Angiotensin II in the treatment of distributive shock: a systematic-review and meta-analysis.

BACKGROUND: While non-norepinephrine vasopressors are increasingly used as a rescue therapy in cases of norepinephrine-refractory shock, data on their efficacy are limited. This systematic review and meta-analysis aims to synthesize existing literature on the efficacy of Angiotensin II (ATII) in distributive shock. METHODS: We pre-registered our meta-analysis with PROSPERO (CRD42023456136). We searched PubMed, Scopus, and gray literature for studies presenting outcomes on ATII use in distributive shock. The primary outcome of the meta-analysis was all-cause mortality. We used a random effects model to calculate pooled risk ratio (RR) and 95% confidence intervals (CI). RESULTS: By incorporating data from 1555 patients included in 10 studies, we found that however all-cause mortality was similar among patients receiving ATII and controls (RR 1.02, 95% CI 0.89 to 1.16, p = 0.81), the reduction in norepinephrine or norepinephrine-equivalent dose at 3 h after treatment initiation was greater among patients receiving ATII (MD -0.06, 95% CI -0.11 to -0.02, p = 0.008), while there were no higher rates of adverse events reported among ATII patients. CONCLUSIONS: While ATII did not reduce mortality among distributive shock patients, it allowed for significant adjunctive vasopressor reduction at 3 h without an increase in reported adverse events, deeming it a viable alternative for the increasingly adopted multimodal vasopressor for minimizing catecholamine exposure and its adverse events.

The Safety and Outcome of Minimally Invasive Staged Segmental Artery Coil Embolization (MIS2ACE) Prior Thoracoabdominal Aortic Aneurysm Repair: A Single-Center Study, Systematic Review, and Meta-Analysis.

BACKGROUND: Minimally Invasive Staged Segmental Artery Coil Embolization (MIS2ACE) is a novel technique of spinal cord preconditioning used to reduce the risk of paraplegia in thoracoabdominal aortic aneurysm (TAAA) repair. In this study, we report our experience with MIS2ACE, including both degenerative and post-dissection TAAA, while we attempt to systematically summarize relevant data available in the literature. DESIGN: single-center observational study with systematic review of the literature and meta-analysis. METHODS: Initial retrospective analysis of 7 patients undergoing MIS2ACE over 12 sessions with a subsequent systematic review of the literature and meta-analysis of the available published data (PROSPERO protocol number: CRD42023477411). Baseline patient and aneurysm characteristics, along with procedural technique and outcomes, were analyzed. One-arm pooling of proportions was used to summarize available published data. RESULTS: We treated seven patients (5 males, 71%) with a median age of 69 years (IQR 55,69). According to the Crawford classification, five patients (1%) had extent II TAAA, and two (29%) had extent III TAAA. Five patients (71%) had post-dissection -TAAA; four of them were after Stanford type A dissection, and one had a chronic type B dissection. Three patients (43%) had connective tissue disease. Of the seven patients, six (86%) underwent previous aortic surgery, while the median aneurysm diameter was 58 mm (IQR 55,58). MIS2ACE was successful in 11 sessions (92%). The median number of embolized arteries was 4 (IQR 1,4). There were no periprocedural complications in any embolization. The median embolization-operation time interval was 37.0 days (IQR 31,78). Two patients had open and five endovascular treatment. There were no events of spinal cord ischemia either after MIS2ACE or after the aortic repair. Out of the 432 initially retrieved articles, we included two studies in the meta-analysis, including patients with MIS2ACE for spinal cord preconditioning in addition to our cohort. The prevalence of pooled postoperative spinal cord ischemia among MIS2ACE patients is 1.9% (95% CI -0.028 to 0.066, p = 0.279; 3 studies; 81 patients, 127 coiling sessions). CONCLUSIONS: While the current published data is limited, our study further confirms that MIS2ACE is a technically feasible and safe option for spinal cord preconditioning.

Potential use of sodium glucose co-transporter 2 inhibitors during acute illness: a systematic review based on COVID-19.

