Age-corrected neurofilament light chain ratio decreases but does not predict relapse in highly active multiple sclerosis patients initiating natalizumab treatment.

BACKGROUND: Neurofilament light chain (NFL) is a biomarker for monitoring disease activity and treatment response in multiple sclerosis (MS). However, while most agree that NFL levels predict disease activity and worsening, the predictive value of NFL on future relapse risk remains uncertain. OBJECTIVE: The primary aim was to evaluate the predictive value of age-corrected serum NFL (sNFL) ratio on relapse risk in highly active relapsing-remitting MS patients (RRMS) treated with natalizumab. A secondary aim was to investigate the predictive value of sNFL ratios for MRI activity. METHODS: From January 1, 2006, to December 31, 2010, 355 patients initiated natalizumab treatment at the Danish Multiple Sclerosis Center. 305 patients were anti-natalizumab antibodies negative and had at least one blood sample available for sNFL analysis using single molecule array analysis at baseline, three, six, or 12 months. The patients were either treatment-naïve (n = 8), switching from interferon-ß or glatiramer acetate (n = 253), or switching from mitoxantrone (n = 44). An age-corrected ratio was calculated for sNFL. Time to first relapse was calculated from baseline and after re-baseline at 90 days. Data were collected from baseline until the two-year follow-up or end of treatment and included disease duration, expanded disability status scale, previous treatments, relapses 12 months prior to natalizumab initiation, smoking intensity, body mass index, and body weight. In addition, the patients underwent annual MRI of the brain. RESULTS: The sNFL ratio was increased in 173 of 287 samples (60.3 %) at baseline, in 119 of 246 samples (48.8 %) at month three, in 109 of 287 samples (38.0 %) at month six, and in 82 of 270 samples (30.4 %) at month 12. The sNFL ratio continuously declined over 12 months with significant decreases for every measuring timepoint: baseline vs. three months p = 3.0 × 10-6; three months vs. six months p = 3.2 × 10-5; six months vs. 12 months p = 0.002. Univariate Cox regression analysis showed that time to first relapse from 1) natalizumab initiation and from 2) re-baseline was associated with the number of relapses in the previous 12 months (hazard ratio 1.31 per relapse, 95 % CI = 1.2-1.5, p = 2.0 × 10-6; and 1.21 per relapse, 95 % CI = 1.1-1.4, p = 0.002, respectively). sNFL ratio at re-baseline was negatively associated with relapse risk (hazard ratio 0.82 per unit; 95 % CI = 0.7-1.0; p = 0.049). A multivariable Cox regression analysis of relapse risk from re-baseline showed that the number of relapses in the 12 months prior to natalizumab treatment (hazard ratio 1.29; 95 % CI = 1.1-1.5; p = 6.0 × 10-4) and smoking (hazard ratio 1.51 per 20 cigarettes per day; 95 % CI = 1.0-2.2; p = 0.030) were associated with increased risk of relapse; sNFL ratio was associated with a lower risk of relapse (hazard ratio = 0.736 per unit; 95 % CI = 0.6-0.9 p = 0.007). In univariate logistic regression analyses, the sNFL ratio at 12 months and values above the 75th and the 90th percentile predicted MRI activity in the following year (odds ratio [OR] = 2.0, 95 % CI = 1.2-3.6, p = 0.012; OR = 2.2, 95 % CI = 1.2-4.1, p = 0.014; and OR = 2.8, 95 % CI = 1.1-6.7, p = 0.026). CONCLUSION: In this highly active RRMS cohort, high sNFL ratios reflected previous relapse activity and decreased after initiation of treatment but were not associated with increased relapse risk in the following two years. Pre-treatment relapses and smoking on treatment were predictors of relapse risk after re-baselining at 90 days. MRI activity in year two was predicted by sNFL ratios at month 12.

10-Year Mortality After ST-Segment Elevation Myocardial Infarction Compared to the General Population.

