Comparison of QT Correction Methods in the Pediatric Population of a Community Hospital: A Retrospective Study

Objective:Accurate measurement of QT interval,the ventricular action potential from depolarization to repolarization,is important for the early detection of Long QT syndrome.The most effective QT correction(QTc)formula has yet to be determined in the pediatric population,although it has intrinsically greater extremes in heart rate(HR)and is more susceptible to errors in measurement.The authors of this study compare six dif-ferent QTc methods(Bazett,Fridericia,Framingham,Hodges,Rautaharju,and a computer algorithm utilizing the Bazett formula)for consistency against variations in HR and RR interval.Methods:Descriptive Retrospective Study.We included participants from a pediatric cardiology practice of a community hospital who had an ECG performed in 2017.All participants were healthy patients with no past medical history and no regular med-ications.Results:ECGs from 95 participants from one month to 21 years of age(mean 9.7 years)were included with a mean HR of 91 beats per minute(bpm).The two-sample paired t-test or Wilcoxon signed-rank test assessed for any difference between QTc methods.A statistically significant difference was observed between every combination of two QTc formulae.The Spearman’s rank correlation analysis explored the QTc/HR and QTc/RR relationships for each formula.Fridericia method was most independent of HR and RR with the lowest absolute value of correlation coefficients.Bazett and Computer had moderate correlations,while Framingham and Rautaharju exhibited strong correlations.Correlations were positive for Bazett and Computer,reflecting results from prior studies demonstrating an over-correction of Bazett at higher HRs.In the linear QTc/HR regression analysis,Bazett had the slope closest to zero,although Computer,Hodges,and Fridericia had comparable values.Alternatively,Fridericia had the linear QTc/RR regression coefficient closest to zero.The Bland-Altman method assessed for bias and the limits of agreement between correction formulae.Bazett and Computer exhibited good agreement with minimal bias along with Framingham and Rautaharju.To account for a possible skewed distri-bution of QT,all the above analyses were also performed excluding the top and bottom 2%of data as sorted by heart rate ranges(N=90).Results from this data set were consistent with those derived from all participants(N=95).Conclusions:Overall,the Fridericia correction method provided the best rate correction in our pedia-tric study cohort.

Clinical and socioeconomic determinants of survival in biliary tract adenocarcinomas

BACKGROUND Despite advances in detection and treatments,biliary tract cancers continue to have poor survival outcomes.Currently,there is limited data investigating the significance of socioeconomic status,race/ethnicity,and environmental factors in biliary tract cancer survival.Data from the Surveillance,Epidemiology,and End Results database for biliary and gallbladder adenocarcinomas were extracted from 1975 to 2016.Socioe-conomic data included smoking,poverty level,education,adjusted household income,and percentage of foreign-born persons and urban population.Survival was calculated with Cox proportional hazards models for death in the 5-year period following diagnosis.RESULTS Our study included 15883 gallbladder,11466 intrahepatic biliary,12869 extrahepatic biliary and 7268 ampulla of Vater adenocarcinoma cases.When analyzing county-specific demographics,patients from counties with higher incomes were associated with higher survival rates[hazard ratio(HR)=0.97,P<0.05].Similarly,counties with a higher percentage of patients with a college level education and counties with a higher urban population had higher 5-year survival rates(HR=0.96,P=0.002 and HR=0.97,P=0.004,respectively).CONCLUSION Worse survival outcomes were observed in lower income counties while higher income and education level were associated with higher 5-year overall survival among gallbladder and biliary malignancies.

Nicotinic acetylcholine signaling is required for motor learning but not for rehabilitation from spinal cord injury

Therapeutic intervention for spinal cord injury is limited,with many approaches relying on strengthening the remaining substrate and driving recovery through rehabilitative training.As compared with learning novel compensatory strategies,rehabilitation focuses on resto ring movements lost to injury.Whether rehabilitation of previously learned movements after spinal cord injury requires the molecular mechanisms of motor learning,or if it engages previously trained motor circuits without requiring novel learning remains an open question.In this study,mice we re randomly assigned to receive intrape ritoneal injection with the pan-nicotinic,non-competitive antagonist mecamylamine and the nicotinicα7 subunit selective antagonist methyllycaconitine citrate salt or vehicle(normal saline)prior to motor learning assays,then randomly reassigned after motor learning for rehabilitation study post-injury.Ce rvical spinal co rd dorsal column lesion was used as a model of in complete injury.Results of this study showed that nicotinic acetylcholine signaling was required for motor learning of the single pellet-reaching task but it was dispensable for the rehabilitation of the same task after injury.Our findings indicate that critical diffe rences exist between the molecular mechanisms supporting compensatory motor learning strategies and the restoration of behavior lost to spinal cord injury.

