Recent research focusing on brown adipose tissue (BAT) function emphasizes its importance in systemic metabolic homeostasis. We show here that genetic and pharmacological inhibition of the mevalonate ...pathway leads to reduced human and mouse brown adipocyte function in vitro and impaired adipose tissue browning in vivo. A retrospective analysis of a large patient cohort suggests an inverse correlation between statin use and active BAT in humans, while we show in a prospective clinical trial that fluvastatin reduces thermogenic gene expression in human BAT. We identify geranylgeranyl pyrophosphate as the key mevalonate pathway intermediate driving adipocyte browning in vitro and in vivo, whose effects are mediated by geranylgeranyltransferases (GGTases), enzymes catalyzing geranylgeranylation of small GTP-binding proteins, thereby regulating YAP1/TAZ signaling through F-actin modulation. Conversely, adipocyte-specific ablation of GGTase I leads to impaired adipocyte browning, reduced energy expenditure, and glucose intolerance under obesogenic conditions, highlighting the importance of this pathway in modulating brown adipocyte functionality and systemic metabolism.
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•The mevalonate pathway is important for adipose tissue browning in mouse and human•Statin use is inversely correlated with brown fat activity in humans•Geranylgeranylation of small GTP-binding proteins promotes adipocyte browning•Small GTP-binding proteins regulate F-actin formation and YAP1/TAZ stability
Through genetic and pharmacological in vivo and in vitro approaches, Balaz et al. show that the mevalonate pathway is important for adipocyte browning. The importance of this pathway is supported by a retrospective clinical study and a small volunteer trial with fluvastatin. The authors identify geranylgeranyl pyrophosphate as the key mevalonate intermediate driving adipocyte browning.
Cardiovascular events remain one of the most frequent causes of mortality and morbidity worldwide. The majority of cardiac events occur in individuals without known coronary artery disease (CAD) and ...in low- to intermediate-risk subjects. Thus, the development of improved preventive strategies may substantially benefit from the identification, among apparently intermediate-risk subjects, of those who have a high probability for developing future cardiac events. Cardiac computed tomography and myocardial perfusion scintigraphy (MPS) by single photon emission computed tomography may play a role in this setting. In fact, absence of coronary calcium in cardiac computed tomography and inducible ischaemia in MPS are associated with a very low rate of major cardiac events in the next 3-5 years. Based on current evidence, the evaluation of coronary calcium in primary prevention subjects should be considered in patients classified as intermediate-risk based on traditional risk factors, since high calcium scores identify subjects at high-risk who may benefit from aggressive secondary prevention strategies. In addition, calcium scoring should be considered for asymptomatic type 2 diabetic patients without known CAD to select those in whom further functional testing by MPS or other stress imaging techniques may be considered to identify patients with significant inducible ischaemia. From available data, the use of MPS as first line testing modality for risk stratification is not recommended in any category of primary prevention subjects with the possible exception of first-degree relatives of patients with premature CAD in whom MPS may be considered. However, the Working Group recognizes that neither the use of computed tomography for calcium imaging nor of MPS have been proven to significantly improve clinical outcomes of primary prevention subjects in prospective controlled studies. This information would be crucial to adequately define the role of imaging approaches in cardiovascular preventive strategies.
The incremental prognostic value of post-stress left ventricular ejection fraction (EF) and volume over perfusion has not been investigated.
We identified 1680 consecutive patients who underwent rest ...Tl-201/stress Tc-99m sestamibi gated single photon emission computed tomography (SPECT) and who were followed-up for 569+/-106 days. Receiver-operator characteristics analysis defined an EF<45%, an end-systolic volume (ESV) >70 mL, and an end-diastolic volume >120 mL as optimal thresholds, yielding moderate sensitivity and high specificity in the prediction of cardiac death. Patients with an EF> or = 45% had mortality rates <1%/year, despite severe perfusion abnormalities, whereas patients with an EF<45% had high mortality rates, even with only mild/moderate perfusion abnormalities (9.2%/year; P<0.00001). Similarly, an ESV< or = 70 mL was related to a low cardiac death rate (<1.2%/year), even for patients with severe perfusion abnormalities, whereas patients with an ESV>70 mL and only mild/moderate perfusion abnormalities had high death rates (8.2%/year; P<0.00001). Patients with an EF<45% and an ESV< or = 70 mL had low cardiac death rates (1.7%/year); those with an EF<45% but an ESV>70 mL had high death rates (7.9%/year; P<0.02). Multivariate Cox proportional hazards regression showed that perfusion variables and ESV were independent predictors of overall coronary events, whereas EF and ESV demonstrated incremental prognostic values over prescan and perfusion information in predicting cardiac death and cardiac death or myocardial infarction.
Post-stress EF and ESV by gated-SPECT have incremental prognostic values over prescan and perfusion information in predicting cardiac death, and they provide clinically useful risk stratification.