BACKGROUND: ST-segment elevation myocardial infarction (STEMI) is associated with high early mortality. However, it remains unclear if patients surviving the early phase have long-term excess mortality. OBJECTIVES: This study aims to assess excess mortality in STEMI patients treated with primary percutaneous coronary intervention (PCI) compared with an age- and- sex-matched general population at landmark periods 0 to 30 days, 31 to 90 days, and 91 days to 10 years. METHODS: Using the Western Denmark Heart Registry, we identified first-time PCI-treated patients who had primary PCI for STEMI from January 2003 to October 2018. Each patient was matched by age and sex to 5 individuals from the general population. RESULTS: We included 18,818 patients with first-time STEMI and 94,090 individuals from the general population. Baseline comorbidity burden was similar in STEMI patients and matched individuals. Compared with the matched individuals, STEMI was associated with a 5.9% excess mortality from 0 to 30 days (6.0% vs 0.2%; HR: 36.44; 95% CI: 30.86-43.04). An excess mortality remained present from 31 to 90 days (0.9% vs 0.4%; HR: 2.43; 95% CI: 2.02-2.93). However, in 90-day STEMI survivors, the absolute excess mortality was only 2.1 percentage points at 10-year follow-up (26.5% vs 24.5%; HR: 1.04; 95% CI: 1.01-1.08). Use of secondary preventive medications such as statins, antiplatelet therapy, and beta-blockers was very high in STEMI patients throughout 10-year follow-up. CONCLUSIONS: In primary PCI-treated STEMI patients with high use of guideline-recommended therapy, patients surviving the first 90 days had 10-year mortality that was only 2% higher than that of a matched general population.

Pharmacists combating antimicrobial resistance: A Delphi study on antibiotic dispensing.

BACKGROUND: The daily work of community pharmacists includes dispensing antibiotics, but little is known about how this should be done to ensure quality use of antibiotics. OBJECTIVE: To define specific tasks of the community pharmacist when dispensing antibiotics and to assess to what extent these tasks can be implemented in practice in Europe. METHODS: A Delphi study with community pharmacist experts in the European Economic Area. Statements on potential tasks for pharmacists during the antibiotic dispensing process were based on a systematic literature review. Participants rated the statements for importance and feasibility of implementation in practice in 3 rounds on a scale from 1 to 9. Consensus of importance was defined as ≥ 80 % of experts rating a statement between 7 and 9. An online expert meeting was conducted between rounds 1 and 2. Scores for all statements were analysed descriptively. RESULTS: Overall, 38 experts from 21 countries participated in the study. Experts reached consensus on 108 statements within 5 themes: 1) collaboration with prescribers, 2) checking prescriptions and dispensing, 3) counselling, 4) education, and 5) pharmacy services. Potential tasks included advising and collaborating with prescribers, performing safety checks, and having access to specific prescription information. Additionally, pharmacists should counsel patients related to the dispensed antibiotic and on antimicrobial resistance and infectious diseases. With few exceptions, pharmacists should not dispense antibiotics without prescriptions or prescribe antibiotics. Consensus on feasibility of implementation was only reached for statements in the categories "counselling patients" and "education". Barriers to changing practice included structure of the healthcare system, resistance to change from prescribers or pharmacy staff, lack of time and finances, legal barriers, and patient expectations. CONCLUSION: Community pharmacists have an important role when dispensing antibiotics. This study provides important steps towards better community pharmacy antibiotic dispensing practices throughout the EEA.

Effects of anti-CD20 therapy on circulating and intrathecal follicular helper T cell subsets in multiple sclerosis.

Follicular helper T (Tfh) cells and their interplay with B cells likely contribute to the pathogenesis of relapsing-remitting multiple sclerosis (RRMS). Tfh cells are enriched in cerebrospinal fluid (CSF) in RRMS, but effects of anti-CD20 therapy are unknown. We investigated Tfh cells in controls, untreated and anti-CD20-treated patients with RRMS using flow cytometry. CSF Tfh cells were increased in untreated patients. Compared to paired blood samples, CD25- Tfh cells were enriched in CSF in RRMS, but not in controls. Contrast-enhancing brain MRI lesions and IgG index correlated with CSF CD25- Tfh cell frequency in untreated patients with RRMS. Anti-CD20 therapy reduced the numbers of circulating PD1+ Tfh cells and CD25- Tfh cells, and the frequency of CSF CD25- Tfh cells. The study suggests that CD25- Tfh cells are recruited to the CSF in RRMS, associated with focal inflammation, and are reduced by anti-CD20 therapy.

