A pathogenic variant in LDLR, APOB, or PCSK9 can be identified in 30% to 80% of patients with clinically-diagnosed familial hypercholesterolemia (FH). Alternatively, ∼20% of clinical FH is thought to ...have a polygenic cause. The cardiovascular disease (CVD) risk associated with polygenic versus monogenic FH is unclear.
This study evaluated the effect of monogenic and polygenic causes of FH on premature (age <55 years) CVD events in patients with clinically diagnosed FH.
Targeted sequencing of genes known to cause FH as well as common genetic variants was performed to calculate polygenic scores in patients with “possible,” “probable,” or “definite” FH, according to Dutch Lipid Clinic Network Criteria (n = 626). Patients with a polygenic score ≥80th percentile were considered to have polygenic FH. We examined the risk of unstable angina, myocardial infarction, coronary revascularization, or stoke.
A monogenic cause of FH was associated with significantly greater risk of CVD (adjusted hazard ratio: 1.96; 95% confidence interval: 1.24 to 3.12; p = 0.004), whereas the risk of CVD in patients with polygenic FH was not significantly different compared with patients in whom no genetic cause of FH was identified. However, the presence of an elevated low-density lipoprotein cholesterol (LDL-C) polygenic risk score further increased CVD risk in patients with monogenic FH (adjusted hazard ratio: 3.06; 95% confidence interval: 1.56 to 5.99; p = 0.001).
Patients with monogenic FH and superimposed elevated LDL-C polygenic risk scores have the greatest risk of premature CVD. Genetic testing for FH provides important prognostic information that is independent of LDL-C levels.
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5-Deazaflavin cofactors enhance the metabolic flexibility of microorganisms by catalyzing a wide range of challenging enzymatic redox reactions. While structurally similar to riboflavin, ...5-deazaflavins have distinctive and biologically useful electrochemical and photochemical properties as a result of the substitution of N-5 of the isoalloxazine ring for a carbon. 8-Hydroxy-5-deazaflavin (Fo) appears to be used for a single function: as a light-harvesting chromophore for DNA photolyases across the three domains of life. In contrast, its oligoglutamyl derivative F420 is a taxonomically restricted but functionally versatile cofactor that facilitates many low-potential two-electron redox reactions. It serves as an essential catabolic cofactor in methanogenic, sulfate-reducing, and likely methanotrophic archaea. It also transforms a wide range of exogenous substrates and endogenous metabolites in aerobic actinobacteria, for example mycobacteria and streptomycetes. In this review, we discuss the physiological roles of F420 in microorganisms and the biochemistry of the various oxidoreductases that mediate these roles. Particular focus is placed on the central roles of F420 in methanogenic archaea in processes such as substrate oxidation, C1 pathways, respiration, and oxygen detoxification. We also describe how two F420-dependent oxidoreductase superfamilies mediate many environmentally and medically important reactions in bacteria, including biosynthesis of tetracycline and pyrrolobenzodiazepine antibiotics by streptomycetes, activation of the prodrugs pretomanid and delamanid by Mycobacterium tuberculosis, and degradation of environmental contaminants such as picrate, aflatoxin, and malachite green. The biosynthesis pathways of Fo and F420 are also detailed. We conclude by considering opportunities to exploit deazaflavin-dependent processes in tuberculosis treatment, methane mitigation, bioremediation, and industrial biocatalysis.
Study Design
Literature review.
Objective
The aim of this literature review was to detail the effects of smoking in spine surgery and examine whether perioperative smoking cessation could mitigate ...these risks.
Methods
A review of the relevant literature examining the effects of smoking and cessation on surgery was conducted using PubMed, Google Scholar, and Cochrane databases.
Results
Current smokers are significantly more likely to experience pseudarthrosis and postoperative infection and to report lower clinical outcomes after surgery in both the cervical and lumbar spines. Smoking cessation can reduce the risks of these complications depending on both the duration and timing of tobacco abstinence.
Conclusion
Smoking negatively affects both the objective and subjective outcomes of surgery in the lumbar and cervical spine. Current literature supports smoking cessation as an effective tool in potentially mitigating these unwanted outcomes. Future investigations in this field should be directed toward developing a better understanding of the complex relationship between smoking and poorer outcomes in spine surgery as well as developing more efficacious cessation strategies.
Patients with dilated cardiomyopathy whose symptoms and cardiac function have recovered often ask whether their medications can be stopped. The safety of withdrawing treatment in this situation is ...unknown.