Prevention,diagnostic evaluation,management and prognostic implications of liver disease in critically ill patients with COVID-19

Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2,broke out in December 2019 in Wuhan city of China and spread rapidly worldwide.Therefore,by March 2020,the World Health Organization declared the disease a global pandemic.Apart from the respiratory system,various other organs of the human body are also seriously affected by the virus.Liver injury in patients with a severe form of COVID-19 is estimated to be 14.8%-53.0%.Elevated levels of total bilirubin,aspartate aminotransferase and alanine aminotransferase and low levels of serum albumin and prealbumin are the main laboratory findings.Patients with pre-existing chronic liver disease and cirrhosis are much more prone to develop severe liver injury.This literature review presented the recent scientific findings regarding the pathophysiological mechanisms responsible for liver injury in critically ill patients with COVID-19,the various interactions between drugs used to treat the disease and the function of the liver and the specific tests providing the possibility of early diagnosis of severe liver injury in these patients.Moreover,it highlighted the burden that COVID-19 put on health systems worldwide and its effect on transplant programs and the care provided to critically ill patients in general and particularly to those with chronic liver disease.

通过预处理短暂诱导缺氧适应不能提高脊髓损伤后雪旺细胞移植的存活率

缺氧预处理在多种损伤和疾病模型中具有保护作用,但它是否对移植到脊髓损伤(SCI)部位的细胞有益在很大程度上尚待探索。本研究分析了缺氧相关的预处理是否能保护移植到挫伤的大鼠胸髓中的雪旺细胞(SC)。雪旺细胞在移植前通过暴露于低氧(1%O2)或药物制剂(去铁胺或adaptaquin)诱导缺氧预处理。所有预处理方法均诱导缺氧适应,包括HIF-1α及其靶基因的表达增加。然而这些适应是短暂的,并在移植后24 h内消失。药理学预处理减弱了脊髓氧化应激,并增强了移植血管形成,但它并没有改善移植细胞的存活或感觉/运动功能的恢复。总之,这些实验结果表明,与缺氧相关的预处理在改善脊髓损伤后移植雪旺细胞的细胞存活或功能方面是无效的。本研究还揭示了在细胞移植疗法中由预处理引起的缺氧相关适应的益处并不普遍。

Pramipexole in Treatment Resistant Depression: A Case Review

Pramipexole is a dopamine agonist used in the treatment of Parkinson’s disease and Restless legs syndrome. Although off-label, the use of Pramipexole as an adjunct therapy in treatment resistant depression has recently been documented in the literature with promising results. We present a 75-year-old male with MDD who has failed trials of SSRIs, SNRIs, TCAs, SGA, TMS, Ketamine, and ECT who was initiated on Pramipexole. We discuss, based on existing literature, the probability of a favorable long-term response to Pramipexole and the potential side effects for our patient. We also highlight the need for future studies designed to test the efficacy of Pramipexole in geriatric patients with TRD.

