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Background: This comprehensive systematic review and meta-analysis investigated the mid- to long-term efficacy and safety of stem cell therapy in patients with acute myocardial infarction (AMI). Methods: The study encompassed 79 randomized controlled trials with 7103 patients, rendering it the most up-to-date and extensive analysis in this field. This study specifically focused on the impact of stem cell therapy on left ventricular ejection fraction (LVEF), major adverse cardiac events (MACE), and infarct size. Results: Stem cell therapy significantly improved LVEF at 6, 12, 24, and 36 months post-transplantation compared to control values, indicating its potential for long-term cardiac function enhancement. A trend toward reduced MACE occurrence was observed in the intervention groups, suggesting the potential of stem cell therapy to lower the risk of cardiovascular death, reinfarction, and stroke. Significant LVEF improvements were associated with long cell culture durations exceeding 1 week, particularly when combined with high injected cell quantities (at least 108 cells). No significant reduction in infarct size was observed. Conclusions: This review highlights the potential of stem cell therapy as a promising therapeutic approach for patients with AMI, offering sustained LVEF improvement and a potential reduction in MACE risk. However, further research is required to optimize cell culture techniques, determine the optimal timing and dosage, and investigate procedural variations to maximize the efficacy and safety of stem cell therapy in this context. [ABSTRACT FROM AUTHOR]

Background: Changes in thyrotropin receptor antibody (TRAb) levels are associated with the clinical outcomes of Graves' hyperthyroidism. However, the effects of the patterns of TRAb changes on patient prognosis according to the treatment duration of antithyroid drugs (ATDs) are not well established. Methods: In this retrospective cohort study, 1,235 patients with Graves' hyperthyroidism who were treated with ATDs for more than 12 months were included. Patients were divided into two groups according to treatment duration: group 1 (12-24 months) and group 2 (>24 months). Risk prediction models comprising age, sex, and either TRAb levels at ATD withdrawal (model A) or patterns of TRAb changes (model B) were compared. Results: The median treatment duration in groups 1 (n=667, 54%) and 2 (n=568, 46%) was 17.3 and 37.1 months, respectively. The recurrence rate was significantly higher in group 2 (47.9%) than in group 1 (41.4%, P=0.025). Group 2 had significantly more goiter, thyroid eye disease, and fluctuating and smoldering type of TRAb pattern compared with group 1 (all P<0.001). The patterns of TRAb changes were an independent risk factor for recurrence after adjusting for other confounding factors in all patients, except in group 1. Integrated discrimination improvement and net reclassification improvement analyses showed that model B performed better than model A in all patients, except in group 1. Conclusion: The dynamic risk model, including the patterns of TRAb changes, was more suitable for predicting prognosis in patients with Graves' hyperthyroidism who underwent longer ATD treatment duration. [ABSTRACT FROM AUTHOR]

Background: Understanding pharmacokinetics (PK) and pharmacodynamics (PD) of the sustained-release liothyronine (SR-T3) is of paramount importance to design therapeutic regimens that are able to simulate normal thyroid hormone secretion while avoiding excursions in the T3 serum concentration. Here, we designed a parallel randomized clinical trial to characterize the PK and PD of the combined preparations of LT4 + SR-T3 in hypothyroid patients. Methods: Radioiodine-treated hypothyroid patients over 20 years of age, who attained euthyroidism with LT4 monotherapy were recruited from the Endocrine Clinic in Tehran. The patients were allocated to two intervention groups of group A: 9 µg SR-T3 plus 68.5 μg LT4 (ratio 1:7.5) and group B: 12 µg SR-T3 plus 60 µg LT4 (ratio 1:5), and a control group with LT4 monotherapy. For PD study, thyroid hormone profile was evaluated at 8 and 12 weeks intervals after intervention. To assess PK properties of SR-T3, T3-Cmax, T3-Tmax and AUC0 − 24 were calculated at the last visit. Results: Serum T4 and FT4 concentrations decreased in the intervention groups after 3 months. No significant difference was observed in serum T3 and FT3 concentrations before and after intervention. Serum T3/T4 ratio increased significantly in the intervention groups after intervention, with the highest increase in group B from 8.6 ± 2.03 at baseline to 12.2 ± 1.6. Comparison of trial groups at follow-up showed no differences in serum TSH, T4, T3 and T3/T4 concentrations among different groups. During 24 h, minimal variation in serum T3 concentration was observed in group B with mean ∆T3 of 15.4 ± 10.5 ng/dl. T3-Tmax, T3-Cmax and AUC0 − 24 in the combined sustained-release preparation were 4.38 ± 1.1 h., 101.0 ± 5.7 ng/dl and 2257 ± 110 ng.h/L, respectively which were significantly different from the control group. Conclusion: Combined treatment with a single dose of SR-T3 plus LT4 is associated with increased serum T3/T4 ratio and minimal excursions in serum T3 concentration during 24 h; however, it was not significantly different from the control group. To incorporate sustained-release T3 in the management of hypothyroidism, a higher ratio of SR-T3 to LT4 than that of the previously recommended by the international organizations is suggested. IRCT registration number: IRCT20100922004794N13. https://www.irct.ir/search/result?query=IRCT20100922004794N13. Registration date: 08/12/2021. [ABSTRACT FROM AUTHOR]

The direct/indirect responsibility of the gut microbiome in disease induction in and outside the digestive tract is well studied. These results are usually from the overpopulation of certain species on the cost of others, interaction with beneficial microflora, interference with normal epigenetic control mechanisms, or suppression of the immune system. Consequently, it is theoretically possible to cure such disorders by rebalancing the microbiome inside our bodies. This can be achieved by changing the lifestyle pattern and diet or by supplementation with beneficial bacteria or their metabolites. Various approaches have been explored to manipulate the normal microbial inhabitants, including nutraceutical, supplementations with prebiotics, probiotics, postbiotics, synbiotics, and antibiotics, or through microbiome transplantation (fecal, skin, or vaginal microbiome transplantation). In the present review, the interaction between the microbiome and epigenetics and their role in disease induction is discussed. Possible future therapeutic approaches via the reestablishment of equilibrium in our internal micro-ecosystem are also highlighted. [ABSTRACT FROM AUTHOR]

Background: Recurrent laryngeal nerve paralysis (RLNP) is a common complication after esophagectomy which can cause severe pulmonary complications. However, bilateral RLNP has been rarely reported in esophagectomy patients. The objective of our study is to investigate the clinical significance of patients who had bilateral RLNP following esophagectomy. Methods: We retrospectively reviewed patients who underwent esophagectomy at a single center from 1994 to 2018. Among these, patients with bilateral vocal cord paralysis were included in this study. Results: A total of 3217 patients were reviewed and 400 (12.4%) patients had RLNP, including 56 patients with bilateral RLNP identified by laryngoscopic examination. During the postoperative managements, 10 of the 56 patients (17.9%) required tracheostomy. Among them, two died of acute respiratory distress syndrome and the other eight patients were discharged after removing the tracheostomy tube. The median lengths of hospital and intensive care unit stay were 19.5 (range 8–157) and 2 (range 1–46) days, respectively. Forty‐six patients (83.6%) were discharged with oral feeding after swallowing therapy including tongue holding maneuver and head tilt exercise. The other five patients (8.9%) were discharged with alternative enteral feeding via jejunostomy, but they were able to achieve oral diet 2–3 months after surgery. Conclusion: Bilateral RLNP following esophagectomy was rare, but it required great attention to prevent severe respiratory complications. However, only a few patients required tracheostomy and the majority achieved oral ingestion after intensive rehabilitation. Feeding education and respiratory rehabilitation are critical during the management of patients with bilateral RLNP. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury (AKI) is a common serious complication in critically ill patients. AKI occurs in up to 50% patients in intensive care unit (ICU), with poor clinical prognosis. Renal replacement therapy (RRT) has been widely used in critically ill patients with AKI. However, in patients without urgent indications such as acute pulmonary edema, severe acidosis, and severe hyperkalemia, the optimal timing of RRT initiation is still under debate. We conducted this systematic review of randomized clinical trials (RCTs) with meta-analysis and trial sequential analysis (TSA) to compare the effects of early RRT initiation versus delayed RRT initiation.Methods: We searched databases (PubMed, EMBASE and Cochrane Library) from inception through to July 20, 2020, to identify eligible RCTs. The primary outcome was 28-day mortality. Two authors extracted the data independently. When the I2 values < 25%, we used fixed-effect mode. Otherwise, the random effects model was used as appropriate. TSA was performed to control the risk of random errors and assess whether the results in our meta-analysis were conclusive.Results: Eleven studies involving 5086 patients were identified. Two studies included patients with sepsis, one study included patients with shock after cardiac surgery, and eight others included mixed populations. The criteria for the initiation of RRT, the definition of AKI, and RRT modalities existed great variations among the studies. The median time of RRT initiation across studies ranged from 2 to 7.6 h in the early RRT group and 21 to 57 h in the delayed RRT group. The pooled results showed that early initiation of RRT could not decrease 28-day all-cause mortality compared with delayed RRT (RR 1.01; 95% CI 0.94-1.09; P = 0.77; I2 = 0%). TSA result showed that the required information size was 2949. The cumulative Z curve crossed the futility boundary and reached the required information size. In addition, early initiation of RRT could lead to unnecessary RRT exposure in some patients and was associated with a higher incidence of hypotension (RR 1.42; 95% CI 1.23-1.63; P < 0.00001; I2 = 8%) and RRT-associated infection events (RR 1.34; 95% CI 1.01-1.78; P = 0.04; I2 = 0%).Conclusions: This meta-analysis suggested that early initiation of RRT was not associated with survival benefit in critically ill patients with AKI. In addition, early initiation of RRT could lead to unnecessary RRT exposure in some patients, resulting in a waste of health resources and a higher incidence of RRT-associated adverse events. Maybe, only critically ill patients with a clear and hard indication, such as severe acidosis, pulmonary edema, and hyperkalemia, could benefit from early initiation of RRT. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review focuses on the therapeutic management and individualized approach to Group 1 pulmonary arterial hypertension (PAH), utilizing Food and Drug Administration-approved PAH-specific therapies and various interventional and surgical options for PAH. Recent Findings: The paradigm for the optimal management of PAH has shifted in recent years. Upfront combination therapy with an endothelin receptor antagonist and a phosphodiesterase 5 inhibitor is now widely accepted as standard of care. In addition, there is increasing emphasis on starting prostanoids early in order to delay time to clinical worsening. However, less is known regarding which prostanoid agent to initiate and the optimum time to do so. In order to facilitate shared decision-making, there is an increasing need for decision tools based on guidelines and collective clinical experiences to navigate between pharmacologic and interventional treatments, as well as explore innovative, therapeutic pathways for PAH. Summary: The management of PAH has become increasingly complex. With a growing number of PAH-specific therapies, intimate knowledge of the therapeutics and the potential barriers to adherence are integral to providing optimal care for this high-risk patient population. While current PAH-specific therapies largely mediate their effects through pulmonary vasodilation, ongoing research efforts are focused on ways to disrupt the mechanisms leading to pulmonary vascular remodeling. By targeting aberrations identified in the metabolism and proliferative state of pulmonary vascular cells, novel PAH treatment pathways may be just on the horizon. [ABSTRACT FROM AUTHOR]