The effect of focused lung ultrasonography on antibiotic prescribing in patients with acute lower respiratory tract infections in Danish general practice: study protocol for a pragmatic randomized controlled trial (PLUS-FLUS).

BACKGROUND: The use of antibiotics is a key driver of antimicrobial resistance and is considered a major threat to global health. In Denmark, approximately 75% of antibiotic prescriptions are issued in general practice, with acute lower respiratory tract infections (LRTIs) being one of the most common indications. Adults who present to general practice with symptoms of acute LRTI often suffer from self-limiting viral infections. However, some patients have bacterial community-acquired pneumonia (CAP), a potential life-threatening infection, that requires immediate antibiotic treatment. Importantly, no single symptom or specific point-of-care test can be used to discriminate the various diagnoses, and diagnostic uncertainty often leads to (over)use of antibiotics. At present, general practitioners (GPs) lack tools to better identify those patients who will benefit from antibiotic treatment. The primary aim of the PLUS-FLUS trial is to determine whether adults who present with symptoms of an acute LRTI in general practice and who have FLUS performed in addition to usual care are treated less frequently with antibiotics than those who only receive usual care. METHODS: Adults (≥ 18 years) presenting to general practice with acute cough (< 21 days) and at least one other symptom of acute LRTI, where the GP suspects a bacterial CAP, will be invited to participate in this pragmatic randomized controlled trial. All participants will receive usual care. Subsequently, participants will be randomized to either the control group (usual care) or to an additional focused lung ultrasonography performed by the GP (+ FLUS). The primary outcome is the proportion of participants with antibiotics prescribed at the index consultation (day 0). Secondary outcomes include comparisons of the clinical course for participants in groups. DISCUSSION: We will examine whether adults who present with symptoms of acute LRTI in general practice, who have FLUS performed in addition to usual care, have antibiotics prescribed less frequently than those given usual care alone. It is highly important that a possible reduction in antibiotic prescriptions does not compromise patients' recovery or clinical course, which we will assess closely. TRIAL REGISTRATION: ClinicalTrials.gov NCT06210282. Registered on January 17, 2024.

A model for the noninvasive, habitat-inclusive estimation of upper limit abundance for synanthropes, exemplified by M. fascicularis.

Accurately estimating population sizes for free-ranging animals through noninvasive methods, such as camera trap images, remains particularly limited by small datasets. To overcome this, we developed a flexible model for estimating upper limit populations and exemplified it by studying a group-living synanthrope, the long-tailed macaque (Macaca fascicularis). Habitat preference maps, based on environmental and GPS data, were generated with a maximum entropy model and combined with data obtained from camera traps, line transect distance sampling, and direct sightings to produce an expected number of individuals. The mapping between habitat preference and number of individuals was optimized through a tunable parameter ρ (inquisitiveness) that accounts for repeated observations of individuals. Benchmarking against published data highlights the high accuracy of the model. Overall, this approach combines citizen science with scientific observations and reveals the long-tailed macaque populations to be (up to 80%) smaller than expected. The model's flexibility makes it suitable for many species, providing a scalable, noninvasive tool for wildlife conservation.

Incidence and assessment of delirium following open cardiac surgery; A systematic review and meta-analysis.