OBJECTIVE: SGLT-2i are increasingly recognized for their benefits in patients with cardiometabolic risk factors. Additionally, emerging evidence suggests potential applications in acute illnesses, including COVID-19. This systematic review aims to evaluate the effects of SGLT-2i in patients facing acute illness, particularly focusing on SARS-CoV-2 infection. METHODS: Following PRISMA guidelines, a systematic search of PubMed, Scopus, medRxiv, Research Square, and Google Scholar identified 22 studies meeting inclusion criteria, including randomized controlled trials and observational studies. Data extraction and quality assessment were conducted independently. RESULTS: Out of the 22 studies included in the review, six reported reduced mortality in DM-2 patients taking SGLT-2i, while two found a decreased risk of hospitalization. Moreover, one study demonstrated a lower in-hospital mortality rate in DM-2 patients under combined therapy of metformin plus SGLT-2i. However, three studies showed a neutral effect on the risk of hospitalization. No increased risk of developing COVID-19 was associated with SGLT-2i use in DM-2 patients. Prior use of SGLT-2i was not associated with ICU admission and need for MV. The risk of acute kidney injury showed variability, with inconsistent evidence regarding diabetic ketoacidosis. CONCLUSION: Our systematic review reveals mixed findings on the efficacy of SGLT-2i use in COVID-19 patients with cardiometabolic risk factors. While some studies suggest potential benefits in reducing mortality and hospitalizations, others report inconclusive results. Further research is needed to clarify optimal usage and mitigate associated risks, emphasizing caution in clinical interpretation.

Who Let the Dogs Out? Unmasking the Neglected: A Semi-Systematic Review on the Enduring Impact of Toxocariasis, a Prevalent Zoonotic Infection.

Toxocariasis remains an important neglected parasitic infection representing one of the most common zoonotic infections caused by the parasite Toxocara canis or, less frequently, by Toxocara cati. The epidemiology of the disease is complex due to its transmission route by accidental ingestion of embryonated Toxocara eggs or larvae from tissues from domestic or wild paratenic hosts. Even though the World Health Organization and Centers for Disease Control classified toxocariasis amongst the top six parasitic infections of priority to public health, global epidemiological data regarding the relationship between seropositivity and toxocariasis is limited. Although the vast majority of the infected individuals remain asymptomatic or experience a mild disease, the infection is associated with important health and socioeconomic consequences, particularly in underprivileged, tropical, and subtropical areas. Toxocariasis is a disease with multiple clinical presentations, which are classified into five distinct forms: the classical visceral larva migrans, ocular toxocariasis, common toxocariasis, covert toxocariasis, and cerebral toxocariasis or neurotoxocariasis. Anthelmintic agents, for example, albendazole or mebendazole, are the recommended treatment, whereas a combination with topical or systemic corticosteroids for specific forms is suggested. Prevention strategies include educational programs, behavioral and hygienic changes, enhancement of the role of veterinarians, and anthelmintic regimens to control active infections.

Antiphospholipid syndrome nephropathy: Current knowledge and unanswered questions.

The definition of acute and chronic antiphospholipid syndrome (APS) nephropathy was recently updated using a multiphase methodology in the context of the development of the new APS classification criteria. Currently, there is no consensus for the treatment of APS nephropathy, which mainly relies on the general recommendations for the management of APS. Based on evidence from experimental studies and a few clinical studies and case series, targeted treatments such as B-cell depletion, anti-B-cell activating factor antibody, complement inhibition, mammalian target of rapamycin inhibition, and neutrophil extracellular traps or interferon targeting may show promise for the treatment of microvascular manifestations in APS, including APS nephropathy. Validation of the new APS nephropathy definition and/or efforts for improvement in proposed terminology, along with the assessment of the safety and efficacy of potential targeted treatments in randomized controlled trials, are major future research directions. In this review, we summarize the current knowledge of APS nephropathy and discuss unanswered questions.

Mortality of intubated patients with COVID-19 during first and subsequent waves: a meta-analysis involving 363,660 patients from 43 countries.

