Acute myeloid leukemia in the era of precision medicine:recent advances in diagnostic classification and risk stratification

Acute myeloid leukemia(AML) is a genetically heterogeneous myeloid malignancy that occurs more commonly in adults, and has an increasing incidence, most likely due to increasing age. Precise diagnostic classification of AML requires clinical and pathologic information, the latter including morphologic, immunophenotypic, cytogenetic and molecular genetic analysis. Risk stratification in AML requires cytogenetics evaluation as the most important predictor, with genetic mutations providing additional necessary information. AML with normal cytogenetics comprises about 40%-50% of all AML, and has been intensively investigated. The currently used 2008 World Health Organization classification of hematopoietic neoplasms has been proposed to be updated in2016, also to include an update on the classification of AML, due to the continuously increasing application of genomic techniques that have led to major advances in our knowledge of the pathogenesis of AML. The purpose of this review is to describe some of these recent major advances in the diagnostic classification and risk stratification of AML.

REDOX IMAGING OF THE p53-DEPENDENT MITOCHONDRIAL REDOX STATE IN COLON CANCER EX VIVO

The mitochondrial redox state and its heterogeneity of colon cancer at tissue level have not been previously reported.Nor has how p53 regulates mitochondial respi ration been measured at(deep)tissue level,presumably due to the unavailability of the technology that has sufficient spatial resolution and tissue penetration depth.Our prior work demonstrated that the mito-chondrial redox state and its intnatumor heterogeneity is associated with cancer aggressiveness in human melanoma and breast cancer in mouse models,with the more metastatic tumons exhi-bit ing localized negions of more oxidized redox state.Using the Chance redox scanner with an in-plane spatial resolution of 200 pm,we imaged the mitochondrial redox state of the wild-type p53 colon tumors(HCT116 p53 ut)and the p5-deleted colon tumors(HCT116 p53-/-)by cllcting the fuorescence si gnals of nicotinamide adenine dimucleotide(NA DH)and oxidized flavoproteins [Fp,including favin adenine dinucleotide(FAD)]from the mouse xenogmafts snap frozen at low temperature.Our results show that:(1)both tumor lines have significant degree of intratumor heterogeneity of the redox state,typically exhibiting a distinct bi modal distribution that either correlates with the spatial core-rim pattern or the“hot/oold”oxida tion-roduction patches;.(2)the p531-group is significantly more beterogencous in the mitochondrial redox state and has a more oxidized turmor core compared to the p53 wt group when the tunor sizes of the two groups are matched;(3)the tumor size dependence of the redox indices(such as Fp and Fp redox ratio)is significant in the p531-group with the larger ones being more oxidized and more hetero-geneous in their redox state,particularly more oxidized in the tumor central regions;(4)the H&E staining images of tumor soctions grossly correlate with the redox images.The present work is the first to reveal at the submillimeter scale the intratumor heterogeneity pattem of the mitochon-drial redox state in colon cancer and the first to indicate that at tissue level the mitochondial redox state is p53 dependent.The findings should assist in our understanding on colon cancer pa thology and developing new imaging biomarkers for dlinical applications.

A novel predictor of unsustained return of spontaneous circulation in cardiac arrest patients through a combination of capnography and pulse oximetry: a multicenter observational study