We did an open-label, pilot, randomised trial to examine the effect of phased withdrawal of heart failure medications in patients with previous dilated cardiomyopathy who were now asymptomatic, whose left ventricular ejection fraction (LVEF) had improved from less than 40% to 50% or greater, whose left ventricular end-diastolic volume (LVEDV) had normalised, and who had an N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) concentration less than 250 ng/L. Patients were recruited from a network of hospitals in the UK, assessed at one centre (Royal Brompton and Harefield NHS Foundation Trust, London, UK), and randomly assigned (1:1) to phased withdrawal or continuation of treatment. After 6 months, patients in the continued treatment group had treatment withdrawn by the same method. The primary endpoint was a relapse of dilated cardiomyopathy within 6 months, defined by a reduction in LVEF of more than 10% and to less than 50%, an increase in LVEDV by more than 10% and to higher than the normal range, a two-fold rise in NT-pro-BNP concentration and to more than 400 ng/L, or clinical evidence of heart failure, at which point treatments were re-established. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02859311.
Between April 21, 2016, and Aug 22, 2017, 51 patients were enrolled. 25 were randomly assigned to the treatment withdrawal group and 26 to continue treatment. Over the first 6 months, 11 (44%) patients randomly assigned to treatment withdrawal met the primary endpoint of relapse compared with none of those assigned to continue treatment (Kaplan-Meier estimate of event rate 45·7% 95% CI 28·5–67·2; p=0·0001). After 6 months, 25 (96%) of 26 patients assigned initially to continue treatment attempted its withdrawal. During the following 6 months, nine patients met the primary endpoint of relapse (Kaplan-Meier estimate of event rate 36·0% 95% CI 20·6–57·8). No deaths were reported in either group and three serious adverse events were reported in the treatment withdrawal group: hospital admissions for non-cardiac chest pain, sepsis, and an elective procedure.
Many patients deemed to have recovered from dilated cardiomyopathy will relapse following treatment withdrawal. Until robust predictors of relapse are defined, treatment should continue indefinitely.
British Heart Foundation, Alexander Jansons Foundation, Royal Brompton Hospital and Imperial College London, Imperial College Biomedical Research Centre, Wellcome Trust, and Rosetrees Trust.
Insect carboxylesterases from the aEsterase gene cluster, such as αE7 (also known as E3) from the Australian sheep blowfly Lucilia cuprina (LcαE7), play an important physiological role in lipid ...metabolism and are implicated in the detoxification of organophosphate (OP) insecticides. Despite the importance of OPs to agriculture and the spread of insect-borne diseases, the molecular basis for the ability of α-carboxy leste rases to confer OP resistance to insects is poorly understood. In this work, we used laboratory evolution to increase the thermal stability of LcαE7, allowing its overexpression in Escherichia coli and structure determination. The crystal structure reveals a canonical α/β-hydrolase fold that is very similar to the primary target of OPs (acetylcholinesterase) and a unique N-terminal α-helix that serves as a membrane anchor. Soaking of LcαE7 crystals in OPs led to the capture of a crystallographic snapshot of LcaEl in its phosphorylated state, which allowed comparison with acetylcholinesterase and rationalization of its ability to protect insects against the effects of OPs. Finally, inspection of the active site of LcαE7 reveals an asymmetric and hydrophobic substrate binding cavity that is well-suited to fatty acid methyl esters, which are hydrolyzed by the enzyme with specificity constants (~10⁶ M⁻¹ s⁻¹) indicative of a natural substrate.
Patients with left ventricular (LV) systolic dysfunction after myocardial infarction are at a high risk of developing heart failure. The addition of neprilysin inhibition to renin angiotensin system ...inhibition may result in greater attenuation of adverse LV remodeling as a result of increased levels of substrates for neprilysin with vasodilatory, antihypertrophic, antifibrotic, and sympatholytic effects.
We performed a prospective, multicenter, randomized, double-blind, active-comparator trial comparing sacubitril/valsartan 97/103 mg twice daily with valsartan 160 mg twice daily in patients ≥3 months after myocardial infarction with a LV ejection fraction ≤40% who were taking a renin angiotensin system inhibitor (equivalent dose of ramipril ≥2.5 mg twice daily) and a β-blocker unless contraindicated or intolerant. Patients in New York Heart Association class ≥II or with signs and symptoms of heart failure were excluded. The primary outcome was change from baseline to 52 weeks in LV end-systolic volume index measured using cardiac magnetic resonance imaging. Secondary outcomes included other magnetic resonance imaging measurements of LV remodeling, change in NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin I, and a patient global assessment of change questionnaire.
