The structure of the Gla-domainless form of the human anticoagulant enzyme activated protein C has been solved at 2.8 A resolution. The light chain is composed of two domains: an epidermal growth factor (EGF)-like domain modified by a large insert containing an additional disulfide, followed by a typical EGF-like domain. The arrangement of the long axis of these domains describes an angle of approximately 80 degrees. Disulfide linked to the light chain is the catalytic domain, which is generally trypsin-like but contains a large insertion loop at the edge of the active site, a third helical segment, a prominent cationic patch analogous to the anion binding exosite I of thrombin and a trypsin-like Ca[II] binding site. The arrangement of loops around the active site partially restricts access to the cleft. The S2 and S4 subsites are much more polar than in factor Xa and thrombin, and the S2 site is unrestricted. While quite open and exposed, the active site contains a prominent groove, the surface of which is very polar with evidence for binding sites on the primed side, in addition to those typical of the trypsin class found on the non-primed side.

The 2.8 A crystal structure of Gla-domainless activated protein C.

EMBO Journal

Fluid resuscitation is typically needed in patients with cirrhosis, sepsis and hypotension. However, the complex circulatory changes associated with cirrhosis with hyperdynamic state, increased splanchnic blood volume and relative central hypovolemia complicates fluid administration and monitoring of fluid status. In patients with advanced cirrhosis, larger volumes of fluids are needed to expand central blood volume and improve sepsis-induced organ hypoperfusion as compared to non-cirrhotic patients, at the cost of further increase in non-central blood volume. Monitoring and targets still need to be defined but echocardiography is promising for bedside assessment of fluid status and responsiveness. Large volumes of saline should be avoided in cirrhosis. Experimental data suggest that independent of volume expansion, albumin is superior to crystalloids at controlling systemic inflammation and preventing acute kidney injury. However, while it is generally accepted that albumin plus antibiotics is superior to antibiotics alone in spontaneous bacterial peritonitis, evidence is lacking in patients with infections other than spontaneous bacterial peritonitis. Patients with advanced cirrhosis, sepsis and hypotension are less likely to be fluid responsive as compared to non-cirrhotic patients and early initiation of vasopressors is recommended. While norepinephrine is the first line option, the role of terlipressin needs to be clarified in this context.

Fluid Resuscitation in Patients with Cirrhosis and Sepsis: A Multidisciplinary Perspective.

Journal of Hepatology

Beyond improving hemoglobin A1c (HbA1c) in adults with type 2 diabetes, glucagon-like peptide 1 receptor agonists (GLP-1RA) have been approved for reducing risk of major adverse cardiovascular events (MACE) with established cardiovascular disease (CVD) or multiple CV risk factors. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) also reduced the risk for the primary composite CV outcome in patients with type 2 diabetes at high risk for CV events. In the American Diabetes Association (ADA) and European Association of Study in Diabetes (EASD) consensus report 2022, there is the description "In people with established atherosclerotic CVD (ASCVD) or with a high risk for ASCVD, GLP-1RA were prioritized over SGLT2i"; however, the evidence supporting such statement is limited. Therefore, we studied the superiority of GLP-1RA over SGLT2i for prevention of ASCVD from various viewpoints. We could not find a meaningful difference in the risk reduction in three-point MACE (3P-MACE), mortality due to any cause, mortality due to CV cause and nonfatal myocardial infarction between GLP-1RA and SGLT2i trials. The risk of nonfatal stroke decreased in all five GLP-1RA trials; however, two of three SGLT2i trials showed an increase in risk of nonfatal stroke. The risk of hospitalization for heart failure (HHF) decreased in all three SGLT2i trials, and one GLP-1RA trial showed an increase in risk of HHF. The risk reduction of HHF in SGLT2i trials was greater than that in GLP-1RA trials. These findings were consistent with current systematic reviews and meta-analyses. The risk reduction of 3P-MACE was significantly and negatively correlated with changes in HbA1c (R = -0.861, P = 0.006) and body weight (R = -0.895, P = 0.003) in GLP-1RA and SGLT2i trials. The studies using SGLT2i failed to reduce carotid intima media thickness (cIMT), the surrogate marker for atherosclerosis; however, several studies using GLP-1RA successfully reduced cIMT in patients with type 2 diabetes. Compared with SGLT2i, GLP-1RA had a higher probability of decreasing serum triglyceride. GLP-1RA have multiple vascular biological anti-atherogenic properties.