BACKGROUND: We attempted to investigate the change in mortality of intubated patients with coronavirus disease (COVID-19) from first to subsequent waves across several countries. METHODS: We pre-registered our meta-analysis with PROSPERO [Anonymized]. We searched PubMed, Scopus, and gray literature for observational studies reporting data on all-cause mortality of intubated patients with COVID-19 recruited both during first and subsequent waves of the pandemic. We considered studies published after 31 August 2020 up to 12 July 2021. The primary outcome of the meta-analysis was all-cause mortality. We used a random effects model to calculate pooled risk ratio (RR) and 95% confidence intervals (CI). RESULTS: By incorporating data of 363,660 patients from 43 countries included in 28 studies, we found that all-cause mortality of intubated patients with COVID-19 increased from first to subsequent waves (from 62.2% to 72.6%; RR 0.90, 95% CI 0.85-0.94, p < 0.00001). This finding was independent of the geo-economic variation of the included studies and persisted in several pre-specified subgroup and sensitivity analyses. CONCLUSIONS: The robust finding of this meta-analysis suggests that mortality of intubated patients with COVID-19 did not improve over time. Future research should target this group of patients to further optimize their management.

Association between timing of intubation and clinical outcomes of critically ill patients: A meta-analysis.

PURPOSE: Optimal timing of intubation is controversial. We attempted to investigate the association between timing of intubation and clinical outcomes of critically ill patients. METHODS: PubMed was systematically searched for studies reporting on mortality of critically ill patients undergoing early versus late intubation. Studies involving patients with new coronavirus disease (COVID-19) were excluded because a relevant meta-analysis has been published. "Early" intubation was defined according to the authors of the included studies. All-cause mortality was the primary outcome. Pooled risk ratio (RR) and 95% confidence intervals (CI) were calculated using a random effects model. The meta-analysis was registered with PROSPERO (CRD42021284850). RESULTS: In total, 27 studies involving 15,441 intubated patients (11,943 early, 3498 late) were included. All-cause mortality was lower in patients undergoing early versus late intubation (7338 deaths; 45.8% versus 53.5%; RR 0.92, 95% CI 0.87-0.97; p = 0.001). This was also the case in the sensitivity analysis of studies defining "early" as intubation within 24 h from admission in the intensive care unit (6279 deaths; 45.8% versus 53.6%; RR 0.93, 95% CI 0.89-0.98; p = 0.005). CONCLUSION: Avoiding late intubation may be associated with lower mortality in critically ill patients without COVID-19.

Effect of Vitamin C on Clinical Outcomes of Critically Ill Patients With COVID-19: An Observational Study and Subsequent Meta-Analysis.

BACKGROUND: Whether vitamin C provides any benefit when administered in critically ill patients, including those with coronavirus disease (COVID-19), is controversial. We endeavored to estimate the effect of administration of vitamin C on clinical outcomes of critically ill patients with COVID-19 by performing an observational study and subsequent meta-analysis. METHODS: Firstly, we conducted an observational study of critically ill patients with laboratory-confirmed COVID-19 who consecutively underwent invasive mechanical ventilation in an academic intensive care unit (ICU) during the second pandemic wave. We compared all-cause mortality of patients receiving vitamin C ("vitamin C" group) or not ("control" group) on top of standard-of-care. Subsequently, we systematically searched PubMed and CENTRAL for relevant studies, which reported on all-cause mortality (primary outcome) and/or morbidity of critically ill patients with COVID-19 receiving vitamin C or not treatment. Pooled risk ratio (RR) and 95% confidence intervals (CI) were calculated using a random effects model. The meta-analysis was registered with PROSPERO. RESULTS: In the observational study, baseline characteristics were comparable between the two groups. Mortality was 20.0% (2/10) in the vitamin C group vs. 47.6% (49/103; p = 0.11) in the control group. Subsequently, the meta-analysis included 11 studies (6 observational; five randomized controlled trials) enrolling 1,807 critically ill patients with COVID-19. Mortality of patients receiving vitamin C on top of standard-of-care was not lower than patients receiving standard-of-care alone (25.8 vs. 34.7%; RR 0.85, 95% CI 0.57-1.26; p = 0.42). CONCLUSIONS: After combining results of our observational cohort with those of relevant studies into a meta-analysis of data from 1,807 patients, we found that administration vitamin C as opposed to standard-of-care alone might not be associated with lower of mortality among critically ill patients with COVID-19. Additional evidence is anticipated from relevant large randomized controlled trials which are currently underway. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier: CRD42021276655.

An Update on Antiphospholipid Syndrome.