中文迁延悲伤量表修订版的效度和信度

目的:评价中文迁延悲伤量表修订版(PG-13-R)的效度和信度。方法:招募符合DSM-5-TR迁延悲伤障碍(PGD)诊断标准的患者200例为研究对象,进行迁延悲伤量表修订版评定,计算组内相关系数(ICC)评价评定者之间的一致性;计算Cronbachα系数评价量表的内部一致性,采取主成份方法计算条目的因子载荷考评量表的结构效度。通过计算PG-13-Revised量表的评分与社会适应量表(WSAS)评分和自评抑郁量表(SDS)的相关性来考察PG-R-13效标效度。以DSM-5-TR诊断标准为依据,计算受试者可接受曲线下面积(AUC)来判断量表的区分效度以及划定量表的划界分。结果:评定者一致性系数ICC为0.97;各个分条目之间的相关系数在0.85~0.99之间。量表总Cronbachα系数为0.85。在PG-13-R的13个条目中,采用主成分分析法算出1个主因子,贡献率达78.98%,高于结构效度检验的标准50%。以临床评估标准为参考,在区分轻度迁延悲伤障碍时划界分为≥25时灵敏度和特异度最好,分别为93.3%和78.2%,AUC为0.82,区分中度迁延悲伤障碍,划界分≥37时灵敏度和特异度最高,分别为92.5%、90.7%,AUC为0.92;在区分重度迁延悲伤障碍时,划界分≥46时灵敏度和特异度最高,分别为95.47%、92.18%,AUC为0.96。结论:中文迁延悲伤量表修订版(PG-13-R)有良好的效度和信度,能够早期测评迁延悲伤障碍的严重程度。

Mechanisms of hepatocellular carcinoma progression

Hepatocellular carcinoma(HCC) is the most common primary malignancy of the liver. It is the second leading cause of cancer-related deaths worldwide, with a very poor prognosis. In the United States, there has been only minimal improvement in the prognosis for HCC patients over the past 15 years. Details of the molecular mechanisms and other mechanisms of HCC progression remain unclear. Consequently, there is an urgent need for better understanding of these mechanisms. HCC is often diagnosed at advanced stages, and most patients will therefore need systemic therapy, with sorafenib being the most common at the present time. However, sorafenib therapy only minimally enhances patient survival. This review provides a summary of some of the known mechanisms that either cause HCC or contribute to its progression. Included in this review are the roles of viral hepatitis, non-viral hepatitis, chronic alcohol intake, genetic predisposition and congenital abnormalities, toxic exposures, and autoimmune diseases of the liver. Well-established molecular mechanisms of HCC progression such as epithelial-mesenchymal transition, tumor-stromal interactions and the tumor microenvironment, cancer stem cells, and senescence bypass are also discussed. Additionally, we discuss the roles of circulating tumor cells,immunomodulation, and neural regulation as potential new mechanisms of HCC progression. A better understanding of these mechanisms could have implications for the development of novel and more effective therapeutic and prognostic strategies, which are critically needed.

Spatial epidemiology of diabetes: Methods and insights

Diabetes mellitus(DM)is a growing epidemic with global proportions.It is estimated that in 2019,463 million adults aged 20-79 years were living with DM.The latest evidence shows that DM continues to be a significant global health challenge and is likely to continue to grow substantially in the next decades,which would have major implications for healthcare expenditures,particularly in developing countries.Hence,new conceptual and methodological approaches to tackle the epidemic are long overdue.Spatial epidemiology has been a successful approach to control infectious disease epidemics like malaria and human immunodeficiency virus.The implementation of this approach has been expanded to include the study of non-communicable diseases like cancer and cardiovascular diseases.In this review,we discussed the implementation and use of spatial epidemiology and Geographic Information Systems to the study of DM.We reviewed several spatial methods used to understand the spatial structure of the disease and identify the potential geographical drivers of the spatial distribution of DM.Finally,we discussed the use of spatial epidemiology on the design and implementation of geographically targeted prevention and treatment interventions against DM.

Epigenetics of gastroenteropancreatic neuroendocrine tumors:A clinicopathologic perspective

Gastroenteropancreatic neuroendocrine tumors(GEP-NETs) are a heterogeneous group of rare tumors whose site-specific tumor incidence and clinical behavior vary widely. Genetic alterations associated with familial inherited syndromes have been well defined; however, the genetic profile of sporadic tumors is less clear as their tumorigenesis does not appear to be controlled by classic oncogenes such as P53, RB, or KRAS. Even within GEP-NETs, there are no common oncogenic drivers; for example, DAXX/ATRX mutations are strongly implicated in the tumorigenesis of pancreatic but not small bowel NETs. Accordingly, the dysregulation of epigenetic mechanisms has been hypothesized as a potential regulator of GEPNET tumorigenesis and has become a major focus of recent studies. Despite the heterogeneity of tumor cohorts evaluated in these studies, it is obvious that there are methylation patterns, chromatin remodeling alterations, and microR NA and long non-coding RNA(lncR NA) differential expression profiles that are distinctive of GEPNETs, some of which are correlated with significant differences in clinical outcomes. Several translational studies have provided convincing data identifying potential prognostic biomarkers, and some of these have demonstrated preliminary success as serum biomarkers that can be used clinically. Nevertheless, there are many opportunities to further define the mechanisms by which these epigenetic modifications influence tumorigenesis, and this will provide better insight into their prognostic and therapeutic utility. Furthermore, these findings form the foundation for future studies evaluating the clinical efficacy of epigenetic modifications as prognostic biomarkers, as well as potential therapeutic targets.