Glucagon-Like Peptide 1 Receptor Agonists Versus Sodium-Glucose Cotransporter 2 Inhibitors for Atherosclerotic Cardiovascular Disease in Patients With Type 2 Diabetes.

Cardiology Research

The proportion of the elderly population continues to increase due to the global increase in longevity. Heart failure with preserved ejection fraction (HFpEF) is common in the elderly due to cellular aging, myocardial stiffness, and multiple comorbidities. This age group is often under-represented in clinical trials. In this narrative review, we looked into the latest evidence-based lines of management of HFpEF in this vulnerable cohort. In this narrative review, we brought the latest evidence on the treatment of HFpEf in the elderly. We searched the largest three scientific databases (Pubmed, Google Scholar, and EMBASE) using the&#xa0;search words (elderly, HFpEF, heart failure with preserved ejection fraction, guidelines, treatment, and management) in different combinations. To date, screening for and treatment of the causes of HFpEF (such as hypertension, coronary artery disease [CAD], valvular heart disease, and cardiac amyloidosis) and associated comorbidities (such as diabetes mellitus [DM], iron deficiency, obesity, and thyroid dysfunction) are the main line of management of HFpEF. A multidisciplinary team, including an HF specialist cardiologist, an HF nurse, a geriatrician, a dietician, a psychologist, a physiotherapist, and an occupational therapist, should manage HFpEF elderly patients. Other specialist input may be needed according to the patient's requirements. The evidence on the effective management of HFpEF in the elderly age group is scarce and controversial. Some studied non-pharmacological approaches include supervised exercise training, pulmonary artery pressure monitoring, and the interatrial shunt device (an emerging modality that includes a small percutaneously inserted interatrial left to right valve aiming to reduce the left atrial and pulmonary wedge pressures). These modalities can only improve the symptoms and HF hospitalizations without robustly impacting cardiovascular (CV) death. Among the pharmacological approaches to treat HFpEF, only the sodium-glucose cotransporter 2 (SGLT-2) inhibitors proved efficacy in reducing the hard outcomes of CV death, HF hospitalizations, and urgent visits for HF when used in elderly HFpEF patients, irrespective of the presence of diabetes mellitus. Diuretics are only beneficial to alleviate the symptoms of fluid overload, with a risk of renal impairment in volume-depleted patients. The evidence on the effectiveness of other HF-specific disease-modifying agents in elderly HFpEF patients is controversial. Elderly patients have a higher risk of having side effects from HF medications due to the higher prevalence of polypharmacy, cognitive decline, and impairment of kidney and liver functions. Therefore, cautious initiation of HF treatment with a close follow-up of the blood pressure, liver functions, kidney functions, and electrolytes are of utmost importance.

Management of Heart Failure With Preserved Ejection Fraction in Elderly Patients: Effectiveness and Safety.

Curēus

Pulmonary hypertension, defined as an elevation in blood pressure in the pulmonary arteries, is associated with an increased risk of death. The prevalence of pulmonary hypertension is increasing, with an aging population, a rising prevalence of heart and lung disease, and improved pulmonary hypertension survival with targeted therapies. Patients with pulmonary hypertension frequently require noncardiac surgery, although pulmonary hypertension is associated with excess perioperative morbidity and death. This scientific statement provides guidance on the evaluation and management of pulmonary hypertension in patients undergoing noncardiac surgery. We advocate for a multistep process focused on (1) classification of pulmonary hypertension group to define the underlying pathology; (2) preoperative risk assessment that will guide surgical decision-making; (3) pulmonary hypertension optimization before surgery to reduce perioperative risk; (4) intraoperative management of pulmonary hypertension to avoid right ventricular dysfunction and to maintain cardiac output; and (5) postoperative management of pulmonary hypertension to ensure recovery from surgery. Last, this scientific statement highlights the paucity of evidence to support perioperative pulmonary hypertension management and identifies areas of uncertainty and opportunities for future investigation.