Context: Invited update on the management of systemic autoimmune Graves disease (GD) and associated Graves orbitopathy (GO).Evidence Acquisition: Guidelines, pertinent original articles, systemic reviews, and meta-analyses.Evidence Synthesis: Thyrotropin receptor antibodies (TSH-R-Abs), foremost the stimulatory TSH-R-Abs, are a specific biomarker for GD. Their measurement assists in the differential diagnosis of hyperthyroidism and offers accurate and rapid diagnosis of GD. Thyroid ultrasound is a sensitive imaging tool for GD. Worldwide, thionamides are the favored treatment (12-18 months) of newly diagnosed GD, with methimazole (MMI) as the preferred drug. Patients with persistently high TSH-R-Abs and/or persistent hyperthyroidism at 18 months, or with a relapse after completing a course of MMI, can opt for a definitive therapy with radioactive iodine (RAI) or total thyroidectomy (TX). Continued long-term, low-dose MMI administration is a valuable and safe alternative. Patient choice, both at initial presentation of GD and at recurrence, should be emphasized. Propylthiouracil is preferred to MMI during the first trimester of pregnancy. TX is best performed by a high-volume thyroid surgeon. RAI should be avoided in GD patients with active GO, especially in smokers. Recently, a promising therapy with an anti-insulin-like growth factor-1 monoclonal antibody for patients with active/severe GO was approved by the Food and Drug Administration. COVID-19 infection is a risk factor for poorly controlled hyperthyroidism, which contributes to the infection-related mortality risk. If GO is not severe, systemic steroid treatment should be postponed during COVID-19 while local treatment and preventive measures are offered.Conclusions: A clear trend towards serological diagnosis and medical treatment of GD has emerged. [ABSTRACT FROM AUTHOR]

Background: None of the current therapeutic approaches for management of Graves' disease has been able to re-establish normal thyroid function in all patients. Objective: To describe the author's 35 years of personal experience in the management of Graves' hyperthyroidism and, in doing so, review current articles published on the long-term medical treatment of hyperthyroidism. Methods: All published articles related to ≥4 years of continuous antithyroid drug (ATD) treatment were searched. Findings were added and compared with studies published by the authors on the same topic. Results: Long-term ATD treatment is effective and safe, both in children and adults, for treatment of hyperthyroidism. Treatment of Graves' patients with ATDs >60 months causes euthyroidism up to 4 years after discontinuation of ATDs in the majority of patients. Long-term ATD therapy is not inferior to radioiodine therapy and may sometimes even be superior in some aspects, when considering serum lipid profile, cardiac function, mood, and cognition. Conclusions: Long-term ATD therapy for Graves' hyperthyroidism is efficient and safe and induces control of hyperthyroidism, without rendering the patient hypothyroid in the majority of patients. [ABSTRACT FROM AUTHOR]

Background: Almost 15% of patients with ulcerative colitis (UC) will require a proctocolectomy with ileal pouch-anal anastomosis (IPAA) as a result of fulminant colitis, dysplasia, cancer, or medical refractory diseases. Around 50% will experience pouchitis, an idiopathic inflammatory condition involving the ileal reservoir, responsible for digestive symptoms, deterioration in quality of life, and disability. Though the majority of initial cases of pouchitis are easily managed with a short course of antibiotics, in about 10% of cases, inflammation of the pouch becomes chronic with very few treatments available. Previous studies have suggested that manipulating the composition of intestinal flora through antibiotics, probiotics, and prebiotics achieved significant results for treating acute episodes of UC-associated pouchitis. However, there is currently no established effective treatment for chronic antibiotic-dependent pouchitis. Fecal microbiota transplantation (FMT) is a novel therapy involving the transfer of normal intestinal flora from a healthy donor to a patient with a medical condition potentially caused by the disrupted homeostasis of intestinal microbiota or dysbiosis.Methods: Our project aims to compare the delay of relapse of chronic recurrent pouchitis after FMT versus sham transplantation. Forty-two patients with active recurrent pouchitis after having undergone an IPAA for UC will be enrolled at 12 French centers. The patients who respond to antibiotherapy will be randomized at a ratio of 1:1 to receive either FMT or sham transplantation.Discussion: On April 30, 2014, the World Health Organization published an alarming report on antibiotic resistance. Finding an alternative medical treatment to antibiotics in order to prevent relapses of pouchitis is therefore becoming increasingly important given the risk posed by multiresistant bacteria. Moreover, if the results of this study are conclusive, FMT, which is less expensive than biologics, could become a routine treatment in the future.Trial Registration: ClinicalTrials.gov, NCT03524352. Registered on 14 May 2018. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is a life-threatening condition arising from the loss and obstructive remodeling of the pulmonary arteries, leading to the sustained elevation of pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) and subsequently right ventricular (RV) failure and death. PH encompasses a group of multifactorial diseases, such as pulmonary arterial hypertension (PAH) and chronic thromboembolic PH, for which there is no treatment that can stop or reverse the progression of remodeling of the pulmonary vasculature. The identification of new molecular targets for the development of more effective drugs is thus urgently needed. In this context, macrophage migration inhibitory factor (MIF), a pleiotropic upstream proinflammatory mediator, is emerging as a promising molecular target, as it contributes to perivascular inflammation and pulmonary arterial remodeling, two key hallmarks of PAH that are not specifically targeted by currently approved therapies. The objective of this review is to summarize the scientific evidence on the pathogenic roles of MIF and its potential as a biomarker and therapeutic target in PH/PAH. [ABSTRACT FROM AUTHOR]

The placebo response is a myth. It does not exist in reality, and continuing to name it is hindering the optimal application of science to healing in medicine. On the surface, it is obvious that, when defined as a biological response to an inert pill (like a sugar pill), the idea of a "response" to a placebo is impossible. Inert treatments by definition do not produce responses. So why do we continue to ponder why people get better from taking inert substances and base our acceptance of legitimate treatments on demonstrating that they go beyond that response? The problem arises because we have flawed assumptions of the value that reductionistic science and the demonstration of specific effects has for healing. To support those flawed assumptions, we support the idea of "the placebo response." This causes confusion among patients, clinicians, regulators, and even scientists. Legitimate medical treatments have become defined as those that do more than produce a placebo response. An entire pharmaceutical industry and its regulators attempt to control and profit by proving that small molecules produce a clinical effect greater than the placebo response. Billions of dollars are made when that is proven, often even when the size of the response in the active over the placebo group is miniscule. The fact is people heal and that inherent healing capacity is both powerful and influenced by mental, social, and contextual factors that are embedded in every medical encounter since the idea of treatment began. In this chapter, I argue that our understanding of healing and ability to enhance it will be accelerated if we stop using the term "placebo response" and call it what it is—the meaning response, and its special application in medicine called the healing response. [ABSTRACT FROM AUTHOR]