Machine learning models and over-fitting considerations

Machine learning models may outperform traditional statistical regression algorithms for predicting clinical outcomes.Proper validation of building such models and tuning their underlying algorithms is necessary to avoid over-fitting and poor generalizability,which smaller datasets can be more prone to.In an effort to educate readers interested in artificial intelligence and model-building based on machine-learning algorithms,we outline important details on crossvalidation techniques that can enhance the performance and generalizability of such models.

Retinal nerve fiber layer changes based on historic CD4 nadir among HIV positive patients undergoing glaucoma evaluation

AIM: To determine relationships between retinal nerve fiber layer(RNFL) thickness and nadir CD4 cell count in human immunodeficiency virus(HIV) positive patients evaluated for glaucoma suspicion.METHODS: Data were reviewed for 329 HIV positive patients evaluated for glaucoma suspicion. High-definition optical coherence tomography(OCT) RNFL measurements were obtained at least 6 mo apart. Analyses were performed to identify relationships between nadir CD4 count and RNFL thickness.RESULTS: Totally 110 eyes of 55 patients met inclusion criteria, of which 46 eyes were from subjects with nadir CD4<200 cells/mm^3 and 64 had nadir CD4≥200 cells/mm^3. Patients with nadir CD4<200 cells/mm^3 had significantly thicker superior(119.7±18.6 μm) and temporal(63.8±11.7 μm) quadrants at time of initial OCT compared to the superior(112.8±16.8 μm, P=0.048) and temporal(57.1±11.9 μm, P=0.004) quadrants of patients with higher nadir CD4. This trend toward thicker RNFL among subjects with lower nadir CD4 cell counts persisted at the time of follow up OCT where participants with nadir CD4<200 cells/mm^3 showed average RNFL thickness in the superior and temporal quadrants of 117.9±18.3 μm and 63.8±12.8 μm, respectively, compared to a superior thickness of 110.5±16.9 μm(P=0.034) and temporal thickness of 57.3±11.6 μm(P=0.007) among those with higher nadir CD4. CONCLUSION: Patients with lower nadir CD4 cell counts have thicker RNFL in the superior and temporal quadrants compared to those with higher nadir CD4 counts. RNFL thickness in HIV positive patients may be affected by historic HIV disease control and should be considered when evaluating HIV positive patients for glaucoma.

New generations of dihydropyridines for treatment of hypertension

自从钙隧道， blocker ( CCB )在世界上为 antihypertensive monotherapy 成为了大多数规定代理人之一，这简短评论将集中于 dihydropyridine ( DHP )的最近的研究和发展 CCB ，为 DHP CCB 的第三和第四代的临床的功效探讨药理学机制，特别在他们位于阴沉的血压下面的可能的中央机制上。

SARS-COV-2 infection(coronavirus disease 2019)for the gastrointestinal consultant

