The pathogenesis of scrapie and other transmissible spongiform encephalopathies (TSEs) following oral uptake of agent is still poorly understood and can best be studied in mice and hamsters. The experiments described here further extend the understanding of the pathways along which infection spreads from the periphery to the brain after an oral challenge with scrapie. Using TSE-specific amyloid protein (TSE-AP, also called PrP) as a marker for infectivity, immunohistochemical evidence suggested that the first target area in the brain of hamsters orally infected with scrapie is the dorsal motor nucleus of the vagus nerve (DMNV), rapidly followed by the commissural solitary tract nucleus (SN). The cervical spinal cord was affected only after TSE-AP had been deposited in the DMNV, SN and other medullary target areas. For the first time, these results demonstrate conclusively that, in our animal model, initial infection of the brain after oral ingestion of scrapie agent occurs via the vagus nerve, rather than by spread along the spinal cord.

Cerebral targeting indicates vagal spread of infection in hamsters fed with scrapie.

Journal of General Virology

Management of type 2 diabetes is advancing beyond glycemic control and is increasingly based on cardiovascular risk stratification. This review summarizes recent advances in the field and identifies existing knowledge gaps and areas of ongoing research.

A bibliographic search was carried out in PubMed for recently published cardiorenal outcome trials, relevant guidelines, and studies on antidiabetic agents in the pipeline.

Findings from cardiovascular outcome trials support the use of glucagon-like peptide 1 (GLP-1) receptor agonists or sodium-glucose cotransporter 2 (SGLT-2) inhibitors for patients with established cardiovascular disease or multiple risk factors, although it as yet remains uncertain whether the benefits are transferable to patients at lower absolute cardiovascular risk. Additionally, robust evidence suggests that SGLT-2 inhibitors improve clinical outcomes for people with concomitant heart failure or chronic kidney disease. Gut hormone multiagonists will likely represent another major addition to the therapeutic armamentarium for morbidly obese individuals with diabetes. Moreover, nonalcoholic fatty liver disease is a common comorbidity and several liver outcome trials are awaited with great interest. Use of insulin as first-line injectable therapy has been displaced by GLP-1 receptor agonists. Once-weekly formulations of basal insulins along with combinations with GLP-1 receptor agonists are also under development and could increase patient convenience. Technologies of glucose sensors are rapidly evolving and have the potential to reduce the burden of frequent blood glucose measurements, mainly for patients treated with intensified insulin regimens.

Management of type 2 diabetes requires a holistic approach and recent breakthroughs are expected to improve the quality of care.

Management of type 2 diabetes in the new era.

Hormones : International Journal of Endocrinology and Metabolism

Most of the evidences for beneficial effects of beta-blockers in patients with acute myocardial infarction (AMI) were from the clinical studies published in the pre-reperfusion era when anti-platelet drugs, statins or inhibitors of renin-angiotensin-aldosterone system which are known to reduce cardiovascular mortality of patients with AMI were not introduced. In the reperfusion era, beta-blockers' benefit has not been clearly shown except in patients with reduced ejection fraction (EF; &#x2264;40%). In the era of the early reperfusion therapy for AMI, a number of patients with mildly reduced EF (&gt;40%, &lt;50%) or preserved EF (&#x2265;50%) become increasing. However, because no randomized clinical trials are available until now, the benefit and the optimal duration of oral treatment with beta-blockers in patients with mildly reduced or preserved EF are questionable. Registry data have not showed the association of oral beta-blocker therapy with decreased mortality in survivors without heart failure or left ventricular systolic dysfunction after AMI. In the Korea Acute Myocardial Infarction Registry-National Institute of Health of in-hospital survivors after AMI, the benefit of beta-blocker therapy at discharge was shown in patients with reduced or mildly reduced EF, but not in those with preserved EF, which provides new information about beta-blocker therapy in patients without reduced EF. However, clinical practice can be changed when the results of appropriate randomized clinical trials are available. Ongoing clinical trials may help to answer the unresolved issues of beta-blocker therapy in patients with AMI.

Beta-blocker therapy in patients with acute myocardial infarction: not all patients need it.

Acute and critical care.

The International Society on Thrombosis and Haemostasis (ISTH) released overt disseminated intravascular coagulation (DIC) diagnostic criteria in 2001. Since then, DIC has been understood as the end-stage consumptive coagulopathy and not the therapeutic target. However, DIC is not merely a decompensated coagulation disorder, but also includes early stages with systemic activation in coagulation. Thus, the ISTH has recently released sepsis-induced coagulopathy (SIC) criteria that can diagnose compensated-phase of coagulopathy with readily available biomarkers.