Background and objectives: An invasive approach is recommended as the treatment of patients with non-ST elevated acute coronary syndromes (NSTE-ACS). However, it remains unclear that the optimal time of angiography and intervention for patients with NSTE-ACS at present. This study was designed to compare the effect of early and delayed invasive strategies on short-medium term prognosis in patients with those. Methods: Pubmed, Cochrane Library and Embase were searched up to Dec-30-2018. Randomized clinical trials comparing an early versus a delayed invasive strategy in patients with NSTE-ACS were included. The primary endpoint (all-cause death and recurrent myocardial infarction) and secondary endpoint (major bleeding and recurrent revascularization), as well as composite endpoint were assessed by random or fixed effected meta-analysis with software RevMan 5.3 version after short-medium term follow up. Result: A total of six randomized clinical trials involving 4,277 early or delayed invasive strategies patients with NSTE-ACS were included in the meta-analysis. Time to coronary angiography varied from 0.5 to 24 h in the early invasive strategy and from 18.6 to 72 h in the delayed invasive strategy. There was a statistical difference in the primary endpoint of all-cause death among patients with NSTE-ACS between early and delayed invasive strategies (4.6% vs 6%; OR:0.76; 95% CI:0.58 to 1.00; P = 0.05; I2 = 0%), but not for recurrent myocardial infarction (6.0% vs 6.3%; OR: 0.94; 95% CI: 0.55 to 1.61; P = 0.82; I2 = 60%). The major bleeding in patients with NSTE-ACS was similar between both invasive strategies (2.7% vs 3.1%; OR:0.88; 95% CI:0.59 to 1.31; P = 0.54; I2 = 0%). However, the composite endpoint in the early invasive strategy patients with NSTE-ACS was significantly lower than that of the delayed invasive strategy (10.9% vs 13.9%; OR:0.76; 95% CI:0.63 to 0.92; P = 0.006; I2 = 0%), and the recurrent revascularization between both strategies was just the opposite (8.7% vs 5.9%; OR:1.5; 95%CI:1.15 to 1.97; P = 0.003; I2 = 0%). Conclusion: The systematic review and meta-analysis demonstrated that the early invasive strategy had a beneficial trend on all-cause death and significantly reduced the composite endpoint in patients with NSTE-ACS, but increased the rate of revascularization. These data could provide a solution for patients with those. [ABSTRACT FROM AUTHOR]

Cardiovascular events are the leading cause of death worldwide. In this sense, cardiovascular diseases (CVD) are the main products of atherosclerosis (ATR), whose origin is multifactorial. The measurable identification of the so-called cardiovascular risk factors (CRF) was a great advance for its prevention. Scientific evidences have shown that the reduction of mortality due to cardiovascular disease is an important achievement of the optimal control of CRF. However, a large proportion of patients have cardiovascular events when CRF is controlled. It is therefore imperative to stratify the patient's risk in order to design the specific and individual treatment strategy. Currently, there are cardiovascular risk classification (CVR) scales that contemplate the combination of the multiple CRF that patients may present, although it is known that most of these algorithms sub- or overestimate the possibility of cardiovascular events. The incorporation of intermediate cardiovascular surrogates to CRF and events, such as the measurement of carotid atherosclerosis, is demonstrating an improvement in the diagnosis and fewer events in the healthy population, with high cardiovascular risk, treated with the incorporation of these to the diagnostic and therapeutic algorithms. [ABSTRACT FROM AUTHOR]

Background: The standard of care in management of hypothyroidism is treatment with levothyroxine (L-T4). Sometimes patients are dissatisfied with L-T4 and the combination of levo-triiodothyronine (L-T3) with L-T4 is considered. Methods: We performed a systematic review and meta-analysis of blinded randomized controlled trials (RCTs), reporting how often hypothyroid patients prefer combination L-T3/L-T4 treatment to L-T4 alone. We also explored for explanatory factors for combination therapy preference in sensitivity analyses examining trial, patient, and disease characteristics. Potential dose-response relationships were explored using meta-regression analyses. We searched 9 electronic databases (from inception until February, 2019), supplemented with a hand-search. Two reviewers independently screened abstracts and citations and reviewed full-text papers, with consensus achieved on the included studies. Two reviewers independently critically appraised the quality of included studies and abstracted the data. Random effects meta-analyses were reported for the percentage of patients preferring combination L-T3/T-T4 therapy over L-T4 alone. A binomial distribution of choices (i.e., preference of combination therapy or no preference for combination therapy) was assumed. Results: We included 7 blinded RCTs including 348 hypothyroid individuals in the primary meta-analysis. The pooled prevalence rate for preference of combination therapy over L-T4 was 46.2% (95% confidence interval 40.2%, 52.4%) (p = 0.231 for the difference from chance). There was no significant statistical heterogeneity among study results (Q = 7.32, degrees of freedom = 6, p = 0.293, I 2 = 18.0%). In sensitivity analyses, combination treatment preference was explained in part by treatment effects on TSH concentration, mood and symptoms, but not quality of life nor body weight. In a secondary dose-response meta-regression analyses, a statistically significant association of treatment preference was identified for total daily L-T3 dose, but not L-T3:L-T4 dose ratio. Conclusions: In conclusion, in RCTs in which patients and investigators were blinded to treatment allocation, approximately half of participants reported preferring combination L-T3 and L-T4 therapy compared to L-T4 alone; this finding was not distinguishable from chance. An observed potential positive L-T3 dose effect on treatment preference deserves further study, with careful consideration of thyroid biochemical indices and patient reported outcomes. [ABSTRACT FROM AUTHOR]

Functional mitral regurgitation (FMR) is associated with poor outcomes in patients with heart failure (HF). However, it is not clear whether FMR is just a consequence of left ventricular (LV) remodelling or a factor contributing to cardiomyopathy progression. There will be more clarity about this controversy when the effects of FMR correction on outcomes will be shown. FMR correction can be performed surgically or, more often, percutaneously with the MitraClip procedure. MitraClip is the most widely used device with more than 70 000 implants performed to date. Observational studies suggest that MitraClip treatment of FMR is safe and associated with improved symptoms, quality of life and functional status in HF patients. Two recently randomized controlled clinical trials have investigated the impact of MitraClip on the outcomes of HF patients: Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation (MITRA-FR) and Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT). Both trials randomized patients to MitraClip plus guideline-directed medical therapy (GDMT) or GDMT alone. No reduction in the primary endpoint of all-cause mortality or HF hospitalizations was shown in MITRA-FR, whereas a significant reduction in HF hospitalizations (primary endpoint) as well as in mortality alone were shown in COAPT. The aim of this review is to summarize the pathophysiology, prevalence, prognostic role and management of FMR, focusing on the differences between MITRA-FR and COAPT and trying to provide possible explanations for the diverging results. We speculate that the two trials should be interpreted as complementary rather than opposite. Patients with severe FMR (effective regurgitant orifice area > 30 mm2 ) despite maximum tolerated GDMT (including cardiac resynchronization therapy), and without too advanced cardiomyopathy seem to be the best candidates for MitraClip treatment. MITRA-FR and COAPT provide us a long awaited 'proof of concept': FMR may be considered a leading actor in cardiomyopathy progression rather than a mere marker of severity. [ABSTRACT FROM AUTHOR]

Newly revealed links between inflammation, obesity, and cardiometabolic syndrome have created opportunities to try previously unexplored therapeutic modalities in these common and life-risking disorders. One potential modulator of these complex disorders is the gut microbiome, which was described in recent years to be altered in patients suffering from features of cardiometabolic syndrome and to transmit cardiometabolic phenotypes upon transfer into germ-free mice. As a result, there is great interest in developing new modalities targeting the altered commensal bacteria as a means of treatment for cardiometabolic syndrome. Fecal microbiota transplantation (FMT) is one such modality in which a disease-associated microbiome is replaced by a healthy microbiome configuration. So far clinical use of FMT has been overwhelmingly successful in recurrent Clostridium difficile infection and is being extensively studied in other microbiome-associated pathologies such as cardiometabolic syndrome. This review will focus on the rationale, promises and challenges in FMT utilization in human disease. In particular, it will overview the role of the gut microbiota in cardiometabolic syndrome and the rationale, experience, and prospects of utilizing FMT treatment as a potential preventive and curative treatment of metabolic human disease. [ABSTRACT FROM AUTHOR]