BACKGROUND:Unsustained return of spontaneous circulation(ROSC)is a critical barrier to survival in cardiac arrest patients.This study examined whether end-tidal carbon dioxide(ETCO_(2))and pulse oximetry photoplethysmogram(POP)parameters can be used to identify unsustained ROSC.METHODS:We conducted a multicenter observational prospective cohort study of consecutive patients with cardiac arrest from 2013 to 2014.Patients’general information,ETCO_(2),and POP parameters were collected and statistically analyzed.RESULTS:The included 105 ROSC episodes(from 80 cardiac arrest patients)comprised 51 sustained ROSC episodes and 54 unsustained ROSC episodes.The 24-hour survival rate was significantly higher in the sustained ROSC group than in the unsustained ROSC group(29.2%vs.9.4%,P<0.05).The logistic regression analysis showed that the difference between after and before ROSC in ETCO_(2)(ΔETCO_(2))and the difference between after and before ROCS in area under the curve of POP(ΔAUCp)were independently associated with sustained ROSC(odds ratio[OR]=0.931,95%confi dence interval[95%CI]0.881-0.984,P=0.011 and OR=0.998,95%CI 0.997-0.999,P<0.001).The area under the receiver operating characteristic curve ofΔETCO_(2),ΔAUCp,and the combination of both to predict unsustained ROSC were 0.752(95%CI 0.660-0.844),0.883(95%CI 0.818-0.948),and 0.902(95%CI 0.842-0.962),respectively.CONCLUSION:Patients with unsustained ROSC have a poor prognosis.The combination ofΔETCO_(2) andΔAUCp showed signifi cant predictive value for unsustained ROSC.

Prevalence of post-traumatic stress disorder and depressive symptoms among civilians residing in armed conflict-affected regions:a systematic review and meta-analysis

Background Globally,populations afflicted by armed conflict are known to have high rates of mental health disorders.Aims This meta-analysis aims to estimate the prevalence of post-traumatic stress disorder(PTSD)and depressive symptoms among civilians residing in armed conflictaffected regions.Methods This meta-analysis was conducted in accordance with the Preferred Reporting Items forSystematic Reviews and Meta-Analyses.A literature search employing MEDLINE(R),Embase Classic+Embase,APA PsyclNFO,Ovid Healthstar,Journal@Ovid Full Text,Cochrane,PTSDpubs and CINAHL was conducted from inception until 19 March 2024 to identify relevant studies.Quality assessment was performed using the Joanna Briggs Institute Critical Appraisal Checklist for Prevalence Studies,and a Comprehensive Meta-Analysiswas usedto conduct the statistical analysis.Results The search yielded 38595 articles,of which 57 were considered eligible for inclusion.The included studies comprised data from 64596 participants.We estimated a prevalence of 23.70%(95%CI 19.50%to28.40%)forPTSD symptomsand 25.60%(95%Cl 20.70%to 31.10%)for depressive features among war-afflicted civilians.The subgroup analysis based on time since the war and the country's economic status revealed the highest prevalence for both PTSD and depressive symptoms was present during the years of war and in low/middle-incomecountries.Conclusions The results of this study provide conclusive evidence of the detrimental impacts of armed conflict on mental health outcomes.Hence,it is crucial to emphasise the significance of both physical and mental health in the aftermath of war and take appropriate humanistic measures to overcome challenges in the management of psychiatric illnesses.

Probiotics for the treatment of Clostridium difficile associated disease

The purpose of this review paper is to update the current and potential future role of probiotics for Clostridium difficile-associated disease (CDAD). Included in this review, is an update on the testing of newer probiotics (e.g. , Bacillus coagulans GBI-30, 6086) in animal models of CDAD. There is a focus on the modulation of signal transduction pathways (i.e. , transcription factors like cAMP response element-binding, activator protein 1, and nuclear factor kappa B), as well as the inhibition of certain kinases (e.g. , p38 mitogen activated protein kinases) by probiotics. Inhibition of signal transduction by probiotics, such as Saccharomyces boulardii , result in multiple effects on intestinal fluid secretion, neutrophil influx into the colon, inflammation, and colonocyte apoptosis that may positively impact CDAD. Recent clinical approaches with probiotics, for the prevention of primary and recurrent CDAD, are also summarized in this review paper. Future directions for the treatment of CDAD by probiotics are also mentioned in this review. In particular, the use of multi-strain probiotic formulations such as Ecologic AAD and VSL #3 may represent a rationale pharmacological approach, particularly as adjunctive therapies for CDAD. Understanding the mechanistic basis of CDAD, and how probiotics interfere at ceratin steps in the pathogenic process, may also present the opportunity to design other multi-strain probiotics that could have a future impact on CDAD.