DIC is a laboratory-based diagnosis due to various critical conditions, although sepsis is the most common underlying disease. The pathophysiology of sepsis-associated DIC is multifactorial, and in addition to coagulation activation with suppressed fibrinolysis, multiple inflammatory responses are initiated by activated leukocytes, platelets, and vascular endothelial cells as part of thromboinflammation. Although overt DIC diagnostic criteria were established by ISTH to diagnose the advanced stage of DIC, additional criteria that can detect an earlier stage of DIC were needed for potential therapeutic considerations. Accordingly, the ISTH introduced SIC criteria in 2019 that are easy to use and require only platelet count, prothrombin time-international normalized ratio, and Sequential Organ Failure Assessment Score. SIC score can be used to evaluate disease severity and determine the timing of potential therapeutic interventions. One of the major disadvantages in treating sepsis-associated DIC is the lack of availability of specific therapeutic approaches beyond treating the underlying infection. Clinical trials to date have failed because included patients who were not coagulopathic. Nevertheless, in addition to infection control, anticoagulant therapy will be the choice for sepsis-associated DIC. Therefore, the efficacy of heparin, antithrombin, and recombinant thrombomodulin has to be proven in future clinical studies.

It is necessary to develop a novel therapeutic strategy against sepsis-associated DIC and improve the outcomes. Consequently, we recommend screening and monitoring DIC using SIC scoring system.

The pathophysiology, diagnosis, and management of sepsis-associated disseminated intravascular coagulation.

Journal of Intensive Care

To examine whether a fluid resuscitation strategy based on guidelines (at least 30&#xa0;mL/kg IV crystalloids) vs. a restrictive approach with &lt;30&#xa0;mL/kg within three hours affects in-hospital mortality in patients with sepsis and a history of heart failure (HF).

On 03/07/2023, we searched Embase, PubMed, and Scopus for peer-reviewed papers and abstracts using the PRISMA guidelines.

The language was limited to English. Studies published since 2016 included if they had sepsis patients with a history of HF, or a subgroup of patients with HF, and in-hospital mortality data on these patients that did or did not meet the 30&#xa0;mL/kg by 3&#xa0;h (30&#xa0;&#xd7;&#xa0;3) goal. Duplicate studies, studies that focused on a broader period than 3&#xa0;h from the diagnosis of sepsis or without mortality breakdown for HF patients or with unrelated title/abstract, or without an IRB approval were excluded.

In-hospital mortality data was taken from the final studies for HF patients with sepsis who did or did not meet the 30&#xa0;&#xd7;&#xa0;3 goal.

The meta-analysis was performed using the Review Manager 5.4 program with ORs as the effect measure. The ProMeta program version 3.0 was used to evaluate the publication bias. Egger's linear regression and Berg and Mazumdar's rank correlation was used to evaluate the publication bias. The result was visually represented by a funnel plot. To estimate the proportion of variance attributable to heterogeneity, the I2 statistic was calculated.

The search yielded 26,069 records, which were narrowed down to 4 studies. Compared to those who met the 30&#xa0;&#xd7;&#xa0;3 goal, the &lt;30&#xa0;&#xd7;&#xa0;3 group had a significantly higher risk of in-hospital mortality (OR&#xa0;=&#xa0;1.81, 95% CI&#xa0;=&#xa0;1.13-2.89, P&#xa0;=&#xa0;0.01).

Restrictive fluid resuscitation increased the risk of in-hospital mortality in HF patients with sepsis. More rigorous research is required to determine the optimal fluid resuscitation strategy for this population.

Guideline-based and restricted fluid resuscitation strategy in sepsis patients with heart failure: A systematic review and meta-analysis.

American Journal of Emergency Medicine

Medical treatment for heart failure (HF) with preserved ejection (HFpEF) and with mildly reduced ejection fraction (HFmrEF) has weaker evidence compared with reduced ejection fraction, despite recent trials with an angiotensin receptor neprilysin inhibitor (ARNI) and sodium-glucose cotransporter-2 inhibitors (SGLT2i).

We aimed to estimate the aggregate therapeutic benefit of drugs for HFmrEF and HFpEF.

We performed a systematic review of MEDLINE, CENTRAL, and Web of Science for randomized trials including patients with HF and left ventricular ejection fraction (LVEF) &gt;40%, treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (analyzed together as renin-angiotensin system inhibitors [RASi]), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), digoxin, ARNI, and SGLT2i. An additive component network meta-analysis was performed. The primary outcome was a composite of cardiovascular (CV) death and first hospitalization for heart failure (HHF); secondary outcomes were CV death, total HHF, and all-cause mortality.

We identified 13 studies with a total of 29,875 patients and a mean LVEF of 56.3% &#xb1; 8.7%. ARNI, MRA, and SGLT2i separately, but not RASi, BB, or digoxin, reduced the primary composite outcome compared with placebo. The combination of ARNI, BB, MRA, and SGLT2i was the most effective (HR: 0.47 [95%&#xa0;CI: 0.31-0.70]); this was largely explained by the triple combination of ARNI, MRA, and SGLT2i (HR: 0.56 [95%&#xa0;CI 0.43-0.71]). Results were similar for CV death (HR: 0.63 [95%&#xa0;CI 0.43-0.91] for ARNI, MRA, and SGLT2i) or total HHF (HR: 0.49 [95%&#xa0;CI 0.33-0.71] for ARNI, MRA, and SGLT2i) alone. In a subgroup analysis, only SGLT2i had a consistent benefit among all LVEF subgroups, whereas the triple combination had the greatest benefit in HFmrEF, robust benefit in patients with LVEF 50% to 59%, and a statistically marginal benefit in patients with LVEF&#xa0;&#x2265;60%.