AIM: This systematic review and meta-analysis sought i) to provide an overview of the incidence of delirium following open cardiac surgery and ii) to investigate how incidences of delirium are associated with different assessment tools. METHODS AND RESULTS: A systematic search of studies investigating delirium following open cardiac surgery were conducted in Medline (Ovid), EMBASE, PsycINFO, CiNAHL and the Cochrane Database. Only studies with patients diagnosed or screened with a validated tool were included. Studies published from 2005 to 2021 were included in the meta-analysis.Of 7,126 individual studies retrieved, 106 met the inclusion criteria for the meta-analysis, hereof 31% of high quality. The weighted pooled incidence of delirium following open cardiac surgery across all studies was 23% (95% CI 20-26%), however we found a considerable heterogeneity (I2 = 99%), which could not be explained by subgroups or further sensitivity analyses. The most commonly applied screening tool for delirium is CAM/CAM-ICU. The lowest estimates of delirium were found by applying the Delirium Observation Scale (incidence 14%, 95% CI 8-20%), and the highest estimates in studies using "other" screening tools (Organic Brain Symptom Scale, Delirium Symptom Interview) pooled incidence of 43%, (95% CI 19 - 66%), however, only two studies applied these. CONCLUSION: Delirium following open cardiac surgery remains a complication with a high incidence of overall 23%, when applying a validated tool for screening or diagnosis. Nevertheless, this systematic review and meta-analyses highlight the significant inconsistency in current evidence regarding assessment tools and regimens. REGISTRATION: Prospero CRD42020215519.

Non-HDL cholesterol and residual cardiovascular risk in statin-treated patients with and without diabetes: The Western Denmark Heart Registry.

AIMS: Assessment of residual cardiovascular risk in statin-treated patients with atherosclerotic cardiovascular disease (ASCVD) is pivotal for optimising secondary preventive therapies. This study investigates if non-high-density lipoprotein cholesterol (non-HDL-C) is associated with residual ASCVD risk in statin-treated ischemic heart disease (IHD) patients with and without diabetes. METHODS: Using the Western Denmark Heart Registry, we identified statin-treated patients with IHD examined by coronary angiography (CAG) from 2011-2020. Non-HDL-C was assessed within one year after CAG. Outcomes were ASCVD (myocardial infarction, ischemic stroke, and cardiovascular death) and all-cause death. Cox regression analyses obtained hazard ratios adjusted for age, sex, smoking, and hypertension. RESULTS: A total of 42,057 patients were included; 8,196 patients with diabetes and 33,861 without diabetes. During median 4.6 years of follow-up event rates per 1000 person-years of ASCVD were 28.8 (27.1-30.5) and 17.2 (16.5-17.8) among patients with and without diabetes. In patients with diabetes the adjusted hazard ratios (HR) of ASCVD as compared with non-HDL-C <25th percentile were 1.0 (0.9-1.2), 1.3 (1.1-1.6), and 1.6 (1.2-2.1) for patients in the 25th-74th, 75th-94th, and ≥95th percentile. In patients without diabetes corresponding adjusted HRs were 1.1 (0.9-1.1), 1.2 (1.1-1.4), and 1.7 (1.4-2.0). Results were consistent across sex, age, clinical presentation, and low-density lipoprotein cholesterol strata. CONCLUSIONS: In statin-treated IHD patients with and without diabetes non-HDL-C, especially above the 75th percentile, is associated with residual cardiovascular risk. These results have implications for secondary prevention targeting patients who may benefit most from intensified preventive therapy.

Relevant to individuals, both with and without diabetes, who receive cholesterol-lowering therapy due to ischemic heart disease, having a high level of non-HDL cholesterol is associated with risk of heart attack, stroke, and death. In individuals with diabetes, having a high compared to a low non-HDL cholesterol level was associated with a 30-60% increased risk of heart attack, stroke, and death. For individuals without diabetes, the high non-HDL cholesterol level was linked to an increased risk by up to 70%.In clinical practice calculation of non-HDL cholesterol, from the standard lipid profile with no inconvenience to the patient, offers a possibility to identify patients who face a high risk of heart attack, stroke, and death. Patients with high levels of non-HDL cholesterol may benefit from optimized preventive therapy.

Neuronal waste management: new roles for autophagy genes in the extrusion of protein aggregates and in longevity.