Altered physiology of gastrointestinal vagal afferents following neurotrauma

The adaptability of the central nervous system has been revealed in several model systems.Of particular interest to central nervous system-injured individuals is the ability for neural components to be modified for regain of function.In both types of neurotrauma,traumatic brain injury and spinal cord injury,the primary parasympathetic control to the gastrointestinal tract,the vagus nerve,remains anatomically intact.However,individuals with traumatic brain injury or spinal cord injury are highly susceptible to gastrointestinal dysfunctions.Such gastrointestinal dysfunctions attribute to higher morbidity and mortality following traumatic brain injury and spinal cord injury.While the vagal efferent output remains capable of eliciting motor responses following injury,evidence suggests impairment of the vagal afferents.Since sensory input drives motor output,this review will discuss the normal and altered anatomy and physiology of the gastrointestinal vagal afferents to better understand the contributions of vagal afferent plasticity following neurotrauma.

Mechanisms mediating the effects of alcohol and HIV anti-retroviral agents on mTORC1,mTORC2 and protein synthesis in myocytes

Alcoholism and acquired immune deficiency syndrome are associated with severe muscle wasting.This impairment in nitrogen balance arises from increased protein degradation and a decreased rate of protein synthesis.The regulation of protein synthesis is a complex process involving alterations in the phosphorylation state and protein-protein interaction of various components of the translation machinery and mammalian target of rapamycin(mTOR) complexes.This review describes mechanisms that regulate protein synthesis in cultured C2C12 myocytes following exposure to either alcohol or human immunodeficiency virus antiretroviral drugs.Particular attention is given to the upstream regulators of mTOR complexes and the downstream targets which play an important role in translation.Gaining a better understanding of these molecular mechanisms could have important implications for preventing changes in lean body mass in patients with catabolic conditions or illnesses.

THE EVOLUTION OF FIELD DEPLOYABLE fNIR SPECTROSCOPY FROM BENCH TO CLINICAL SETTINGS

In the late 1980s and early 1990s,Dr.Britton Chance and his colleagues,using picosecond-long laser pulses,spearheaded the development of time-resolved spectroscopy techniques in an effort to obtain quantitative information about the optical characteristics of the tissue.These efforts by Chance and colleagues expedited the translation of near-infrared spectroscopy(NIRS)-based techniques into a neuroimaging modality for various cognitive studies.Beginning in the early 2000s,Dr.Britton Chance guided and steered the collaboration with the Optical Brain Imaging team at Drexel University toward the development and application of afield deployable continuous wave functional near-infrared spectroscopy(fNIR)system as a means to monitor cognitive functions,particularly during attention and working memory tasks as well as for complex tasks such as war games and air tra±c control scenarios performed by healthy volunteers under operational conditions.Further,these collaborative efforts led to various clinical applications,including traumatic brain injury,depth of anesthesia monitoring,pediatric pain assessment,and brain
computer interface in neurology.In this paper,we introduce how these collaborative studies have made fNIR an excellent candidate for specified clinical and research applications,including repeated cortical neuroimaging,bedside or home monitoring,the elicitation of a positive effect,and protocols requiring ecological validity.This paper represents a token of our gratitude to Dr.Britton Chance for his influence and leadership.Through this manuscript we show our appreciation by contributing to his commemoration and through our work we will strive to advance thefield of optical brain imaging and promote his legacy.

Transdermal delivery of 4-aminopyridine accelerates motor functional recovery and improves nerve morphology following sciatic nerve crush injury in mice

Oral 4-aminopyridine(4-AP)is clinically used for symptomatic relief in multiple sclerosis and we recently demonstrated that systemic 4-AP had previously unknown clinically-relevant effects after traumatic peripheral nerve injury including the promotion of re-myelination,improvement of nerve conductivity,and acceleration of functional recovery.We hypothesized that,instead of oral or injection administration,transdermal 4-AP(TD-4-AP)could also improve functional recovery after traumatic peripheral nerve injury.Mice with surgical traumatic peripheral nerve injury received TD-4AP or vehicle alone and were examined for skin permeability,pharmacokinetics,functional,electrophysiological,and nerve morphological properties.4-AP showed linear pharmacokinetics and the maximum plasma 4-AP concentrations were proportional to TD-4-AP dose.While a single dose of TD-4-AP administration demonstrated rapid transient improvement in motor function,chronic TD-4-AP treatment significantly improved motor function and nerve conduction and these effects were associated with fewer degenerating axons and thicker myelin sheaths than those from vehicle controls.These findings provide direct evidence for the potential transdermal applicability of 4-AP and demonstrate that 4-AP delivered through the skin can enhance in-vivo functional recovery and nerve conduction while decreasing axonal degeneration.The animal experiments were approved by the University Committee on Animal Research(UCAR)at the University of Rochester(UCAR-2009-019)on March 31,2017.