The present study used inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) to compare survival benefits among 112 patients with resectable, stage II–IV esophageal squamous cell carcinoma (SCC) treated between 1996 and 2016 with neoadjuvant chemoradiotherapy (NAC) plus surgery (Group A, n=55) or with surgery alone (Group B, n=57). Their propensity scores (PS) were calculated using a multivariable logistic regression model in which age, sex, cancer site, primary tumor length, cTNM stage, lymph node metastasis and depth of tumor invasion were the independent variables, and used to match Groups A and B according to the IPTW and matching method. After IPTW and PSM, univariate analysis was used to assess overall survival (OS) and disease-free survival (DFS), followed by Cox proportional hazard models for OS using IPTW between the two groups and the subgroups. After PSM, 5-year OS and DFS were significantly higher in Group A (OS: 65.2%, DFS: 65.2%) compared with Group B (OS: 31.2%, DFS: 20.87%). Similarly, after IPTW, OS and DFS were significantly higher in Group A compared with Group B patients. Five-year OS was 73.18% for Group A and 37.69% for Group B (hazard ratio: 0.2899, 95% confidence interval: 0.1167–0.7205). To conclude, treatment was more effective in Group A patients with clinical stage II, N0 and T3 disease involving the mid-esophagus. It was concluded that for patients with esophageal SCC, NAC plus esophagectomy exhibited improved survival compared with surgery alone, as demonstrated by use of IPTW and PSM methods. [ABSTRACT FROM AUTHOR]

The incidence of esophagogastric junction (EGJ) cancer has been significantly increasing in Western countries. Appropriate planning for surgical therapy requires a reliable classification of EGJ cancers with respect to their exact location. Clinically, the most accepted classification of EGJ cancers is "adenocarcinoma of the EGJ" (AEG or "Siewert"), which divides tumor center localization into AEG type I (distal esophagus), AEG type II ("true junction"), and AEG type III (subcardial stomach). Treatment strategies in western countries routinely employ perioperative chemotherapy or neoadjuvant chemoradiation for cases of locally advanced cancers. The standard surgical treatment strategies are esophagectomy for AEG type I and gastrectomy for AEG type III cancers. For "true junctional cancers," i.e., AEG type II, whether the extension of resection in the oral or aboral direction represents the most effective surgical therapy remains debatable. This article reviews the history of surgical EGJ cancer treatment and current surgical strategies from a Western perspective. [ABSTRACT FROM AUTHOR]

Thyroid hormones have long been known to have a range of effects on the cardiovascular system. However, significant knowledge gaps exist concerning the precise molecular and biochemical mechanisms governing these effects and the optimal strategies for management of abnormalities in thyroid function in patients with and without preexisting cardiovascular disease. In September 2017, The National Heart, Lung, and Blood Institute convened a Working Group with the goal of developing priorities for future scientific research relating thyroid dysfunction to the progression of cardiovascular disease. The Working Group reviewed and discussed the roles of normal thyroid physiology, the consequences of thyroid dysfunction, and the effects of therapy in three cardiovascular areas: cardiac electrophysiology and arrhythmias, the vasculature and atherosclerosis, and the myocardium and heart failure. This report describes the current state of the field, outlines barriers and challenges to progress, and proposes research opportunities to advance the field, including strategies for leveraging novel approaches using omics and big data. The Working Group recommended research in three broad areas: 1) investigation into the fundamental biology relating thyroid dysfunction to the development of cardiovascular disease and into the identification of novel biomarkers of thyroid hormone action in cardiovascular tissues; 2) studies that define subgroups of patients with thyroid dysfunction amenable to specific preventive strategies and interventional therapies related to cardiovascular disease; and 3) clinical trials focused on improvement in cardiovascular performance and cardiovascular outcomes through treatment with thyroid hormone or thyromimetic drugs. [ABSTRACT FROM AUTHOR]

Objective: Renal replacement therapy (RRT) is the treatment of choice for severe acute kidney injury, but there are no firm guidelines as to the time of initiation of RRT in the critically ill. The primary objective of this study is to determine 1-month mortality rates of early versus late dialysis in critical care. As secondary end points, we provide a cost analysis of early versus late RRT initiation, intensive care unit (ICU) length of stay (LOS), hospital LOS, and number of patients on dialysis at day 60 postrandomization. Data Sources: We identified all randomized controlled trials (RCTs) through EMLINE and MEDBASE that examined adult patients admitted to critical care who were randomized to receiving early dialysis versus standard of care. Study Selection: Inclusion criteria: (1) RCTs conducted after the year 2000, (2) the population evaluated had to be adults admitted to ICU, (3) the intervention had to be early RRT versus standard care, and (4) outcomes had to measure patient mortality. Data Extraction: Two independent investigators reviewed search results and identified appropriate studies. Information was extracted using standardized case report forms. Data Synthesis: Overall, 7 RCTs were included with a total of 1400 patients. Early RRT showed no survival benefit when compared to standard treatment (odds ratio [OR], 0.90 95% confidence interval [95% CI] 0.70-1.15, P = .39). There was no significant difference in length of hospital stay in patients with early RRT (−1.55 days [95% CI −4.75 to 1.65, P = .34]), in length of ICU stay (−0.79 days [95% CI −2.09 to 0.52], P = .24), or proportion of patients on dialysis at day 60 (OR 0.93 [95% CI 0.62 to 1.43], P = .79). Per patient, there is likely a small increase in costs (

Acute kidney injury (AKI) is common in critically ill patients and associated with increased morbidity and mortality. With the increased use of renal replacement therapy (RRT) for severe AKI, the optimal time for initiation of RRT has become one of the most probed and debated topic in the field of nephrology and critical care. There appears to be an increased trend toward earlier initiation of RRT to avoid life-threatening complications associated with AKI. Despite the presence of a plethora of studies in this field, the lack of uniformity in study design, patient population types, definition of early and late initiation, modality of RRT, and results, the optimal time for starting RRT in AKI still remains unknown. The beneficial effects reported in observational studies have not been supported by clinical trials. Recently, 2 of the largest randomized control trials evaluating the timing of RRT in critically ill patients with AKI showed differing results. We provide an in-depth review of the available data on the timing of dialysis in patients with AKI. [ABSTRACT FROM AUTHOR]

Summary: Ancillary factors, not directly related to treatment, often play a significant role by affecting therapeutic outcome. A search of the literature was conducted including words related to the placebo phenomenon and orofacial diseases. Therefore, critical factors have been grouped into three major categories: (a) the natural course of the diseases; (b) the regression of the symptoms to their mean intensity; and (c) placebo response. This topical narrative review describes the elements mentioned above, provides an up‐to‐date overview of the hot topics and gaps in the field and indicates developing and future research direction of the orofacial pain field. Such a knowledge might be positively used during daily clinical practice to optimise the management of orofacial pain diseases, as well as in conducting future clinical trials for validating new interventions. [ABSTRACT FROM AUTHOR]

Background: Next of kin are considered a resource for both the patient and the health service. Need for information varies with severity and duration of health changes. A clear requirement is about what to expect upon homecoming, and what supportive services are available. The picture of relatives' access to involvement and information is still somewhat unclear. Objective: To investigate what information, knowledge, and involvement next of kin considered important for managing their caring role and collaboration with their close relatives who experienced events that led to chronic illness. Design, setting, and methods: A qualitative exploratory design. Seventeen informants were recruited through various courses offered to relatives. Data were collected in 2017 from individual interviews, analyzed in an interpretative tradition, and involved qualitative content analysis. Results: The results reflect a long intervening period in between the activating incident and a clarification of the situation. This period was characterized by unpreparedness for duration of anxiety and amount of energy involved in balancing the relationship. Further, the interviewees saw retrospectively that information about disease and treatment was available, but they had to find such resources themselves. Information about how to handle the situation was almost absent. Ultimately, they were disappointed over not being involved. Conclusion: Previously provided prospective information about the embedded anxiety in the situation and consequences for relationships, involvement in patients' services, and better communication about existing services seem to be significant. Health care professionals, especially in outpatient care, may improve their services by debating how they can implement family-oriented care in personalized treatment as usual. Focus on prospective information, early involvement, and relevant information about existing resources may empower relatives and relieve the experience of care burden. [ABSTRACT FROM AUTHOR]