Evaluation and Management of Pulmonary Hypertension in Noncardiac Surgery: A Scientific Statement From the American Heart Association.

Circulation

Non-alcoholic fatty liver disease (NAFLD) is a serious health problem due to its high incidence and consequences. In view of the existing controversies, new therapeutic options for NAFLD are still being sought. Therefore, the aim of our review was to evaluate the recently published studies on the treatment of NAFLD patients. We searched for articles in the PubMed database using appropriate terms, including "non-alcoholic fatty liver disease", "nonalcoholic fatty liver disease", "NAFLD", "diet", "treatment", "physical activity", "supplementation", "surgery", "overture" and "guidelines". One hundred forty-eight randomized clinical trials published from January 2020 to November 2022 were used for the final analysis. The results show significant benefits of NAFLD therapy associated with the use of not only the Mediterranean but also other types of diet (including low-calorie ketogenic, high-protein, anti-inflammatory and whole-grain diets), as well as enrichment with selected food products or supplements. Significant benefits in this group of patients are also associated with moderate aerobic physical training. The available therapeutic options indicate, above all, the usefulness of drugs related to weight reduction, as well as the reduction in insulin resistance or lipids level and drugs with anti-inflammatory or antioxidant properties. The usefulness of therapy with dulaglutide and the combination of tofogliflozin with pioglitazone should be emphasized. Based on the results of the latest research, the authors of this article suggest a revision of the therapeutic recommendations for NAFLD patients.

What's New in the Treatment of Non-Alcoholic Fatty Liver Disease (NAFLD).

Journal of Clinical Medicine

Viral epidemics or pandemics of acute respiratory infections (ARIs) pose a global threat. Examples are influenza (H1N1) caused by the H1N1pdm09 virus in 2009, severe acute respiratory syndrome (SARS) in 2003, and coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 in 2019. Antiviral drugs and vaccines may be insufficient to prevent their spread. This is an update of a Cochrane Review last published in 2020. We include results from studies from the current COVID-19 pandemic.

To assess the effectiveness of physical interventions to interrupt or reduce the spread of acute respiratory viruses.

We searched CENTRAL, PubMed, Embase, CINAHL, and two trials registers in October 2022, with backwards and forwards citation analysis on the new studies.

We included randomised controlled trials (RCTs) and cluster-RCTs investigating physical interventions (screening at entry ports, isolation, quarantine, physical distancing, personal protection, hand hygiene, face masks, glasses, and gargling) to prevent respiratory virus transmission.&#xa0; DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures.