PURPOSE OF REVIEW: To review the recent available evidence on epidemiology, pathogenesis, clinical phenotypes, and management of antiphospholipid syndrome (APS) and summarize potential future research perspectives. RECENT FINDINGS: Accumulating evidence has further expanded our understanding of the disease, including new data about the incidence and prevalence of APS, novel pathways supporting the role of thrombo-inflammation in APS including platelet, monocyte and endothelial cell activation, pro-inflammatory cytokine and chemokine production, complement activation, neutrophil extracellular trap release, and type I interferon gene expression that could yield to new potential treatment targets, better identification of criteria and non-criteria clinical phenotypes, antiphospholipid antibody profiles and their associations with clinical outcomes, prognostic tools, and treatment strategies based on recent evidence-based recommendations for patients with thrombotic and obstetric APS, with or without systemic lupus erythematosus. Ongoing research efforts and international collaborations enhance our knowledge of this rare and often devastating syndrome and help improve patient care and health outcomes.

Abnormal Right Ventricular Free Wall Strain Prior to Prone Ventilation May Be Associated With Worse Outcome of Patients With COVID-19-Associated Acute Respiratory Distress Syndrome.

We investigated the effect of prone ventilation on right ventricular (RV) function of intubated patients with COVID-19-associated acute respiratory distress syndrome by measuring both conventional RV functional variables (namely, tricuspid annular peak systolic velocity, tricuspid annular plane systolic excursion, and fractional area change) and right ventricular free wall strain (RVFWS) using transthoracic speckle-tracking echocardiography at baseline (before prone positioning), 18 hours after prone positioning, and 1 hour after supine repositioning. We found that transthoracic echocardiography was feasible in a considerable proportion (nine patients, 75% of our cohort) of patients undergoing prone ventilation. Also, abnormal as opposed to normal RVFWS values (in the absence of conventional variables of RV dysfunction) at baseline were associated with higher mortality (100% vs 20%; p = 0.048). Finally, we found that, among patients without acute cor pulmonale or conventional markers of RV dysfunction, one session of prone ventilation may not affect right myocardial strain.

Effect of timing of intubation on clinical outcomes of critically ill patients with COVID-19: a systematic review and meta-analysis of non-randomized cohort studies.

BACKGROUND: Although several international guidelines recommend early over late intubation of patients with severe coronavirus disease 2019 (COVID-19), this issue is still controversial. We aimed to investigate the effect (if any) of timing of intubation on clinical outcomes of critically ill patients with COVID-19 by carrying out a systematic review and meta-analysis. METHODS: PubMed and Scopus were systematically searched, while references and preprint servers were explored, for relevant articles up to December 26, 2020, to identify studies which reported on mortality and/or morbidity of patients with COVID-19 undergoing early versus late intubation. "Early" was defined as intubation within 24 h from intensive care unit (ICU) admission, while "late" as intubation at any time after 24 h of ICU admission. All-cause mortality and duration of mechanical ventilation (MV) were the primary outcomes of the meta-analysis. Pooled risk ratio (RR), pooled mean difference (MD) and 95% confidence intervals (CI) were calculated using a random effects model. The meta-analysis was registered with PROSPERO (CRD42020222147). RESULTS: A total of 12 studies, involving 8944 critically ill patients with COVID-19, were included. There was no statistically detectable difference on all-cause mortality between patients undergoing early versus late intubation (3981 deaths; 45.4% versus 39.1%; RR 1.07, 95% CI 0.99-1.15, p = 0.08). This was also the case for duration of MV (1892 patients; MD - 0.58 days, 95% CI - 3.06 to 1.89 days, p = 0.65). In a sensitivity analysis using an alternate definition of early/late intubation, intubation without versus with a prior trial of high-flow nasal cannula or noninvasive mechanical ventilation was still not associated with a statistically detectable difference on all-cause mortality (1128 deaths; 48.9% versus 42.5%; RR 1.11, 95% CI 0.99-1.25, p = 0.08). CONCLUSIONS: The synthesized evidence suggests that timing of intubation may have no effect on mortality and morbidity of critically ill patients with COVID-19. These results might justify a wait-and-see approach, which may lead to fewer intubations. Relevant guidelines may therefore need to be updated.

Management of Non-criteria Manifestations in Antiphospholipid Syndrome.