Progress has been made into research on new therapies, mechanical and pharmacological approaches and repair/regenerative cellular therapy to treat irreversible cardiovascular pathologies, such as acute myocardial infarction. Research into cellular therapies is exploring the use of new cellular types. Although the therapeutic effects of cell therapy remain modest, results from clinical trials are encouraging. To expand this improvement, advances are being made that involve the paracrine function of stem cells, the use of growth factors, miRNA and new biomaterials. In the near future, these therapies should become part of routine clinical practice. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate the effectiveness of a greater occipital nerve (GON) blockade against a placebo and classical treatments (non‐steroidal anti‐inflammatory drugs + metoclopramide) among patients who were admitted to the emergency department (ED) with acute migraine headaches. Method: This prospective‐randomized controlled study was conducted on patients with acute migraine headaches. The patients were randomly assigned to 3 treatment groups: the GON blockade group (nerve blockade with bupivacaine), the placebo group (injection of normal saline into the GON area), and the intravenous (IV) treatment group (IV dexketoprofen and metoclopramide). Sixty acute migraine attack patients were assigned to 3 groups of 20 patients each. The pain severity was assessed at 5, 15, 30, and 45 minutes with a 10‐point pain scale score (PSS). Results: The mean decreases in the 5‐, 15‐, 30‐, and 45‐minutes PSS scores were greater in the GON blockade group than in the dexketoprofen and placebo groups. When comparing the 30‐ and 45‐minutes PSS changes, a statistically significant difference was found among the 3 groups (P = .03 and P = .03, respectively). Conclusion: A GON blockade was as effective as an IV dexketoprofen + metoclopramide treatment and superior to a placebo in patients with acute migraine headaches. Despite being an invasive procedure, a GON blockade might be an effective option for acute migraine treatment in the ED due to its rapid, easy, and safe application. [ABSTRACT FROM AUTHOR]

Background: Low molecular weight heparin (LMWH) is the guideline-endorsed treatment for cancer-associated venous thromboembolism (cVTE). Study objectives were to compare the efficacy and safety of rivaroxaban and enoxaparin in cVTE. Methods: Using a cohort study design, consecutive patients with cVTE (3/1/20137/31/2016), enrolled in the Mayo Thrombophilia Clinic Direct Oral Anticoagulants Registry, were compared to contemporary cancer patients receiving enoxaparin. The cumulative incidence of venous thromboembolism (VTE) recurrence, major and clinically relevant non-major bleeding, and survival were assessed at 3 and 12 months. Results: Ninety-eight patients received rivaroxaban (51% female, mean age 63 ± 12 years) and 168 enoxaparin (34.5% female, mean age 62 ± 15 years). The most common cancers included gastrointestinal/pancreatic, genitourinary and hematologic cancers. More than half of patients had pulmonary emboli at presentation. More than half had metastases, and two-thirds were receiving chemotherapy. At 3 months, there were no differences in VTE recurrence (rivaroxaban 1.0% vs enoxaparin 4.2%; P = .15), major bleeding (rivaroxaban 5.1% vs enoxaparin 3.6%; P = .55), or all-cause mortality (rivaroxaban 4.1% vs enoxaparin 8.9%; P = .14). At 12 months, these outcomes did not differ by treatment strategy. Conclusion: The results of this "real-world" experience with cVTE suggest that rivaroxaban may offer a safe and effective alternative to LMWH. [ABSTRACT FROM AUTHOR]

Introduction and hypothesis: To determine the effectiveness of the muscarinic receptor antagonist solifenacin (VESIcare®) in the treatment of postvoid dribbling (PVD).Methods: We carried out a multicenter, 12-week, double-blind, randomized, placebo-controlled, parallel design study. Between 2012 and 2015, a total of 118 women (age 18-89 years) with PVD at least twice/weekly, were randomized to receive solifenacin (5 mg; n = 58) or placebo (n = 60) once daily. The primary outcome was the percentage reduction in PVD episodes. Secondary outcomes included the percentage of patients with ≥50% reduction in PVD episodes and changes in quality of life.Results: There were no differences in either the primary or secondary outcome variables. Subgroup analysis, based on those with more severe disease (>10 PVD episodes/week), showed a greater and significant percentage reduction in the frequency of PVD episodes per day (60.3% vs 32.1%; p = 0.035) and a higher percentage of patients showing ≥50% reduction in the frequency of PVD episodes with solifenacin (68.1% vs 45.8%; p = 0.0476). A significant solifenacin effect occurred at week 2 and continued through week 12 for the subgroup. For solifenacin, PVD reduction was the same for the entire cohort and subgroup, whereas for placebo, it was 10% lower in the subgroup, declining from 42% to 32%.Conclusion: There were no differences in PVD outcomes between the solifenacin and placebo groups. Solifenacin may play a role in treating women with the most severe symptoms. Because of the powerful placebo response seen in this study, behavior-based interventions may be useful for treating PVD. [ABSTRACT FROM AUTHOR]

Acute myocardial infarction (AMI) is more frequently observed in patients with chronic kidney disease (CKD) than in patients without CKD. Initial treatment strategy for AMI includes primary percutaneous coronary intervention (PCI), which requires substantial amount of contrast media. We hypothesized that the clinical outcomes are comparable or worse in patients with AMI and advanced CKD off chronic hemodialysis as compared to patients with AMI and advanced CKD on chronic hemodialysis. The purpose of this study was to compare the clinical outcomes of patients with AMI and advanced CKD on hemodialysis versus off hemodialysis. A total of 148 patients with estimated glomerular filtration rate < 30 ml/min/1.73 m2 on admission were included and were divided into the HD group (n = 68) and non-HD group (n = 80). The length of hospitalization was significantly less in the HD group (15.7 ± 14.8 days) than in the non-HD group (22.4 ± 21.3 days) (P = 0.01). In-hospital death was significantly less in the HD group (10.3%) than in the non-HD group (25.0%) (P = 0.02). While the non-HD group was not significantly associated with in-hospital death after controlling clinical covariates, the non-HD group (odd ratio 2.89, 95% confidence interval 1.03-8.12, P = 0.04) was significantly associated with long hospitalization even after controlling clinical covariates. In conclusion, as compared to advanced CKD on chronic hemodialysis, advanced CKD off hemodialysis had higher morbidity and mortality in patients with AMI. Advanced CKD off hemodialysis was closely associated with long hospitalization even after controlling clinical factors. [ABSTRACT FROM AUTHOR]

The article discusses the aspects of hypothermic targeted temperature management (TTM) in the post-resuscitation care after a cardiac arrest. Topics discussed include reduction in the intracellular accumulation of calcium, pro-inflammatory response and apoptosis due to Hypothermia; improvement in neurological outcomes after induction of mild hypothermia; and the future protocols in regulation of body temperature post-cardiac arrest.

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Background: Levothyroxine sodium is widely prescribed to treat primary hypothyroidism. Conventionally, levothyroxine is asked to be taken in the morning on an empty stomach. A pilot study showed that levothyroxine intake at bedtime significantly decreased thyrotropin levels and increased free thyroxine (fT) and total triiodothyronine levels. Till date, no large randomized trial investigating the best time of levothyroxine intake, including quality-of-life evaluation has been performed. Materials and Methods: The primary objective of this study was to compare the serum thyroid stimulating hormone and fT4level between patients taking evening dose of levothyroxine with patients taking morning dose. The secondary objectives were to compare lipid profile between patients of the two groups. Results: A total of 147 patients were recruited and randomized into either of the study groups (73 in Group A and 72 in Group B). A total of 58 patients in Group A and 57 patients in Group B were considered for statistical evaluation. There was no statistical difference in achievement of euthyroidism and improvement of thyroid profile between the two groups. Changes in values of total cholesterol, triglyceride, low-density lipoprotein (LDL), very LDL and high-density lipoprotein were not significantly different between the groups. Conclusions: Levothyroxine taken at bedtime improved thyroid hormone level. Serum lipid levels showed no significant changes with bedtime versus morning intake. Clinicians may consider prescribing levothyroxine at bedtime as an alternative to the conventional morning dose. [ABSTRACT FROM AUTHOR]

Objective: Outcomes of Out-of-Hospital Cardiac Arrest (OHCA) are influenced by many factors. We postulate that paramedics who have participated in a greater number of OHCA resuscitations will have improved patient outcomes when compared to paramedics who participated in fewer resuscitations. Methods: We conducted a retrospective analysis of prospectively collected data abstracted from the cardiac arrest database of a large urban EMS system. All OHCA cases where resuscitation was attempted during the year 2014 were reviewed. Our outcome of interest was the rate of sustained Return of Spontaneous Circulation (ROSC), which is defined as ROSC for five continuous minutes or greater. The rate of sustained ROSC was calculated from cases when paramedics served in the role of the lead medic. These rates were then analyzed using the Chi-Square test. Results: A total of 1,145 cases of OHCA met criteria for inclusion in this study, of which 343 paramedics participated in at least one cardiac arrest in 2014. The median number of resuscitations was 10 with a range from 1 to 26 resuscitations. The paramedics were dichotomized into two groups; those who participated in <10 OHCAs (120/343), labeled “less experienced,” and those who participated in ≥10 OHCAs (223/343), labeled “more experienced.” Paramedics in the less experienced group had a sustained ROSC rate of 22.2% for resuscitations in which they were the lead medic, while those in the more experienced group had a rate of 28.9% (p-value = 0.047), RR 1.30 (95% CI 1.001, 1.692). Conclusions: This study demonstrated that more experienced paramedics had a statistically significant increase in achieving sustained ROSC when they were functioning in a lead role compared to less experienced paramedics. We found no other clinically significant patient outcomes related to the provider's experience. [ABSTRACT FROM AUTHOR]