We included 11&#xa0;new RCTs and cluster-RCTs (610,872 participants) in this update, bringing the total number of RCTs to 78. Six of the new trials were conducted during the COVID-19 pandemic; two from Mexico, and one each from Denmark, Bangladesh, England, and Norway. We identified four&#xa0;ongoing studies, of which one is completed, but unreported, evaluating masks concurrent with the COVID-19 pandemic. Many studies were conducted during non-epidemic influenza periods. Several were conducted during the 2009 H1N1 influenza pandemic, and others in epidemic influenza seasons up to 2016. Therefore, many studies were conducted in the context of lower respiratory viral circulation and transmission compared to COVID-19. The included studies were conducted in heterogeneous settings, ranging from suburban schools to hospital wards in high-income countries; crowded inner city settings in low-income countries; and an immigrant neighbourhood in a high-income country. Adherence with interventions was low in many studies. The risk of bias for the RCTs and cluster-RCTs was mostly high or unclear. Medical/surgical masks compared to no masks We included 12 trials (10 cluster-RCTs) comparing medical/surgical masks versus no masks to prevent the spread of viral respiratory illness (two trials with healthcare workers and 10 in the community). Wearing masks in the community probably makes little or no difference to the outcome of influenza-like illness (ILI)/COVID-19 like illness compared to not wearing masks (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.84 to 1.09; 9 trials, 276,917 participants; moderate-certainty evidence. Wearing masks in the community probably makes little or no difference to the outcome of laboratory-confirmed influenza/SARS-CoV-2 compared to not wearing masks (RR 1.01, 95% CI 0.72 to 1.42; 6 trials, 13,919 participants; moderate-certainty evidence). Harms were rarely measured and poorly reported (very low-certainty evidence). N95/P2 respirators compared to medical/surgical masks We pooled trials comparing N95/P2 respirators with medical/surgical masks (four in healthcare settings and one in a household setting). We are very uncertain on the effects of N95/P2 respirators compared with medical/surgical masks on the outcome of clinical respiratory illness (RR 0.70, 95% CI 0.45 to 1.10; 3 trials, 7779 participants; very low-certainty evidence). N95/P2 respirators compared with medical/surgical masks may be effective for ILI (RR 0.82, 95% CI 0.66 to 1.03; 5 trials, 8407 participants; low-certainty evidence). Evidence is limited by imprecision and heterogeneity for these subjective outcomes. The use of a N95/P2 respirators compared to medical/surgical masks probably makes little or no difference for the objective and more precise outcome of laboratory-confirmed influenza infection (RR 1.10, 95% CI 0.90 to 1.34; 5 trials, 8407 participants; moderate-certainty evidence). Restricting pooling to healthcare workers made no difference to the overall findings. Harms were poorly measured and reported, but discomfort wearing medical/surgical masks or N95/P2 respirators was mentioned in several studies (very low-certainty evidence).&#xa0; One previously reported ongoing RCT&#xa0;has now been published and observed that medical/surgical masks were non-inferior to N95 respirators in a large study of 1009 healthcare workers in four countries providing direct care to COVID-19 patients.&#xa0; Hand hygiene compared to control Nineteen trials compared hand hygiene interventions with controls with sufficient data to include in meta-analyses. Settings included&#xa0;schools, childcare centres and homes. Comparing hand hygiene interventions with controls (i.e. no intervention),&#xa0;there was a 14% relative reduction in the number of people with ARIs in the hand hygiene group (RR 0.86, 95% CI 0.81 to 0.90; 9 trials, 52,105 participants; moderate-certainty evidence), suggesting a probable benefit. In absolute terms this benefit would result in a reduction from 380 events per 1000 people to 327 per 1000 people (95% CI 308 to 342). When considering the more strictly defined outcomes of ILI and laboratory-confirmed influenza, the estimates of effect for ILI (RR 0.94, 95% CI 0.81 to 1.09; 11 trials, 34,503 participants; low-certainty evidence), and laboratory-confirmed influenza (RR 0.91, 95% CI 0.63 to 1.30; 8 trials, 8332 participants; low-certainty evidence), suggest the intervention made little or no&#xa0;difference. We pooled 19 trials (71, 210 participants) for the composite outcome of ARI or ILI or influenza, with each study only contributing once and the most comprehensive outcome reported. Pooled data showed that hand hygiene may be beneficial with an 11% relative reduction of respiratory illness (RR 0.89, 95% CI 0.83 to 0.94; low-certainty evidence), but with high heterogeneity. In absolute terms this benefit would result in a reduction from 200 events per 1000 people to 178 per 1000 people (95% CI 166 to 188). Few trials measured and reported harms (very low-certainty evidence). We found no RCTs on gowns and gloves, face shields, or screening at entry ports.

The high risk of bias in the trials, variation in outcome measurement, and relatively low adherence with the interventions during the studies hampers drawing firm conclusions. There were additional RCTs during the pandemic related to physical interventions but a relative paucity given the importance of the question of masking and its relative effectiveness and the concomitant measures of mask adherence which would be highly relevant to the measurement of effectiveness, especially in the elderly and in young children. There is uncertainty about the effects of face masks. The low to moderate certainty of evidence means our confidence in the effect estimate is limited, and that the true effect may be different from the observed estimate of the effect. The pooled results of RCTs did not show a clear reduction in respiratory viral infection with the use of medical/surgical masks. There were no clear differences between the use of medical/surgical masks compared with N95/P2 respirators in healthcare workers when used in routine care to reduce respiratory viral infection. Hand hygiene is likely to modestly reduce the burden of respiratory illness, and although this effect was also present when ILI and laboratory-confirmed influenza were analysed separately, it was not found to be a significant difference for the latter two outcomes. Harms associated with physical interventions were under-investigated. There is a need&#xa0;for large, well-designed RCTs addressing the effectiveness of many of these interventions in multiple settings and populations, as well as the impact of adherence on effectiveness, especially in those most at risk of ARIs.