The current pandemic due to the severe acute respiratory syndrome coronavirus 2 has caused an extreme burden for health care systems globally,and the number of cases is expected to continue to increase,at least in the immediate future.The virus is estimated to have infected more than 1.5 million individuals.The available reports suggest that gastrointestinal(GI)involvement in coronavirus disease 2019(COVID-19)is common and in some cases the GI symptoms may precede the respiratory symptoms.In addition to direct effects of severe acute respiratory syndrome coronavirus 2,the infected patients remain at risk for the complications commonly managed by gastroenterology and hepatology consultants.The most commonly reported GI manifestation of COVID-19 is diarrhea,which is reported in a third to up to more than half of the patients.Mild to moderate elevation of the liver enzymes are also common,although no case of acute liver failure has been reported so far.Many of the medications used for treatment of COVID-19 can also be associated with GI symptoms or liver injury and can be included in the differential diagnosis in these patients.Although the diagnosis of the infection is currently based on RNA analysis in respiratory samples,the available literature on fecal shedding of this virus suggests that fecal RNA testing might prove to be a useful diagnostic test.It is reasonable to delay all non-urgent endoscopic procedures during the peak of the pandemic and use additional protective equipment such as N95 respirators during endoscopy while most patients can be considered high risk for having been exposed to the virus.

Oxytocin and cancer: An emerging link

The neuropeptide hormone oxytocin, which is released from the posterior pituitary gland, is involved in a number of physiological processes. Understanding of its effects is gradually increasing due to new research in this area. While mostly recognized as a reproductive system hormone, oxytocin also regulates other organ systems such as the brain and cardiovascular system. Recently, research has focused on unraveling its involvement in cancer, and emerging evidence suggests a potential role for oxytocin as a cancer biomarker. This review summarizes observations linking oxytocin and cancer, with a special emphasis on prostate cancer, where it may promote cell proliferation. Research suggests that oxytocin effects may depend on cell type, concentration of the hormone, its interactions with other hormones in the microenvironment, and the precise localization of its receptor on the cell membrane. Future research is needed to further elucidate the involvement of oxytocin in cancer, and whether it could be a clinical cancer biomarker or therapeutic target.

Gastric food retention at endoscopy is associated with severity of liver cirrhosis

BACKGROUND Gastrointestinal symptoms are prevalent in patients with cirrhosis.Cirrhotic patients have a known predilection to delayed gastric emptying compared to those without cirrhosis.However,the contributing factors have not been fully elucidated.Retained gastric food on esophagogastroduodenoscopy(EGD)has been used as a surrogate marker for delayed gastric emptying with reasonably high specificity.Therefore,we hypothesize that the frequency of retained gastric food contents at EGD will be higher in a cirrhotic population compared to a control population without liver disease.Additionally,we hypothesize that increased frequency of gastric food contents will be associated with increased severity of cirrhosis.AIM To determine the relative frequency of delayed gastric emptying among cirrhotics as compared to non-cirrhotics and to identify associated factors.METHODSWe performed a retrospective case-control study of cirrhotic subjects whounderwent EGD at an academic medical center between 2000 and 2015. Threehundred sixty-four patients with confirmed cirrhosis, who underwent a total of1044 EGDs for the indication of esophageal variceal screening or surveillance,were identified. During the same period, 519 control patients without liverdisease, who underwent a total of 881 EGDs for the indication of anemia, wereidentified. The presence of retained food on EGD was used as a surrogate fordelayed gastric emptying. The relative frequency of delayed gastric emptyingamong cirrhotics was compared to non-cirrhotics. Characteristics of patients withand without retained food on EGD were compared using univariable andmultivariable logistic regression analysis to identify associated factors.RESULTSOverall, 40 (4.5%) patients had evidence of retained food on EGD. Cirrhotics weremore likely to have retained food on EGD than non-cirrhotics (9.1% vs 1.4%, P <0.001). Characteristics associated with retained food on univariable analysisincluded age less than 60 years (12.6% vs 5.2%, P = 0.015), opioid use (P = 0.004),Child-Pugh class C (24.1% Child-Pugh class C vs 6.4% Child-Pugh class A, P =0.007), and lower platelet count (P = 0.027). On multivariate logistic regressionanalysis, in addition to the presence of cirrhosis (adjusted OR = 5.83;95%CI: 2.32-14.7, P < 0.001), diabetes mellitus (types 1 and 2 combined) (OR = 2.34;95%CI:1.08-5.06, P = 0.031), opioid use (OR = 3.08;95%CI: 1.29-7.34, P = 0.011), andChild-Pugh class C (OR = 4.29;95%CI: 1.43-12.9, P = 0.01) were also associatedwith a higher likelihood of food retention on EGD.CONCLUSIONCirrhotics have a higher frequency of retained food at EGD than non-cirrhotics.Decompensated cirrhosis, defined by Child-Pugh class C, is associated with ahigher likelihood of delayed gastric emptying.