A rise in reactive oxygen species (ROS) may contribute to cardiovascular disease by reducing nitric oxide (NO) levels, leading to loss of NO's vasodilator and anti-inflammatory effects. Although primarily studied in larger conduit arteries, excess ROS release and a corresponding loss of NO also occur in smaller resistance arteries of the microcirculation, but the underlying mechanisms and therapeutic targets have not been fully characterized. We examined whether either of the two subunits of telomerase, telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC), affect microvascular ROS production and peak vasodilation at baseline and in response to in vivo administration to angiotensin II (ANG II). We report that genetic loss of TERT [maximal dilation: 52.0 ± 6.1% with vehicle, 60.4 ± 12.9% with Nω-nitro-L-arginine methyl ester (L-NAME), and 32.2 ± 12.2% with polyethylene glycol-catalase (PEG-Cat) (P ＜ 0.05), means ± SD, n = 9-19] but not TERC [maximal dilation: 79 ± 5% with vehicle, 10.7 ± 9.8% with L-NAME (P ＜ 0.05), and 86.4 ± 8.4% with PEGCat, n = 4-7] promotes flow-induced ROS formation. Moreover, TERT knockout exacerbates the microvascular dysfunction resulting from in vivo ANG II treatment, whereas TERT overexpression is protective [maximal dilation: 88.22 ± 4.6% with vehicle vs. 74.0 ± 7.3% with ANG II (1,000 ng·kg-1·min-1) (P = not significant), n = 4]. Therefore, loss of TERT but not TERC may be a key contributor to the elevated microvascular ROS levels and reduced peak dilation observed in several cardiovascular disease pathologies. [ABSTRACT FROM AUTHOR]

Background: Levothyroxine replacement treatment in hypothyroidism is unable to restore physiological thyroxine and triiodothyronine concentrations in serum and tissues completely. Normal serum thyroid stimulating hormone (TSH) concentrations reflect only pituitary euthyroidism and, therefore, novel biomarkers representing tissue-specific thyroid state are needed. MicroRNAs (miRNAs), small non-coding regulatory RNAs, exhibit tissue-specific expression patterns and can be detectable in serum. Previous studies have demonstrated differential expression of (precursors of) miRNAs in tissues under the influence of thyroid hormone. Objective: To study if serum miRNA profiles are changed in different thyroid states. Design and methods: We studied 13 athyroid patients (6 males) during TSH suppressive therapy and after 4 weeks of thyroid hormone withdrawal. A magnetic bead capture system was used to isolate 384 defined miRNAs from serum. Subsequently, the TaqMan Array Card 3.0 platform was used for profiling after individual target amplification. Results: Mean age of the subjects was 44.0 years (range 20–61 years). Median TSH levels were 88.9 mU/l during levothyroxine withdrawal and 0.006 mU/l during LT4 treatment with a median dosage of 2.1 μg/kg. After normalization to allow inter-sample analysis, a paired analysis did not demonstrate a significant difference in expression of any of the 384 miRNAs analyzed on and off LT4 treatment. Conclusion: Although we previously showed an up-regulation of pri-miRNAs 133b and 206 in hypothyroid state in skeletal muscle, the present study does not supply evidence that thyroid state also affects serum miRNAs in humans. [ABSTRACT FROM AUTHOR]

Antithyroid drugs are generally selected as the first-line treatment for Graves’ Disease (GD); however, the existence of patients showing resistance or severe side effects to these drugs is an important issue to be solved. The (pro)renin receptor [(P)RR] is a multi-functional protein that activates the tissue renin-angiotensin system and is an essential constituent of vacuolar H+-ATPase, necessary for the autophagy-lysosome pathway. (P)RR is cleaved to soluble (s)(P)RR, which reflects the status of (P)RR expression. In this retrospective study, we aimed to investigate whether serum s(P)RR concentration can be used as a biomarker to predict the outcome of antithyroid drug treatment in GD patients. Serum s(P)RR levels were measured in 54 untreated GD patients and 7 control participants. Effects of medical treatment with antithyroid drugs on these levels were investigated in GD patients. Serum s(P)RR levels were significantly higher in patients with Graves’ disease than in control subjects (P<0.005) and were significantly reduced after medical treatment for Graves’ disease. High serum s(P)RR levels were associated with resistance to antithyroid drug treatment, suggesting that serum s(P)RR concentration can be used as a useful biomarker to predict the outcome of antithyroid drug treatment in these patients. Patients with Graves’ disease with low body mass index showed higher levels of serum soluble (pro)renin receptor levels than those with high body mass index. In addition, in patients with Graves’ disease, serum triglyceride levels were negatively correlated with serum soluble (pro)renin receptor levels. All these data indicated an association between low nutrient condition due to hyperthyroidism and increased (pro)renin receptor expression in these patients, suggesting that (pro)renin receptor expression could be increased in the process of stimulating intracellular energy production via activating autophagy function to compensate energy loss. [ABSTRACT FROM AUTHOR]

Background: During recent years, systematic reviews of observational studies have compared digoxin to no digoxin in patients with atrial fibrillation or atrial flutter, and the results of these reviews suggested that digoxin seems to increase the risk of all-cause mortality regardless of concomitant heart failure. Our objective was to assess the benefits and harms of digoxin for atrial fibrillation and atrial flutter based on randomized clinical trials. Methods: We searched CENTRAL, MEDLINE, Embase, LILACS, SCI-Expanded, BIOSIS for eligible trials comparing digoxin versus placebo, no intervention, or other medical interventions in patients with atrial fibrillation or atrial flutter in October 2016. Our primary outcomes were all-cause mortality, serious adverse events, and quality of life. Our secondary outcomes were heart failure, stroke, heart rate control, and conversion to sinus rhythm. We performed both random-effects and fixed-effect meta-analyses and chose the more conservative result as our primary result. We used Trial Sequential Analysis (TSA) to control for random errors. We used GRADE to assess the quality of the body of evidence. Results: 28 trials (n = 2223 participants) were included. All were at high risk of bias and reported only short-term follow-up. When digoxin was compared with all control interventions in one analysis, we found no evidence of a difference on all-cause mortality (risk ratio (RR), 0.82; TSA-adjusted confidence interval (CI), 0.02 to 31.2; I2 = 0%); serious adverse events (RR, 1.65; TSA-adjusted CI, 0.24 to 11.5; I2 = 0%); quality of life; heart failure (RR, 1.05; TSA-adjusted CI, 0.00 to 1141.8; I2 = 51%); and stroke (RR, 2.27; TSA-adjusted CI, 0.00 to 7887.3; I2 = 17%). Our analyses on acute heart rate control (within 6 hours of treatment onset) showed firm evidence of digoxin being superior compared with placebo (mean difference (MD), -12.0 beats per minute (bpm); TSA-adjusted CI, -17.2 to -6.76; I2 = 0%) and inferior compared with beta blockers (MD, 20.7 bpm; TSA-adjusted CI, 14.2 to 27.2; I2 = 0%). Meta-analyses on acute heart rate control showed that digoxin was inferior compared with both calcium antagonists (MD, 21.0 bpm; TSA-adjusted CI, -30.3 to 72.3) and with amiodarone (MD, 14.7 bpm; TSA-adjusted CI, -0.58 to 30.0; I2 = 42%), but in both comparisons TSAs showed that we lacked information. Meta-analysis on acute conversion to sinus rhythm showed that digoxin compared with amiodarone reduced the probability of converting atrial fibrillation to sinus rhythm, but TSA showed that we lacked information (RR, 0.54; TSA-adjusted CI, 0.13 to 2.21; I2 = 0%). Conclusions: The clinical effects of digoxin on all-cause mortality, serious adverse events, quality of life, heart failure, and stroke are unclear based on current evidence. Digoxin seems to be superior compared with placebo in reducing the heart rate, but inferior compared with beta blockers. The long-term effect of digoxin is unclear, as no trials reported long-term follow-up. More trials at low risk of bias and low risk of random errors assessing the clinical effects of digoxin are needed. Systematic review registration: PROSPERO CRD42016052935 [ABSTRACT FROM AUTHOR]

Background: Whilst trials of combination levothyroxine/liothyronine therapy versus levothyroxine monotherapy for thyroid hormone replacement have not shown any superiority, there remains a small subset of patients who do not feel well on monotherapy. Whilst current guidelines do not suggest routine use of combination therapy they do acknowledge a trial in such patients may be appropriate. It appears that use of combination therapy and dessicated thyroid extract is not uncommon but often being used by non-specialists and not adequately monitored. This review aims to provide practical advice on selecting patients, determining dose and monitoring of such a trial. Main body: It is important to select the correct patient for a trial so as to not delay diagnosis or potentially worsen an undiagnosed condition. An appropriate starting dose may be calculated but accuracy is limited by available formulations and cost. Monitoring of thyroid function, benefits and adverse effects are vital in the trial setting given lack of evidence of safe long term use. Also important is that patients understand set up of the trial, potential risks involved and give consent. Conclusion: Whilst evidence is lacking on whether a small group of patients may benefit from combination therapy a trial may be indicated in those who remain symptomatic despite adequate levothyroxine monotherapy. This should be undertaken by clinicians experienced in the field with appropriate monitoring for adverse outcomes in both short and long term. [ABSTRACT FROM AUTHOR]