PURPOSE OF THE REVIEW: To review the available evidence on the management of a variety of non-criteria manifestations in antiphospholipid syndrome (APS), including valvular disease, alveolar hemorrhage, thrombocytopenia, hemolytic anemia, APS nephropathy, skin ulcers, livedo reticularis, cognitive dysfunction, and epilepsy. RECENT FINDINGS: Current treatment relies on low-level evidence and mainly on expert consensus due to the rarity and the heterogeneity of non-criteria APS manifestations and the diversity in management approaches. Conventional anticoagulation and/or antiplatelet APS treatment do not adequately control most of non-criteria manifestations. Increasing knowledge about the contribution of inflammatory in addition to, or independently of, thrombotic mechanisms in non-criteria APS manifestations provides insight into the potential effect of novel therapies targeting B-cells, mammalian target of rapamycin, neutrophil, and complement or interferon pathways. Existing evidence is limited by lack of high-quality studies. Better understanding of the pathophysiology and clinical phenotypes of APS and well-designed prospective studies of homogenous populations are needed to provide evidence-based recommendations for the management of non-criteria APS manifestations.

Effect of Early vs. Delayed or No Intubation on Clinical Outcomes of Patients With COVID-19: An Observational Study.

Background: Optimal timing of initiation of invasive mechanical ventilation in patients with acute hypoxemic respiratory failure due to COVID-19 is unknown. Thanks to early flattening of the epidemiological curve, ventilator demand in Greece was kept lower than supply throughout the pandemic, allowing for unbiased comparison of the outcomes of patients undergoing early intubation vs. delayed or no intubation. Methods: We conducted an observational study including all adult patients with laboratory-confirmed COVID-19 consecutively admitted in Evangelismos Hospital, Athens, Greece between March 11, 2020 and April 15, 2020. Patients subsequently admitted in the intensive care unit (ICU) were categorized into the "early intubation" vs. the "delayed or no intubation" group. The "delayed or no intubation" group included patients receiving non-rebreather mask for equal to or more than 24 h or high-flow nasal oxygen for any period of time or non-invasive mechanical ventilation for any period of time in an attempt to avoid intubation. The remaining intubated patients comprised the "early intubation" group. Results: During the study period, a total of 101 patients (37% female, median age 65 years) were admitted in the hospital. Fifty-nine patients (58% of the entire cohort) were exclusively hospitalized in general wards with a mortality of 3% and median length of stay of 7 days. Forty-two patients (19% female, median age 65 years) were admitted in the ICU; all with acute hypoxemic respiratory failure. Of those admitted in the ICU, 62% had at least one comorbidity and 14% were never intubated. Early intubation was not associated with higher ICU-mortality (21 vs. 33%), fewer ventilator-free days (3 vs. 2 days) or fewer ICU-free days than delayed or no intubation. Conclusions: A strategy of early intubation was not associated with worse clinical outcomes compared to delayed or no intubation. Given that early intubation may presumably reduce virus aerosolization, these results may justify further research with a randomized controlled trial.

Type I interferon gene expression in antiphospholipid syndrome: Pathogenetic, clinical and therapeutic implications.

Type I Interferon gene expression has been shown to play an important role in the pathogenesis of several systemic autoimmune disorders, paving the way for its potential use as a surrogate marker or a therapeutic tool. While the concept of type I interferon signature and its correlation with clinical phenotypes and disease activity, along with anti-interferon targeted therapy have been vastly investigated in patients with systemic lupus erythematosus, there is a paucity of data concerning antiphospholipid syndrome patients. In this review, we summarize the current knowledge on the pathogenetic and clinical implications of type I interferon expression in antiphospholipid syndrome and discuss the therapeutic possibility of targeting molecules along the interferon signaling pathway. A number of recent studies have shown a type I interferon gene expression induction in patients with primary antiphospholipid syndrome via the plasmacytoid dendritic cell pathway, toll like receptors (TLRs) such as TLR7 and TLR9, anti-beta2glycoprotein I antibody-mediated neutrophil activation and neutrophil extracellular traps (NETs) release in a TLR4-dependent fashion, and a subsequent B cell and plasmablast activation. An association between type I interferon expression and several demographic, clinical and laboratory characteristics including age, gender, pregnancy complications such as eclampsia, anti-beta2glycoprotein I antibodies, and a negative correlation with hydroxychloroquine and/or statin use, has been shown. Correlation of high interferon scores to worse outcomes in prospective studies could direct the initiation for a prompt treatment in high-risk populations. Potential therapeutic approaches targeting type I interferon production and signaling pathway components might include anti-interferon or interferon receptor monoclonal antibodies, or an interferon based therapeutic vaccine as was indicated from previous systemic lupus erythematosus studies, TLR inhibitors including hydroxychloroquine and anti-TLR antibodies, plasmacytoid dendritic cell inhibition, adenosine-receptor agonists, and plasmablast targeting treatments. Well-designed studies are needed to further assess the immunomodulatory potential of the above targets for therapeutic intervention in patients with primary antiphospholipid syndrome.