From July 2018 to June 2019, we randomized 93 patients with the following characteristics: mean age, 60.7±10.4 years; median time from myocardial infarction, 3.6 years (interquartile range, 1.2-7.2); mean LV ejection fraction, 36.8%±7.1%; and median NT-proBNP, 230 pg/mL (interquartile range, 124-404). Sacubitril/valsartan, compared with valsartan, did not significantly reduce LV end-systolic volume index; adjusted between-group difference, -1.9 mL/m
(95% CI, -4.9 to 1.0);
=0.19. There were no significant between-group differences in NT-proBNP, high-sensitivity cardiac troponin I, LV end-diastolic volume index, left atrial volume index, LV ejection fraction, LV mass index, or patient global assessment of change.
In patients with asymptomatic LV systolic dysfunction late after myocardial infarction, treatment with sacubitril/valsartan did not have a significant reverse remodeling effect compared with valsartan. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03552575.
Study Design
Literature review.
Objective
The aim of this literature review is to examine the effects of obesity on postoperative complications and functional outcomes after spine surgery.
Methods
A ...review of the relevant literature examining the effects of obesity and spine surgery was conducted using PubMed, Google Scholar, and Cochrane databases.
Results
Obesity contributes to disk degeneration and low back pain and potentially increases the risk of developing operative pathology. Obese patients undergoing spine surgery have a higher risk of developing postoperative complications, particularly surgical site infection and venous thromboembolism. Though functional outcomes in this population may not mirror the general population, the treatment effect associated with surgery is at least equivalent if not better in obese individuals. This reduction is primarily due to worse outcomes associated with nonoperative treatment in the obese population.
Conclusion
Obese individuals represent a unique patient population with respect to nonoperative treatment, postoperative complication rates, and functional outcomes. However, given the equivalent or greater treatment effect of surgery, this comorbidity should not prohibit obese patients from undergoing operative intervention. Future investigations in this area should attempt to develop strategies to minimize complications and improve outcomes in obese individuals and also examine the role of controlled weight loss preoperatively to mitigate these risks.
Background
For patients with heart failure, there is an inverse relation between body mass index (BMI) and mortality, sometimes called the obesity-paradox. However, the relationship might be either ...U- or J-shaped and might differ between patients with reduced (HFrEF) or preserved left ventricular ejection fraction (HFpEF). We sought to investigate this further in a dose–response meta-analysis of published studies.
Methods
PubMed and Embase from June 1980 to April 2017 were searched for prospective cohort studies evaluating associations between BMI and all-cause mortality in patients with HFrEF (LVEF < 40%) or HFpEF (LVEF ≥ 50%). Summary estimated effect sizes were obtained by using a random-effects model. Potential non-linear relationships were evaluated by using random-effects restricted cubic spline models.
Results
Ten studies were identified that included 96,424 patients of whom 59,263 had HFpEF (mean age 68 years of whom 38% were women) and 37,161 had HFrEF (mean age 60 years of whom 17% were women). For patients with HFpEF, the summary hazard ratio (HR) for all-cause mortality was: 0.93 (95% CI 0.89–0.97) per 5 units increase in BMI (
I
2
= 75.8%,
p
for heterogeneity = 0.01 and Begg’s test,
p
= 1.0, Egger’s test,
p
= 0.29) but the association was U-shaped (
p
for non-linearity < 0.01) with the nadir of risk at a BMI of 32–33 kg/m
2
. For patients with HFrEF, the summary HR for all-cause mortality was: 0.96 (95% CI 0.92–0.99) (
I
2
= 95%,
p
for heterogeneity < 0.001 and Begg’s test,
p
= 0.45, Egger’s test,
p
= 0.01). The relationship was also U-shaped (
p
< 0.01), although ‘flatter’ than for HFpEF, with the nadir at a BMI of 33 kg/m
2
.
Conclusions
For patients with heart failure, the relation between BMI and mortality is U-shaped with a similar nadir of risk for HFpEF and HFrEF at a BMI of 32–33 kg/m
2
. Whether interventions that alter weight in either direction can alter risk is unknown.
Atrazine chlorohydrolase (AtzA) and its close relative melamine deaminase (TriA) differ by just nine amino acid substitutions but have distinct catalytic activities. Together, they offer an ...informative model system to study the molecular processes that underpin the emergence of new enzymatic function. Here we have constructed the potential evolutionary trajectories between AtzA and TriA, and characterized the catalytic activities and biophysical properties of the intermediates along those trajectories. The order in which the nine amino acid substitutions that separate the enzymes could be introduced to either enzyme, while maintaining significant catalytic activity, was dictated by epistatic interactions, principally between three amino acids within the active site: namely, S331C, N328D and F84L. The mechanistic basis for the epistatic relationships is consistent with a model for the catalytic mechanisms in which protonation is required for hydrolysis of melamine, but not atrazine.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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