In patients with HF and LVEF&gt;40%, the quadruple combination of ARNI, BB, MRA, and SGLT2i provides the largest reduction in the risk of CV death and HHF; driven by the robust effect of the triple combination of ARNI, MRA, and SGLT2i. The benefit was more pronounced in HFmrEF patients.

Pharmacological Treatments in Heart Failure With Mildly Reduced and Preserved Ejection Fraction: Systematic Review and Network Meta-Analysis.

JACC. Heart Failure

Despite overwhelming epidemiological evidence, the contribution of hypertension (HTN) to heart failure (HF) development has been undermined in current clinical practice. This is because approximately half of HF patients have been labeled as suffering from HF with preserved left ventricular (LV) ejection fraction (EF) (HFpEF), with HTN, obesity, and diabetes mellitus (DM) being considered virtually equally responsible for its development. However, this suggestion is obviously inaccurate, since HTN is by far the most frequent and devastating morbidity present in HFpEF. Further, HF development in obesity or DM is rare in the absence of HTN or coronary artery disease (CAD), whereas HTN often causes HF per se. Finally, unlike HTN, for most major comorbidities present in HFpEF, including anemia, chronic kidney disease, pulmonary disease, DM, atrial fibrillation, sleep apnea, and depression, it is unknown whether they precede HF or result from it. The purpose of this paper is to provide a contemporary overview on hypertensive HF, with a special emphasis on its inflammatory nature and association with autonomic nervous system (ANS) imbalance, since both are of pathophysiologic and therapeutic interest.

Hypertensive Heart Failure.

Journal of Clinical Medicine

Sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like-peptide-1 receptor (GLP-1-R) agonists are novel therapeutic agents used for the management of type 2 diabetes mellitus (T2DM). Recently, large-scale randomized clinical trials have been conducted to assess the cardiovascular safety of these medications. The findings of these trials have revealed that both SGLT2 inhibitors and GLP-1-R agonists exhibit favorable cardioprotective effects, including reduction in cardiovascular and all-cause mortality, a decreased risk of chronic kidney disease progression, a decrease in hospitalization for heart failure (HF), an effect shown by SGLT2 inhibitors, and stroke prevention, an effect shown by GLP-1-R agonists. Based on the results from above studies, the European and American Diabetes Associations have issued new recommendations strongly endorsing the use of SGLT2 inhibitors and GLP-1-R agonists in combination with metformin for patients with T2DM who have additional cardiovascular (CV) comorbidities or risk factors. The primary aim of this combined therapy is to prevent CV events. Although both medication groups offer beneficial effects, they demonstrate slightly different profiles. SGLT2 inhibitors have exhibited better effects regarding a reduced incidence of HF, whereas GLP-1-R agonists have shown a reduced risk of CV events, particularly stroke. Moreover, recent European Society of Cardiology as well as American College of Cardiology and American Heart Association guidelines of HF treatment stressed the importance of SGLT2 inhibitor administration in patients with HF regardless of T2DM. In this context, we present and discuss the outcomes of the most recent trials investigating the impact of SGLT2 inhibitors and GLP-1-R agonists on renal and cardiovascular outcomes in patients, both with and without T2DM. Additionally, we explore the synergistic effects of combining SGLT2 inhibitors and GLP-1-R agonists in patients with cardiovascular disease.

SGLT2 Inhibitors vs. GLP-1 Agonists to Treat the Heart, the Kidneys and the Brain.

Journal of Cardiovascular Development and Disease

Patients with bacteremia caused by gram positive bacteria are at risk for infective endocarditis (IE). Since IE needs long antibiotic treatment and sometimes heart valve surgery, it is very important to identify patients with IE.

In this narrative review we present and discuss how to determine which investigations to detect IE that are needed in individual patients with gram positive bacteremia.

Published original studies and previous reviews in English, within the relevant field are used.

First, the different qualities of the bacteremia in relation to IE-risk are discussed. The risk for IE in bacteremia is related to the species of the bacterium but also to monomicrobial bacteremia and the number of positive cultures. Secondly, patient-related factors for IE risk in bacteremia are presented. Next, the risk stratification systems to determine the risk for IE in gram positive bacteremia caused by Staphylococcus aureus, viridans streptococci and Enterococcus faecalis are presented and their use is discussed. In the last part of the review, an account for the different modalities of IE-investigations is given. The main focus is on echocardiography which is the cornerstone of IE-investigations. Furthermore, 18 F-FDG PET/CT and cardiac CT are presented and their use is also discussed. A brief account for investigations used to identify embolic phenomena in IE is also given. Finally, we present a flow-chart suggesting which investigations to perform in relation to IE in patients with gram positive bacteremia.

For the individual patient as well as the healthcare system, it is important both to diagnose IE and to decide when to stop looking for IE. This review might be helpful in finding that balance.

Cerebral targeting indicates vagal spread of infection in hamsters fed with scrapie.

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Cerebral targeting indicates vagal spread of infection in hamsters fed with scrapie.

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