Commentary on“Solving the benign prostatic hyperplasia puzzle”

Benign prostatic hyperplasia(BPH)is a common condition affecting over 50% of men as they reach the 5th decade of their life[1].While over half of these patients have symptoms,it is not clear why some of these men do while others do not.The article Solving the benign prostatic hyperplasia puzzle by Keong Tatt Foo[2],delves into the different conundrums urologists face when trying to treat their patients.

Verteporfin synergizes the efflcacy of anti-PD-1 in cholangiocarcinoma

Background:Cholangiocarcinoma(CCA)is one of the primary hepatobiliary malignant neoplasms with only 10%of 5-year survival rate.Promising immunotherapy with the blockade of immune checkpoints has no clear benefit in CCA.The inhibition of YAP1 signaling by verteporfin has shown encouraging results by inhibiting cell proliferation and inducing apoptosis.This study aimed to evaluate the potential benefit of the combination of verteporfin and anti-programmed cell death 1(PD-1)in CCA mouse model.Methods:We assessed the cytotoxicity of verteporfin in human CCA cell lines in vitro,including both intrahepatic CCA and extrahepatic CCA cells.We examined the in vitro effect of verteporfin on cell proliferation,apoptosis,and stemness.We evaluated the in vivo efflcacy of verteporfin,anti-PD-1,and a combination of both in subcutaneous CCA mouse model.Results:Our study showed that verteporfin reduced tumor cell growth and enhanced apoptosis of human CCA tumor cells in vitro in a dose-dependent fashion.Nevertheless,verteporfin impaired stemness evidenced by reduced spheroid formation and colony formation,decreased numbers of cells with aldehyde dehydrogenase activity and positive cancer stem cell markers(all P<0.05).The combination of verteporfin and anti-PD-1 reduced tumor burden in CCA subcutaneous SB1 tumor model compared to either agent alone.Conclusions:Verteporfin exhibits antitumor effects in both intrahepatic and extrahepatic CCA cell lines and the combination with anti-PD-1 inhibited tumor growth.

Pre-Metastatic Niche Formation Has Taken Its TOLL

Pre-Metastatic Niches(PMNs)result from communications between primary tumors and the microenvironment of future distant metastasis via tumor-derived factors.In this issue of Cancer Cell,Liu et al.show that TLR3 activation in lung epithelial cells by tumor exosomal RNAs triggers neutrophil recruitment,which contributes to PMN formation and metastasis.

Extramammary Paget’s disease: Updates in the workup and management

Objective:Extramammary Paget’s disease(EMPD)is a rare cutaneous malignant disease.Due to its rarity,there is a paucity of data regarding best treatment strategy.EMPD primarily affects apocrine gland-bearing skin areas such as the vulva,scrotum,and penis.Our objective was to provide a present-day rationale for diagnosis,pathogenesis,and treatment of EMPD with a focus on recent progress in workup and management of the disease.Methods:Literature on EMPD until February 2022 was assessed through PubMed,MEDLINE databases,and Google scholar.A narrative review of the most relevant articles was provided.Results:EMPD usually presents with indolent growth while usually being diagnosed primarily as carcinoma in situ.The foundation of EMPD treatment centers around prompt and accurate diagnosis,wide local or Mohs micrographic surgical excision with proper management towards the margin status,and careful consideration for lymphadenectomy in patients with regionally positive disease.Conventional chemotherapies are alternative treatments modality for patients with distant metastases;however,they sometimes have suboptimal efficacy.At present,there is no agreement regarding adjuvant or systemic therapies,although recent studies have shown several insights into the molecular pathogenesis,tumor biology,and genomics of the development and advancement of EMPD,which may lead to novel and targeted treatment approaches for metastatic EMPD in the future.Conclusion:Patients with EMPD should seek care from physicians with expertise in disease management and patient counseling.These patients should be surveilled with close follow-up to evaluate them for disease recurrence or progression.Global collaborations with groups such as the Global Society for Rare Genitourinary Tumors,and especially patient support groups are crucial in designing clinical trials to help elucidate more robust data in this orphan disease.