Role of aberrant Sonic hedgehog signaling pathway in cancers and developmental anomalies

Development is a sophisticated process maintained by various signal transduction pathways,including the Hedgehog(Hh)pathway.Several important functions are executed by the Hh signaling cascade such as organogenesis,tissue regeneration,and tissue homeostasis,among various others.Considering the multiple functions carried out by this pathway,any mutation causing aberrant Hh signaling may lead to myriad developmental abnormalities besides cancers.In the present review article,we explored a wide range of diseases caused by aberrant Hh signaling,including developmental defects and cancers.Finally,we concluded this mini-review with various treatment strategies for Hh-induced diseases.

Global health disparities in vulnerable populations of psychiatric patients during the COVID-19 pandemic

The coronavirus disease 2019 pandemic affects psychiatric patients disproportionately compared to the general population.In this narrative review,we examine the impact of the pandemic on significant global health disparities affecting vulnerable populations of psychiatric patients:People of diverse ethnic background and color,children with disabilities,sexual and gender minorities,pregnant women,mature adults,and those patients living in urban and rural communities.The identified disparities cause worsened mental health outcomes placing psychiatric patients at higher risk for depression,anxiety and posttraumatic stress disorder symptoms.Those psychiatric patients who are ethnic minorities display barriers to care,including collective trauma and structural racism.Sexual and gender minorities with mental illness face discrimination and limited access to treatment.Pregnant women with psychiatric diagnoses show higher exposure to domestic violence.Children with disabilities face a higher risk of worsening behavior.Mature adults with psychiatric problems show depression due to social isolation.Psychiatric patients who live in urban communities face pollutants and overcrowding compared to those living in rural communities,which face limited access to telehealth services.We suggest that social programs that decrease discrimination,enhance communal resilience,and help overcome systemic barriers of care should be developed to decrease global health disparities in vulnerable population.

Nerve growth factor in muscle afferent neurons of peripheral artery disease and autonomic function

In peripheral artery disease patients,the blood supply directed to the lower limbs is reduced.This results in severe limb ischemia and thereby enhances pain sensitivity in lower limbs.The painful perception is induced and exaggerate during walking,and is relieved by rest.This symptom is termed by intermittent claudication.The limb ischemia also amplifies autonomic responses during exercise.In the process of pain and autonomic responses originating exercising muscle,a number of receptors in afferent nerves sense ischemic changes and send signals to the central nervous system leading to autonomic responses.This review integrates recent study results in terms of perspectives including how nerve growth factor affects muscle sensory nerve receptors in peripheral artery disease and thereby alters responses of sympathetic nerve activity and blood pressure to active muscle.For the sensory nerve receptors,we emphasize the role played by transient receptor potential vanilloid type 1,purinergic P2X purinoceptor 3 and acid sensing ion channel subtype 3 in amplified sympathetic nerve activity responses in peripheral artery disease.