Anti-diabetic treatment leads to changes in gut microbiome.

Numerous micro-organisms naturally reside in the human body assuming a symbiotic, or, at times, even a dysbiotic relationship with the host. These microbial populations are referred to as the human microbiota. Host microbial populations are an important mediator of gastro-intestinal mucosal permeability, bile acid metabolism, short-chain fatty acids synthesis, fermentation of dietary polysaccharides and FXR/TGR5 signaling. Variations in the composition and function of gut microbiota have been observed in type 2 diabetes mellitus, insulin resistance and obesity, as well as in inflammatory bowel diseases. The microbial imbalance induced by such pathological processes is described as dysbiosis. In this review, we describe the pathophysiological links between type 2 diabetes mellitus and gut microbiota, explore the effect of anti-diabetic drugs on gut microbiota and suggest possible therapeutic targets.

Antidiabetic treatment on memory and spatial learning: From the pancreas to the neuron.

The detrimental effects of constant hyperglycemia on neural function have been quantitatively and qualitatively evaluated in the setting of diabetes mellitus. Some of the hallmark features of diabetic encephalopathy (DE) are impaired synaptic adaptation and diminished spatial learning capacity. Chronic and progressive cognitive dysfunction, perpetuated by several positive feedback mechanisms in diabetic subjects, facilitates the development of early-onset dementia and Alzheimer's disease. Despite the numerous clinical manifestations of DE having been described in detail and their pathophysiological substrate having been elucidated in both type 1 and type 2 diabetes mellitus, an effective therapeutic approach is yet to be proposed. Therefore, the aim of this review is to summarize the growing body of evidence concerning the effect of current antidiabetic treatment options on diabetic and non-DE.

Effects of antidiabetic drugs on epicardial fat.

Epicardial adipose tissue is defined as a deposit of adipocytes with pathophysiological properties similar to those of visceral fat, located in the space between the myocardial muscle and the pericardial sac. When compared with subcutaneous adipose tissue, visceral adipocytes show higher metabolic activity, lipolysis rates, increased insulin resistance along with more steroid hormone receptors. The epicardial adipose tissue interacts with numerous cardiovascular pathways via vasocrine and paracrine signalling comprised of pro- and anti-inflammatory cytokines excretion. Both the physiological differences between the two tissue types, as well as the fact that fat distribution and phenotype, rather than quantity, affect cardiovascular function and metabolic processes, establish epicardial fat as a biomarker for cardiovascular and metabolic syndrome. Numerous studies have underlined an association of altered epicardial fat morphology, type 2 diabetes mellitus (T2DM) and adverse cardiovascular events. In this review, we explore the prospect of using the epicardial adipose tissue as a therapeutic target in T2DM and describe the underlying mechanisms by which the antidiabetic drugs affect the pathophysiological processes induced from adipose tissue accumulation and possibly allow for more favourable cardiovascular outcomes though epicardial fat manipulation.

Circulating microRNAs as biomarkers for diabetic neuropathy: A novel approach.

Oxidative stress stemming from tissue exposure to constant hyperglycemia is one of the major pathogenetic pathways of diabetic macro- and microvascular complications. Diabetic polyneuropathy, commonly manifesting as distal, symmetrical sensorimotor polyneuropathy, is characterized by progressive severity of symptoms, with rates analogous to the quality of glycemic control achieved by the patients and physicians. Palliative care with analgesics and aggressive glycemic control often improve quality of life in the absence of causative treatment. Currently, there is a growing body of evidence indicating the role of microRNAs in the pathogenesis of diabetic complications, with emphasis on diabetic nephropathy and neuropathy. Therefore, in this review, we aim to explore the role of microRNAs and their polymorphisms in the pathophysiology of diabetic polyneuropathy, as well as, the possibility of novel diagnostic and therapeutic applications by epigenetic profiling and manipulation.