As a family of hormones with pleiotropic effects, natriuretic peptide (NP) system includes atrial NP (ANP), B-type NP (BNP), C-type NP (CNP), dendroaspis NP and urodilatin, with NP receptor-A (guanylate cyclase-A), NP receptor-B (guanylate cyclase-B) and NP receptor-C (clearance receptor). These peptides are genetically distinct, but structurally and functionally related for regulating circulatory homeostasis in vertebrates. In humans, ANP and BNP are encoded by NP precursor A (NPPA) and NPPB genes on chromosome 1, whereas CNP is encoded by NPPC on chromosome 2. NPs are synthesized and secreted through certain mechanisms by cardiomyocytes, fibroblasts, endotheliocytes, immune cells (neutrophils, T-cells and macrophages) and immature cells (embryonic stem cells, muscle satellite cells and cardiac precursor cells). They are mainly produced by cardiovascular, brain and renal tissues in response to wall stretch and other causes. NPs provide natriuresis, diuresis, vasodilation, antiproliferation, antihypertrophy, antifibrosis and other cardiometabolic protection. NPs represent body's own antihypertensive system, and provide compensatory protection to counterbalance vasoconstrictor-mitogenic-sodium retaining hormones, released by renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS). NPs play central roles in regulation of heart failure (HF), and are inactivated through not only NP receptor-C, but also neutral endopeptidase (NEP), dipeptidyl peptidase-4 and insulin degrading enzyme. Both BNP and N-terminal proBNP are useful biomarkers to not only make the diagnosis and assess the severity of HF, but also guide the therapy and predict the prognosis in patients with HF. Current NP-augmenting strategies include the synthesis of NPs or agonists to increase NP bioactivity and inhibition of NEP to reduce NP breakdown. Nesiritide has been established as an available therapy, and angiotensin receptor blocker NEP inhibitor (ARNI, LCZ696) has obtained extremely encouraging results with decreased morbidity and mortality. Novel pharmacological approaches based on NPs may promote a therapeutic shift from suppressing the RAAS and SNS to re-balancing neuroendocrine dysregulation in patients with HF. The current review discussed the synthesis, secretion, function and metabolism of NPs, and their diagnostic, therapeutic and prognostic values in HF. [ABSTRACT FROM AUTHOR]

Aims: Iron deficiency (ID) is a common co-morbidity in patients with heart failure (HF) and has been suggested to be associated with poor prognosis. Recently completed double-blind randomised controlled trials (RCTs) studying HF patients with ID have shown improvements in functional capacity, symptoms and quality of life when treated with i.v. ferric carboxymaltose (FCM). This individual patient data meta-analysis investigates the effect of FCM vs. placebo on recurrent hospitalisations and mortality in HF patients with ID.Methods and Results: Individual patient data were extracted from four RCTs comparing FCM with placebo in patients with systolic HF and ID. The main outcome measures were recurrent cardiovascular (CV) hospitalisations and CV mortality. Other outcomes included cause-specific hospitalisations and death. The main analyses of recurrent events were backed up by time-to-first-event analyses. In total, 839 patients, of whom 504 were randomised to FCM, were included. Compared with those taking placebo, patients on FCM had lower rates of recurrent CV hospitalisations and CV mortality [rate ratio 0.59, 95% confidence interval (CI) 0.40-0.88; P = 0.009]. Treatment with FCM also reduced recurrent HF hospitalisations and CV mortality (rate ratio 0.53, 95% CI 0.33-0.86; P = 0.011) and recurrent CV hospitalisations and all-cause mortality (rate ratio 0.60, 95% CI 0.41-0.88; P = 0.009). Time-to-first-event analyses showed similar findings, with somewhat attenuated treatment effects. The administration of i.v. FCM was not associated with an increased risk for adverse events.Conclusions: Treatment with i.v. FCM was associated with a reduction in recurrent CV hospitalisations in systolic HF patients with ID. [ABSTRACT FROM AUTHOR]

The article offers update from the European Society of Cardiology (ESC) and European Association for Cardio-Thoracic Surgery (EACTS) on dual antiplatelet therapy in coronary artery disease. Topics discussed are efficacy and safety of dual antiplatelet therapy and risk stratification tools, dual antiplatelet therapy after percutaneous coronary intervention and dual antiplatelet therapy for patients treated with coronary artery bypass and those with medically managed acute coronary syndrome.

Background: There are currently no reliable biomarkers to predict relapse in Graves' disease (GD). In the present study, we investigated novel diagnostic biomarkers to predict the long-term remission of or relapse in GD. Methods: A DNA microarray analysis was performed to examine gene expression in the peripheral leukocytes of a frequently relapsing patient with GD and a patient in long-term remission after the discontinuation of antithyroid drugs (ATDs). Based on the DNA microarray analysis, we focused on Sialic acid-binding immunoglobulin-like lectin1 ( SIGLEC1) as a candidate novel biomarker to predict GD relapse. Three hundred and fifty-eight patients with GD in the thyroid clinics of four different hospitals in Japan were included in a cross-sectional study to establish whether SIGLEC1 mRNA levels distinguish GD relapse experience from long-term remission. An additional 55 patients with GD were enrolled in a prospective study to clarify whether SIGLEC1 mRNA levels at ATD discontinuation predict GD relapse. Results: SIGLEC1 mRNA levels were significantly higher in patients with GD relapse experience than in those in long-term remission. Based on the receiver operating characteristic analysis, we found that high SIGLEC1 mRNA levels (≥258.9 copies) significantly distinguished GD relapse experience from long-term remission ( p < 0.0001; sensitivity 66.7%, specificity 70.1%). In the prospective study, when the optimal cutoff value from the receiver operating characteristic curve analysis was applied to SIGLEC1 mRNA positivity at ATD discontinuation, SIGLEC1-positive patients (≥258.9 copies) showed a significantly higher cumulative risk of relapse than SIGLEC1-negative patients (<258.9 copies) ( p = 0.022, the log-rank test). Conclusions: SIGLEC1 mRNA levels have potential as a novel predictive biomarker for GD relapse. [ABSTRACT FROM AUTHOR]

The impact of liver parenchymal abnormalities on survival post-heart transplant remains unknown in pediatric Fontan patients. We assessed pediatric Fontan patients who underwent heart transplant and had documented pretransplant hepatic ultrasound (U/S) studies. Liver U/S findings were classified as normal (Group 1), mildly abnormal (Group 2, hepatomegaly/vascular congestion), or severely abnormal (Group 3, heterogeneous echotexture/nodularity). Among 30 study patients, 8 were classified as Group 1, 14 as Group 2, while 8 met Group 3 criteria. Pretransplant liver biochemistry and synthetic function were similar in all groups. Six Group 3 patients underwent liver biopsy; 4 demonstrated perisinusoidal or centrilobular fibrosis, and 2 had cirrhosis. Overall mortality was 30% (n = 9). Median follow-up was 5 years (range, 0.25-13 years). One-year survival was similar among all 3 groups ( P = .37), with a trend toward higher cumulative 5-year survival in Group 1 (100%). The majority of pediatric Fontan patients who underwent heart transplant demonstrated abnormal preoperative liver ultrasound findings. Heterogeneous echotexture or nodularity detected on U/S frequently indicates underlying liver parenchymal abnormalities. The presence of severe liver abnormalities was not associated with higher early mortality post-heart transplant in pediatric Fontan patients; however, late outcomes must be further elucidated. [ABSTRACT FROM AUTHOR]

Purpose: This study evaluated whether serum lactate levels (SLL) at admission in patients with cardiac arrest (CA) can predict successful return of spontaneous circulation (ROSC) or short-term survival, especially within the first 24 h. Materials and methods: This prospective, observational study was conducted in the emergency department (ED) of a training and research hospital from April 2015 through February 2016. It included all patients older than 18 years who presented to the ED during the study period with non-traumatic out-ofhospital cardiac arrest (OHCA). The study measured two outcomes: whether ROSC was achieved and whether short-term survival was achieved. ROSC was defined as the presence of spontaneous circulation for the first hour after cardiopulmonary resuscitation (CPR). Survival was defined as having survived for a minimum of 24 h after ROSC. Results: The study included 140 patients who were admitted to the ED with OHCA. ROSC was achieved in 55 patients (39.3%), and survival for 24 h following CAwas achieved in 42 patients (30%). The mean SLL in the ROSC (þ) and ROSC (-) groups were 9.1 ± 3.2 mmol/L and 9.8 ± 2.9 mmol/L, respectively. The mean SLL in the survivor and non-survivor groups were 8.6 ± 2.9 mmol/L and 10 ± 3.1 mmol/L, respectively. These differences were not statistically significant (p = 0.1). A multivariate regression model assessing the factors that predicted both ROSC and 24-h survival showed the odds ratio (OR) of initial SLL was 1.3 (95% CI: 1.05e1.6) and 1.1 (95% CI: 0.9e1.3), respectively. Conclusions: This study showed that in OHCA patients, SLL on admission was not associated with increased ROSC achievement or 24-h survival. [ABSTRACT FROM AUTHOR]