A decline in macroautophagic/autophagic activity with age contributes to the accumulation of damaged molecules and is associated with the impairment of neuronal functions and the onset of age-related diseases, particularly neurodegenerative disorders. To learn about the neuronal-specific roles of autophagy genes in aging, we specifically inhibited autophagy genes pan-neuronally in C. elegans, which leads to unexpected positive impacts on neuronal homeostasis including polyQ aggregate load and organismal lifespan. These improvements are independent of canonical, degradative autophagy in neurons and instead correlate with an increase in the secretion of large, extracellular vesicles, known as exophers. We found that the ATG-16.2 WD40 domain, a conserved domain critical for at least some noncanonical autophagy functions of ATG16L1 in mammalian cells, is required for the increased exopher biogenesis, reduction in polyQ aggregate load, and lifespan extension induced by neuronal inhibition of early-acting autophagy genes. Our study suggests that noncanonical functions of ATG-16.2, and potentially other early-acting autophagy genes, may play a role in neuronal exopher formation and C. elegans aging, extending beyond their canonical degradative functions in the autophagy process.

Autophagy protein ATG-16.2 and its WD40 domain mediate the beneficial effects of inhibiting early-acting autophagy genes in C. elegans neurons.

While autophagy genes are required for lifespan of long-lived animals, their tissue-specific roles in aging remain unclear. Here, we inhibited autophagy genes in Caenorhabditis elegans neurons, and found that knockdown of early-acting autophagy genes, except atg-16.2, increased lifespan, and decreased neuronal PolyQ aggregates, independently of autophagosomal degradation. Neurons can secrete protein aggregates via vesicles called exophers. Inhibiting neuronal early-acting autophagy genes, except atg-16.2, increased exopher formation and exopher events extended lifespan, suggesting exophers promote organismal fitness. Lifespan extension, reduction in PolyQ aggregates and increase in exophers were absent in atg-16.2 null mutants, and restored by full-length ATG-16.2 expression in neurons, but not by ATG-16.2 lacking its WD40 domain, which mediates noncanonical functions in mammalian systems. We discovered a neuronal role for C. elegans ATG-16.2 and its WD40 domain in lifespan, proteostasis and exopher biogenesis. Our findings suggest noncanonical functions for select autophagy genes in both exopher formation and in aging.

Removal from the wild endangers the once widespread long-tailed macaque.

In 2022, long-tailed macaques (Macaca fascicularis), a once ubiquitous primate species, was elevated to Endangered on the International Union for Conservation of Nature (IUCN) Red List of Threatened Species. In 2023, recognizing that the long-tailed macaque is threatened by multiple factors: (1) declining native habitats across Southeast Asia; (2) overutilization for scientific, commercial, and recreational purposes; (3) inadequate regulatory mechanisms; and (4) culling due to human-macaque conflicts, a petition for rulemaking was submitted to the United States Fish and Wildlife Service to add the species to the US Endangered Species Act, the nation's most effective law to protect at risk species. The long-tailed macaque remains unprotected across much of its geographical range despite the documented continual decline of the species and related sub-species and the recent IUCN reassessment. This commentary presents a review of the factors that have contributed to the dramatic decline of this keystone species and makes a case for raising the level of protection they receive.

The Third Annual Symposium of the Midwest Aging Consortium.

The geroscience hypothesis suggests that addressing the fundamental mechanisms driving aging biology will prevent or mitigate the onset of multiple chronic diseases, for which the largest risk factor is advanced age. Research that investigates the root causes of aging is therefore of critical importance given the rising healthcare burden attributable to age-related diseases. The third annual Midwest Aging Consortium symposium was convened as a showcase of such research performed by investigators from institutions across the Midwestern United States. This report summarizes the work presented during a virtual conference across topics in aging biology, including immune function in the lung-particularly timely given the Corona Virus Immune Disease-2019 pandemic-along with the role of metabolism and nutrient-regulated pathways in cellular function with age, the influence of senescence on stem cell function and inflammation, and our evolving understanding of the mechanisms underlying observation of sex dimorphism in aging-related outcomes. The symposium focused on early-stage and emerging investigators, while including keynote presentations from leaders in the biology of aging field, highlighting the diversity and strength of aging research in the Midwest.