Human equivalent dose of oral 4-aminopyridine differentiates nerve crush injury from transection injury and improves post-injury function in mice

4-Aminopyridine(4-AP), an FDA-approved drug for the symptomatic treatment of multiple sclerosis, is used to improve neuromuscular function in patients with diverse demyelinating disorders. We recently demonstrated that local, transdermal or injectable forms of 4-AP improve myelination, nerve conduction velocity, muscle atrophy, and motor function after traumatic peripheral nerve injury in mice. While oral 4-AP is most commonly used in the clinic, it is unknown whether human equivalent oral doses of 4-AP have effects on traumatic peripheral nerve injury differentiation, myelination, muscle atrophy, functional recovery, and post-injury inflammatory processes in animals. Mice with sciatic nerve crush or denervation injury received oral or intraperitoneal 4-AP(10 μg) or vehicle alone and were examined for pharmacokinetics, motor function, muscle mass, intrinsic muscle force, nerve morphological and gene expression profiles. 4-AP showed linear pharmacokinetics and the maximum plasma 4-AP concentrations were proportional to 4-AP dose. Acute single dose of oral 4-AP administration induced a rapid transient improvement in motor function that was different in traumatic peripheral nerve injury with or without nerve continuity, chronic daily oral 4-AP treatment significantly enhanced post crush injury motor function recovery and this effect was associated with improved myelination, muscle mass, and ex vivo muscle force. Polymerase chain reaction array analysis with crushed nerve revealed significant alterations in gene involved in axonal inflammation and regeneration. These findings provide convincing evidence that regardless of the route of administration, 4-AP can acutely differentiate traumatic peripheral nerve injury with or without nerve continuity and can enhance in vivo functional recovery with better preservation of myelin sheaths, muscle mass, and muscle force. The animal experiments were approved by the University Committee on Animal Research(UCAR) at the University of Rochester(UCAR-2009-019) on March 31, 2017.

Review of barriers and interventions to promote treatment engagement for pediatric attention deficit hyperactivity disorder care

Attention deficit hyperactivity disorder(ADHD)is a common and impairing behavioral health disorder,impacting over 5%of children worldwide.There are multiple evidence-based pharmacological and psychosocial treatments for ADHD,and greater service utilization is associated with improved acute and long-term outcomes.However,long-term outcomes are suboptimal as multimodal treatments are often not accessed and most care ends prematurely.This narrative review discusses barriers to engagement for children and adolescents with ADHD and their families as well as interventions to overcome these barriers.Families face a variety of structural and attitudinal barriers,ranging from cost and access to stigma and low self-efficacy to successfully implement change.There are multiple interventions that may enhance engagement with ADHD care including psychoeducation,integration of behavioral services in general medical settings,telehealth as well as specific adaptations to existing ADHD treatments,such as the use of motivational interviewing or shared decision making.Integration of behavioral health into general medical settings and telehealth have been found in controlled studies to increase access by reducing both structural and attitudinal barriers.Adding motivational interviewing,shared decision making and other engagement interventions to evidence-based ADHD treatments has been found to reduce attitudinal barriers that translates into improved participation and satisfaction while enhancing outcomes.However,little is known about how to promote extended engagement with ADHD services even though a chronic care model for ADHD is recommended.

Unexpected Increase in Arterial to End-Tidal CO₂Gradient in a Child Undergoing Embolization of MAPCAs

A 17-month-old infant with multiple aorto-pulmonary collateral arteries (MAPCAs) and pulmonary hypertension presented for diagnostic catheterization. On the day of the procedure, the infant was asymptomatic with oxygen saturation in the 90’s on 1.0 L/min O2 nasal cannula. His parents denied any recent illness. During the procedure, one coil was inadvertently embolized into the right lung resulting in markedly increased pulmonary artery pressures. The Pa-etCO2 gradient increased to 25 mmHg from a baseline of 2 mmHg. Therapy was initiated to reduce the PaCO2. The patient could not be weaned from mechanical ventilation due to elevated PA pressures.