About 5%-10% of hypothyroid patients on T4 replacement therapy have persistent symptoms, despite normal TSH levels. It was hoped that T4 + T3 combination therapy might provide better outcomes, but that was not observed according to a meta-analysis of 11 randomized clinical trials comparing T4 monotherapy with T4 + T3 combination therapy. However, the issue is still subject of much research because normal thyroid function tests in serum may not necessarily indicate an euthyroid state in all peripheral tissues. This review evaluates recent developments in the field of T4 + T3 combination therapy. T4 monotherapy is associated with higher serum FT4 levels than in healthy subjects, and subnormal serum FT3 and FT3/FT4 ratios are observed in about 15% and 30% respectively. T4 + T3 combination therapy may mimic more closely thyroid function tests of healthy subjects, but it has not been demonstrated that relatively low serum FT3 or FT3/FT4 ratios are linked to persistent symptoms. One study reports polymorphism Thr92Ala in DIO2 is related to lower serum FT3 levels after thyroidectomy, and that the D2-Ala mutant reduces T4 to T3 conversion in cell cultures. Peripheral tissue function tests such as serum cholesterol reflect thyroid hormone action in target tissues. Using such biochemical markers, patients who had a normal serum TSH during postoperative T4 monotherapy, were mildly hypothyroid, whereas those with a TSH 0.03-=0.3 mU/L were closest to euthyroidism. Peripheral tissue function tests suggest euthyroidism more often in patients randomized to T4 + T3 rather than that to T4. Preference for T4 + T3 combination over T4 monotherapy was dose-dependently related to the presence of two polymorphisms in MCT10 and DIO2 in one small study. It is not known if persistent symptoms during T4 monotherapy disappear by switching to T4 + T3 combination therapy. The number of patients on T4 + T3 therapy has multiplied in the last decade, likely induced by indiscriminate statements on the internet. Patients are sometimes not just asking but rather demanding this treatment modality. It creates tensions between patients and physicians. Only continued research will answer the question whether or not T4 + T3 combination therapy has true benefits in some patients. [ABSTRACT FROM AUTHOR]

Dual antiplatelet therapy (DAPT) prevents recurrent ischemic events after an acute coronary syndrome (ACS) as well as stent thrombosis (ST) in patients with prior stent implantation. Nevertheless, these benefits are counterbalanced by a significant bleeding hazard, which is directly related to the treatment duration. Although DAPT has been extensively studied in numerous clinical trials, optimal treatment duration is still debated, mostly because of apparent inconsistencies among studies. Shortened treatment duration of 6 or 3 months was shown to mitigate bleeding risk compared with consensus-grounded 12-month standard duration, without any apparent excess of ischemic events. However, recent trials showed that a >12-month course of treatment reduces ischemic events but increases bleeding compared with 12 months. The inconsistent benefit of a longer DAPT course compared with shorter treatment durations is puzzling, and requires a careful appraisal of between-studies differences. We sought to summarize the existing evidence aiming at reconciling apparent inconsistencies among these studies, as well as thoroughly discuss the possible increased risk of fatal events associated with long-term DAPT. Benefits and risks of prolonging or shortening DAPT duration will be discussed, with a focus on treatment individualization. Finally, we will provide an outlook for possible future directions in the field. [ABSTRACT FROM AUTHOR]

Despite technological advances, the mortality rate for critically ill oldest old patients remains high. The intensive caring should be able to combine technology and a deep humanity considering that the patients are living the last part of their lives. In addition to the traditional goals of ICU of reducing morbidity and mortality, of maintaining organ functions and restoring health, caring for seriously oldest old patients should take into account their end-of-life preferences, the advance or proxy directives if available, the prognosis, the communication, their life expectancy and the impact of multimorbidity. The aim of this review was to focus on all these aspects with an emphasis on some intensive procedures such as mechanical ventilation, noninvasive mechanical ventilation, cardiopulmonary resuscitation, renal replacement therapy, hemodynamic support, evaluation of delirium and malnutrition in this heterogeneous frail ICU population. [ABSTRACT FROM AUTHOR]

Graves' disease (GD) is one of the most common endocrine diseases. Antithyroid drugs (ATDs) treatment is frequently used as the first-choice therapy for GD patients in most countries due to the superiority in safety and tolerance. However, GD patients treated with ATD have a relatively high recurrence rate after drug withdrawal, which is a main limitation for ATD treatment. It is of great importance to identify some predictors of the higher recurrence risk for GD patients, which may facilitate an appropriate therapeutic approach for a given patient at the time of GD diagnosis. The genetic factor was widely believed to be an important pathogenesis for GD. Increasing studies were conducted to investigate the relationship between gene polymorphisms and the recurrence risk in GD patients. In this article, we updated the current literatures to highlight the predictive value of gene polymorphisms on recurrence risk in GD patients after ATD withdrawal. Some gene polymorphisms, such as CTLA4 rs231775, human leukocyte antigen polymorphisms (DRB1*03, DQA1*05, and DQB1*02) might be associated with the high recurrence risk in GD patients. Further prospective studies on patients of different ethnicities, especially studies with large sample sizes, and long-term follow-up, should be conducted to confirm the predictive roles of gene polymorphism. [ABSTRACT FROM AUTHOR]

Background: The link between autoimmune thyroid diseases and Vitamin D deficiency has been reported. However, there are controversies in this regard. We conducted a double-blind randomized placebo-controlled clinical trial to investigate the effect of Vitamin D deficiency treatment on thyroid function and autoimmunity marker (thyroid peroxidase antibody [TPO-Ab]) in patients with Hashimoto's thyroiditis. Materials and Methods: Fifty-six patients with Hashimoto's thyroiditis and Vitamin D deficiency (25-hydroxyvitamin D level ≤20 ng/mL) were randomly allocated into two groups to receive Vitamin D (50000 IU/week, orally) or placebo for 12 weeks, as Vitamin D-treated (n = 30) and control (n = 26) groups, respectively. TPO-Ab, thyroid-stimulating hormone (TSH), parathormone, calcium, albumin, and creatinine concentrations were compared before and after trial between and within groups. The data were presented as mean (standard error [SE]) and analyzed by appropriate tests. Results: Mean (SE) of Vitamin D was increased in Vitamin D-treated group (45.5 [1.8] ng/mL vs. 12.7 [0.7] ng/mL, P = 0.01). Mean (SE) of TPO-Ab did not significantly change in both groups (734 [102.93] IU/mL vs. 820.25 [98.92] IU/mL, P = 0.14 in Vitamin D-treated and 750.03 [108.7] [IU/mL] vs. 838.07 [99.4] [IU/mL] in placebo-treated group, P = 0.15). Mean (SE) of TSH was not changed in both groups after trial, P = 0.4 and P = 0.15 for Vitamin D-treated and control groups, respectively. No significant difference was observed between two study groups in none studied variables (P > 0.05). Conclusion: Vitamin D treatment in Vitamin D deficient patients with Hashimoto's thyroiditis could not have significant effect on thyroid function and autoimmunity. [ABSTRACT FROM AUTHOR]

Delirium, a prevalent organ dysfunction in critically ill patients, is independently associated with increased morbidity. This last decade has witnessed an exponential growth in delirium research in hospitalized patients, including those critically ill, and this research has highlighted that delirium needs to be better understood mechanistically to help foster research that will ultimately lead to its prevention and treatment. In this invited, evidence-based paper, a multinational and interprofessional group of clinicians and researchers from within the fields of critical care medicine, psychiatry, pediatrics, anesthesiology, geriatrics, surgery, neurology, nursing, pharmacy, and the neurosciences sought to address five questions: (1) What is the current standard of care in managing ICU delirium? (2) What have been the major recent advances in delirium research and care? (3) What are the common delirium beliefs that have been challenged by recent trials? (4) What are the remaining areas of uncertainty in delirium research? (5) What are some of the top study areas/trials to be done in the next 10 years? Herein, we briefly review the epidemiology of delirium, the current best practices for management of critically ill patients at risk for delirium or experiencing delirium, identify recent advances in our understanding of delirium as well as gaps in knowledge, and discuss research opportunities and barriers to implementation, with the goal of promoting an integrated research agenda. [ABSTRACT FROM AUTHOR]