Physical interventions to interrupt or reduce the spread of respiratory viruses.

Cochrane Database of Systematic Reviews

Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus&#xa0;2 (SARS-CoV-2) infections. More than 200 symptoms have been identified with impacts on multiple organ systems. At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily. Biomedical research has made substantial progress in identifying various pathophysiological changes and risk factors and in characterizing the illness; further, similarities with other viral-onset illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome have laid the groundwork for research in the field. In this Review, we explore the current literature and highlight key findings, the overlap with other conditions, the variable onset of symptoms, long COVID in children and the impact of vaccinations. Although these key findings are critical to understanding long COVID, current diagnostic and treatment options are insufficient, and clinical trials must be prioritized that address leading hypotheses. Additionally, to strengthen long COVID research, future studies must account for biases and SARS-CoV-2 testing issues, build on viral-onset research, be inclusive of marginalized populations and meaningfully engage patients throughout the research process.

Long COVID: major findings, mechanisms and recommendations.

Nature Reviews. Microbiology

Since the publication of the EULAR recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in 2016, several randomised clinical trials have been published that have the potential to change clinical care and support the need for an update.

Using EULAR standardised operating procedures, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 16 countries. We modified existing recommendations and created new recommendations.

Four overarching principles and 17 recommendations were formulated. We recommend biopsies and ANCA testing to assist in establishing a diagnosis of AAV. For remission induction in life-threatening or organ-threatening AAV, we recommend a combination of high-dose glucocorticoids (GCs) in combination with either rituximab or cyclophosphamide. We recommend tapering of the GC dose to a target of 5&#x2009;mg prednisolone equivalent/day within 4-5&#x2009;months. Avacopan may be considered as part of a strategy to reduce exposure to GC in granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Plasma exchange may be considered in patients with rapidly progressive glomerulonephritis. For remission maintenance of GPA/MPA, we recommend rituximab. In patients with relapsing or refractory eosinophilic GPA, we recommend the use of mepolizumab. Azathioprine and methotrexate are alternatives to biologics for remission maintenance in AAV.

In the light of recent advancements, these recommendations provide updated guidance on AAV management. As substantial data gaps still exist, informed decision-making between physicians and patients remains of key relevance.

EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update.

Annals of the Rheumatic Diseases

Electrolyte and acid-base disorders are frequently encountered in patients with malignancy, either due to cancer itself or as a complication of its therapy. However, spurious electrolyte disorders can complicate the interpretation and management of these patients. There are several electrolytes that can be artifactually increased or decreased serum electrolyte values that do not correspond to their actual systemic levels, potentially resulting in extensive diagnostic investigations and therapeutic interventions. Examples of spurious derangements include pseudohyponatremia, pseudohypokalemia, pseudohyperkalemia, pseudohypophosphatemia, pseudohyperphosphatemia, and artifactual acid-base abnormalities. Correctly interpreting these artifactual laboratory abnormalities is imperative as it might avoid unnecessary and potentially harmful interventions for the cancer patient. It is also important that factors influencing these spurious results be recognized, and steps are taken to minimize them. We present a narrative review of commonly reported pseudo-electrolyte disorders and describe strategies to exclude erroneous interpretations of these laboratory values and avoid pitfalls. Awareness and recognition of spurious electrolyte and acid-base disorders can prevent unnecessary and harmful treatments.

The 2.8 A crystal structure of Gla-domainless activated protein C.

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The 2.8 A crystal structure of Gla-domainless activated protein C.

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