Reducing antibiotic prescribing in general practice in Australia: a cluster randomised controlled trial of a multimodal intervention.

BACKGROUND: The health and economic burden of antimicrobial resistance (in Australia is significant. Interventions that help guide and improve appropriate prescribing for acute respiratory tract infections in the community represent an opportunity to slow the spread of resistant bacteria. Clinicians who work in primary care are potentially the most influential health care professionals to address the problem of antimicrobial resistance, because this is where most antibiotics are prescribed. METHODS: A cluster randomised trial was conducted comparing two parallel groups of 27 urban general practices in Queensland, Australia: 13 intervention and 14 control practices, with 56 and 54 general practitioners (GPs), respectively. This study evaluated an integrated, multifaceted evidence-based package of interventions implemented over a 6-month period. The evaluation included quantitative and qualitative components, and an economic analysis. RESULTS: A multimodal package of interventions resulted in a reduction of 3.81 prescriptions per GP per month. This equates to 1280.16 prescriptions for the 56GPs in the intervention practices over the 6-month period. The cost per prescription avoided was A$148. The qualitative feedback showed that the interventions were well received by the GPs and did not impact on consultation time. Providing GPs with a choice of tools might enhance their uptake and support for antimicrobial stewardship in the community. CONCLUSIONS: A multimodal package of interventions to enhance rational prescribing of antibiotics is effective, feasible and acceptable in general practice. Investment in antimicrobial stewardship strategies in primary care may ultimately provide the important returns for public health into the future.

Neurofilament light chain levels in serum among a large mixed memory clinic cohort: Confounders and diagnostic usefulness.

INTRODUCTION: Early and accurate diagnosis of neurocognitive disorders including neurodegenerative dementia remains challenging. This study explores the impact of biological factors on serum neurofilament light chain (NfL) levels and clinical usefulness for the detection of neurocognitive disorders in a mixed memory clinic. METHODS: Serum samples and clinical data were obtained from 1188 patients who underwent diagnostic investigations for memory complaints between January 2018 and September 2019. Serum NfL was measured using single molecule array technology. RESULTS: NfL exhibited a moderate association with age, estimated glomerular filtration rate (eGFR), and Fazekas score. NfL was able to differentiate between patients with neurocognitive disorders and those without with a sensitivity and specificity of 80%. NfL could, however, not distinguish between different dementia etiologies. DISCUSSION: Serum NfL could aid early diagnostic triage by identifying patients requiring further diagnostic procedures and therefore aid in a more focused use of health-care resources.

A drug-like molecule engages nuclear hormone receptor DAF-12/FXR to regulate mitophagy and extend lifespan.

Autophagy-lysosomal function is crucial for maintaining healthy lifespan and preventing age-related diseases. The transcription factor TFEB plays a key role in regulating this pathway. Decreased TFEB expression is associated with various age-related disorders, making it a promising therapeutic target. In this study, we screened a natural product library and discovered mitophagy-inducing coumarin (MIC), a benzocoumarin compound that enhances TFEB expression and lysosomal function. MIC robustly increases the lifespan of Caenorhabditis elegans in an HLH-30/TFEB-dependent and mitophagy-dependent manner involving DCT-1/BNIP3 while also preventing mitochondrial dysfunction in mammalian cells. Mechanistically, MIC acts by inhibiting ligand-induced activation of the nuclear hormone receptor DAF-12/FXR, which, in turn, induces mitophagy and extends lifespan. In conclusion, our study uncovers MIC as a promising drug-like molecule that enhances mitochondrial function and extends lifespan by targeting DAF-12/FXR. Furthermore, we discovered DAF-12/FXR as a previously unknown upstream regulator of HLH-30/TFEB and mitophagy.

Misconceptions and Knowledge Gaps on Antibiotic Use and Resistance in Four Healthcare Settings and Five European Countries-A Modified Delphi Study.

