receptor–positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension.MethodsPatients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study.ResultsA total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1–4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected.ConclusionEculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population.ClinicalTrials.gov IdentifierREGAIN, NCT01997229; REGAIN open-label extension, NCT02301624.Classification of EvidenceThis study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo.

BACKGROUND Colonic perfusion status can be assessed easily by indocyanine green (ICG) angiography to predict ischemia related anastomotic complications during laparoscopic colorectal surgery. Recently, various parameter-based perfusion analysis have been studied for quantitative evaluation, but the analysis results differ depending on the use of quantitative parameters due to differences in vascular anatomical structure. Therefore, it can help improve the accuracy and consistency by artificial intelligence (AI) based real-time analysis microperfusion (AIRAM). AIM To evaluate the feasibility of AIRAM to predict the risk of anastomotic complication in the patient with laparoscopic colorectal cancer surgery. METHODS The ICG curve was extracted from the region of interest (ROI) set in the ICG fluorescence video of the laparoscopic colorectal surgery. Pre-processing was performed to reduce AI performance degradation caused by external environment such as background, light source reflection, and camera shaking using MATLAB 2019 on an I7-8700k Intel central processing unit (CPU) PC. AI learning and evaluation were performed by dividing into a training patient group (n = 50) and a test patient group (n = 15). Training ICG curve data sets were classified and machine learned into 25 ICG curve patterns using a self-organizing map (SOM) network. The predictive reliability of anastomotic complications in a trained SOM network is verified using test set. RESULTS AI-based risk and the conventional quantitative parameters including T1/2max, time ratio (TR), and rising slope (RS) were consistent when colonic perfusion was favorable as steep increasing ICG curve pattern. When the ICG graph pattern showed stepped rise, the accuracy of conventional quantitative parameters decreased, but the AI-based classification maintained accuracy consistently. The receiver operating characteristic curves for conventional parameters and AI-based classification were comparable for predicting the anastomotic complication risks. Statistical performance verifications were improved in the AI-based analysis. AI analysis was evaluated as the most accurate parameter to predict the risk of anastomotic complications. The F1 score of the AI-based method increased by 31% for T1/2max, 8% for TR, and 8% for RS. The processing time of AIRAM was measured as 48.03 s, which was suitable for real-time processing. CONCLUSION In conclusion, AI-based real-time microcirculation analysis had more accurate and consistent performance than the conventional parameter-based method.

Multidrug resistance (MDR) remains one of the major impediments for efficacious cancer chemotherapy. Increased efflux of multiple chemotherapeutic drugs by transmembrane ATP-binding cassette (ABC) transporter superfamily is considered one of the primary causes for cancer MDR, in which the role of P-glycoprotein (P-gp/ABCB1) has been most well-established. The clinical co-administration of P-gp drug efflux inhibitors, in combination with anticancer drugs which are P-gp transport substrates, was considered to be a treatment modality to surmount MDR in anticancer therapy by blocking P-gp-mediated multidrug efflux. Extensive attempts have been carried out to screen for sets of nontoxic, selective, and efficacious P-gp efflux inhibitors. In this review, we highlight the recent achievements in drug design, characterization, structure-activity relationship (SAR) studies, and mechanisms of action of the newly synthetic, potent small molecules P-gp inhibitors in the past 5 years. The development of P-gp inhibitors will increase our knowledge of the mechanisms and functions of P-gp-mediated drug efflux which will benefit drug discovery and clinical cancer therapeutics where P-gp transporter overexpression has been implicated in MDR.

We evaluated whether combining the serum albumin level and the Prediction Rule for Admission policy in Complicated urinary Tract InfeCtion LEiden (PRACTICE) class could be a prognostic predictor in elderly patients with urinary tract infection (UTI).We retrospectively included adult patients (age ≥ 65 years) with UTI who were hospitalized in the emergency department (ED) between January 1, 2014 and December 31, 2018. We graded the serum albumin level and classified the PRACTICE score; the modified PRACTICE was defined as the sum of the albumin level grade and the PRACTICE class. We comparatively assessed the predictive value for in-hospital mortality and admission to the intensive care unit (ICU) in survivor and non-survivor groups.In total, the study analysis included 1159 patients, and in-hospital mortality was 3.4% (n = 39). The modified PRACTICE score (4.0 [1.4] vs 6.1 [1.2], p 0.001) was significantly increased in the non-survivor group. The area under the curve value of factors associated with in-hospital mortality were the Modified Early Warning Score (MEWS) 0.57 (95% CI 0.54-0.60), albumin 0.83 (95% CI 0.81-0.85), PRACTICE 0.71 (95% CI 0.69-0.74), and the modified PRACTICE 0.86 (95% CI 0.84-0.88). Factors associated with ICU admission were MEWS 0.65 (95% CI 0.62-0.68), albumin 0.66 (95% CI 0.64-0.69), PRACTICE 0.66 (95% CI 0.63-0.68), and the modified PRACTICE 0.72 (95% CI 0.69-0.74).The modified PRACTICE score can be a useful prognostic predictor in elderly patients with UTI.

Background. The optimal type of anastomosis after proximal gastrectomy (PG) is still controversial. A novel technique termed “double-flap” esophagogastrostomy (EG) has been introduced. The application of this technique after PG is reported to have little gastroesophageal reflux without the need of creating an esophagojejunostomy. However, this procedure is technically challenging and hence difficult to apply in laparoscopic PG. This technical report describes in detail how to perform single-incision proximal gastrectomy (SIPG) with double-flap EG with the use of novel laparoscopic instruments. Methods. Two patients diagnosed with early gastric cancer underwent SIPG. A 2.5 cm incision was made, and a scope holder was used in place of a scopist. After performing PG with D1+ lymphadenectomy, double seromuscular flaps were created on the anterior wall of the stomach. After tagging the esophagus to the inferior edge of the flap window, the stomach and esophagus were opened through electrocautery. EG was performed intracorporeally using continuous barbed sutures, and the flap is then secured to the anastomosis. To facilitate this procedure, an intra-abdominal organ retractor and an articulating needle holder were used. The supplementary video illustrates in detail how these devices are used to perform the technique. Results. Total operation times were 190 and 110 minutes each, and anastomosis took 75 and 46 minutes each. Patients had no complications and were both discharged on postoperative day 6. Conclusion. Double-flap PG is technically feasible through a single incision with the use of articulating laparoscopic devices and intra-abdominal organ retractors to assist in intracorporeal anastomosis.