General anesthetic agents induce neurotoxicity through astrocytes

Neuroscientists have recognized the importance of astrocytes in regulating neurological function and their influence on the release of glial transmitters.Few studies,however,have focused on the effects of general anesthetic agents on neuroglia or astrocytes.Astrocytes can also be an important target of general anesthetic agents as they exert not only sedative,analgesic,and amnesic effects but also mediate general anesthetic-induced neurotoxicity and postoperative cognitive dysfunction.Here,we analyzed recent advances in understanding the mechanism of general anesthetic agents on astrocytes,and found that exposure to general anesthetic agents will destroy the morphology and proliferation of astrocytes,in addition to acting on the receptors on their surface,which not only affect Ca^(2+)signaling,inhibit the release of brain-derived neurotrophic factor and lactate from astrocytes,but are even involved in the regulation of the pro-and anti-inflammatory processes of astrocytes.These would obviously affect the communication between astrocytes as well as between astrocytes and neighboring neurons,other neuroglia,and vascular cells.In this review,we summarize how general anesthetic agents act on neurons via astrocytes,and explore potential mechanisms of action of general anesthetic agents on the nervous system.We hope that this review will provide a new direction for mitigating the neurotoxicity of general anesthetic agents.

General anesthetic agents induce neurotoxicity through oligodendrocytes in the developing brain

General anesthetic agents can impact brain function through interactions with neurons and their effects on glial cells.Oligodendrocytes perform essential roles in the central nervous system,including myelin sheath formation,axonal metabolism,and neuroplasticity regulation.They are particularly vulnerable to the effects of general anesthetic agents resulting in impaired proliferation,differentiation,and apoptosis.Neurologists are increasingly interested in the effects of general anesthetic agents on oligodendrocytes.These agents not only act on the surface receptors of oligodendrocytes to elicit neuroinflammation through modulation of signaling pathways,but also disrupt metabolic processes and alter the expression of genes involved in oligodendrocyte development and function.In this review,we summarize the effects of general anesthetic agents on oligodendrocytes.We anticipate that future research will continue to explore these effects and develop strategies to decrease the incidence of adverse reactions associated with the use of general anesthetic agents.

新型冠状病毒感染相关疼痛

目前研究表明,有相当一部分病人在感染新型冠状病毒同时或后期出现头痛、腹痛、关节痛、肌痛、骨痛和或神经病理性疼痛等相关症状。为了加强疼痛科医师对新型冠状病毒感染相关疼痛的认识,提高新型冠状病毒感染相关疼痛的诊断水平和完善相关治疗方案,本文将对新型冠状病毒感染相关疼痛的发病率、可能机制和影像学表现等方面进行综述,以期为临床有效预防和治疗新型冠状病毒感染相关疼痛提供参考。

紫杉醇诱导的胰腺癌SW1990细胞凋亡过程中转录激活因子5和Bax表达水平的变化

目的转录激活因子5(Activating transcription factor 5,ATF5)是一个新的与肿瘤细胞分化、增殖及凋亡密切相关的因子。文中检测胰腺癌SW1990细胞中ATF5的表达,并进一步研究紫杉醇(Paclitaxel,PTX)诱导的人胰腺癌SW1990细胞凋亡的水平,及其与ATF5、Bax表达水平的相关性。方法 RT-PCR检测未经药物处理的SW1990细胞中ATF5 mRNA表达水平;以不同浓度的紫杉醇(0、6.25、12.5、25、50、100、200 nmol/L)作用SW1990细胞不同时间(0、6、12、24、48 h),噻唑蓝(MTT)比色法检测细胞增殖情况;用100 nmol/L紫杉醇作用SW1990细胞不同时间(0、12、24、48 h)后,观察形态学变化并用Annexin V/7-AAD双染法,流式细胞仪检测细胞凋亡情况;采用RT-PCR检测紫杉醇作用不同时间后ATF5、Bax的mRNA表达变化。结果胰腺癌SW1990细胞中表达ATF5。紫杉醇抑制胰腺癌SW1990细胞的增殖,并在一定范围内呈剂量、时间相关性。随着紫杉醇作用时间的增加,流式细胞仪检测凋亡率显著提高。半定量RT-PCR检测结果显示:ATF5、Bax mRNA表达均明显增强,且两者之间存在相关性(r=0.916,P<0.05)。结论 ATF5在胰腺癌SW1990细胞中高表达,并且在紫杉醇诱导的细胞凋亡过程中,表达量进一步上升,其变化趋势与Bax基因相似。提示ATF5参与紫杉醇诱导的细胞凋亡,并可能与Bax的凋亡途径存在相关性。