Misconceptions and knowledge gaps about antibiotics contribute to inappropriate antibiotic use and antimicrobial resistance. This study aimed to identify and prioritize misconceptions and knowledge gaps about antibiotic use from a healthcare professionals' perspective. A modified Delphi study with a predefined list of statements, two questionnaire rounds, and an expert meeting was conducted. The statements were rated by healthcare professionals from France, Greece, Lithuania, Poland, and Spain, and from general practice, out-of-hour services, nursing homes, and pharmacies. A total of 44 pre-defined statements covered the following themes: (1) antimicrobial resistance in general, (2) use of antibiotics in general, (3) use of antibiotics for respiratory tract infections, and (4) use of antibiotics for urinary tract infections. Consensus was defined as ≥80% agreement between the professionals during the second Delphi round. For 30% of the statements, professionals from the four settings together reached consensus. In each setting individually, at least 50% of the statements reached consensus, indicating that there are still many misconceptions and knowledge gaps that need to be addressed. Six educational tools (leaflets, posters, checklists) were developed to address the knowledge gaps and misconceptions. These can be used by patients and healthcare professionals to improve the use of antibiotics in practice.

Impact of Coronary Artery Disease in Women With Newly Diagnosed Heart Failure and Reduced Ejection Fraction.

BACKGROUND: The representation of women in heart failure studies has been inadequate, resulting in a knowledge gap regarding the prognostic impact of coronary artery disease (CAD) on all-cause mortality in women with newly diagnosed heart failure and reduced ejection fraction (HFrEF). OBJECTIVES: This study aims to assess the prognostic impact of CAD in women with HFrEF. METHODS: Using the Western Denmark Heart Registry, the authors identified 891 women and 2,403 men referred for first-time coronary angiography because of HFrEF. The authors stratified for presence of CAD, estimated 10-year all-cause mortality, and calculated crude and adjusted HRs (aHRs) with 95% CIs. RESULTS: The 10-year mortality was 60% in women with CAD and 27% in women without CAD; for men, the corresponding numbers were 54% and 36%. When adjusted for comorbidities, women without CAD had a lower relative 10-year mortality than men without CAD (aHR: 0.73; 95% CI: 0.58-0.91), whereas women with CAD had similar relative mortality as men with CAD (aHR: 1.00; 95% CI: 0.81-1.24) (Pinteraction = 0.037). Assessed by the number of coronary vessels with significant stenosis, CAD extent was associated with mortality for both women (P < 0.01) and men (P < 0.01). However, compared to those without CAD, the aHR was higher for women with any degree of CAD (aHR ranging from 1.61 [95% CI: 1.09-2.38] for diffuse CAD to 2.01 [95% CI: 1.19-3.40] for 3-vessel disease) than for men with 3-vessel disease (aHR: 1.51; 95% CI: 1.19-1.91). CONCLUSIONS: In patients with newly diagnosed HFrEF, the presence and extent of CAD has significantly greater prognostic impact among women than among men.

Post-translational modifications of ATG8 proteins - an emerging mechanism of autophagy control.

Autophagy is a recycling mechanism involved in cellular homeostasis with key implications for health and disease. The conjugation of the ATG8 family proteins, which includes LC3B (also known as MAP1LC3B), to autophagosome membranes, constitutes a hallmark of the canonical autophagy process. After ATG8 proteins are conjugated to the autophagosome membranes via lipidation, they orchestrate a plethora of protein-protein interactions that support key steps of the autophagy process. These include binding to cargo receptors to allow cargo recruitment, association with proteins implicated in autophagosome transport and autophagosome-lysosome fusion. How these diverse and critical protein-protein interactions are regulated is still not well understood. Recent reports have highlighted crucial roles for post-translational modifications of ATG8 proteins in the regulation of ATG8 functions and the autophagy process. This Review summarizes the main post-translational regulatory events discovered to date to influence the autophagy process, mostly described in mammalian cells, including ubiquitylation, acetylation, lipidation and phosphorylation, as well as their known contributions to the autophagy process, physiology and disease.