BACKGROUND: The aim of these clinical standards is to provide guidance on 'best practice´ for diagnosis, treatment and management of drug-susceptible pulmonary TB (PTB).METHODS: A panel of 54 global ...experts in the field of TB care, public health, microbiology,
and pharmacology were identified; 46 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all 46 participants.RESULTS: Seven clinical standards were defined: Standard 1,
all patients (adult or child) who have symptoms and signs compatible with PTB should undergo investigations to reach a diagnosis; Standard 2, adequate bacteriological tests should be conducted to exclude drug-resistant TB; Standard 3, an appropriate regimen recommended by WHO and national
guidelines for the treatment of PTB should be identified; Standard 4, health education and counselling should be provided for each patient starting treatment; Standard 5, treatment monitoring should be conducted to assess adherence, follow patient progress, identify and manage adverse events,
and detect development of resistance; Standard 6, a recommended series of patient examinations should be performed at the end of treatment; Standard 7, necessary public health actions should be conducted for each patient. We also identified priorities for future research into PTB.CONCLUSION:
These consensus-based clinical standards will help to improve patient care by guiding clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment for PTB.
ObjectivesPredicting the presence or absence of coronary artery disease (CAD) is clinically important. Pretest probability (PTP) and CAD consortium clinical (CAD2) model and risk scores used in the ...guidelines are not sufficiently accurate as the only guidance for applying invasive testing or discharging a patient. Artificial intelligence without the need of additional non-invasive testing is not yet used in this context, as previous results of the model are promising, but available in high-risk population only. Still, validation in low-risk patients, which is clinically most relevant, is lacking.DesignRetrospective cohort study.SettingSecondary outpatient clinic care in one Dutch academic hospital.ParticipantsWe included 696 patients referred from primary care for further testing regarding the presence or absence of CAD. The results were compared with PTP and CAD2 using receiver operating characteristic (ROC) curves (area under the curve (AUC)). CAD was defined by a coronary stenosis >50% in at least one coronary vessel in invasive coronary or CT angiography, or having a coronary event within 6 months.Outcome measuresThe first cohort validating the memetic pattern-based algorithm (MPA) model developed in two high-risk populations in a low-risk to intermediate-risk cohort to improve risk stratification for non-invasive diagnosis of the presence or absence of CAD.ResultsThe population contained 49% male, average age was 65.6±12.6 years. 16.2% had CAD. The AUCs of the MPA model, the PTP and the CAD2 were 0.87, 0.80, and 0.82, respectively. Applying the MPA model resulted in possible discharge of 67.7% of the patients with an acceptable CAD rate of 4.2%.ConclusionsIn this low-risk to intermediate-risk population, the MPA model provides a good risk stratification of presence or absence of CAD with a better ROC compared with traditional risk scores. The results are promising but need prospective confirmation.
Summary
Background
IBD diagnosed after the age of 60 is increasing. Data on post‐operative complications in elderly onset IBD are scarce.
Aim
To describe the incidence of and factors associated with ...post‐operative complications in elderly onset IBD, diagnosed after the age of 60.
Methods
Using EPIMAD Cohort (1988‐2006), among 841 incident IBD patients, 139 (17%) underwent intestinal surgery, including 100 Crohn's disease (CD) and 39 ulcerative colitis (UC).
Results
After a median post‐operative follow‐up of 6 years (2‐10), 50 (36%) patients experienced at least 1 complication with a total of 69. During the first 30 post‐operative days, the mortality rate was 4%. Thirty‐two early complications (<30 days) were observed in 23 patients (17%), with 15 infectious, without significant difference between CD and UC. More than half early post‐operative complications (n = 19, 59%) were severe (>grade 2) without significant difference between CD and UC (P = 0.28). Thirty‐seven long‐term adverse effects of surgical therapy (≥30 days) were observed in 33 patients (24%). Multivariate analysis found (1) acute severe colitis (OR = 7.84 2.15‐28.52) and emergency surgery (OR = 4.46 1.75‐11.36) were associated with early post‐operative complications, and (2) Female gender (HR = 2.10 1.01‐4.37) and delay before surgery >3 months (HR = 2.09 1.01‐4.31) with long‐term adverse effects of surgical therapy.
Conclusions
One‐third of elderly IBD patients experienced at least 1 post‐operative complication. Half of the early complications were severe, and infectious. Emergency surgery was the key driver for post‐operative complication.
Linked ContentThis article is linked to Myrelid and Savoye et al papers. To view these articles visit https://doi.org/10.1111/apt.14833 and https://doi.org/10.1111/apt.14854.
Well-established tuberculosis screening units in Western Europe were selectively sampled. Three screening units in Norway, two in the UK, one in the Netherlands and one in Switzerland were evaluated. ...The aim of this study was to describe a range of service models used at a number of individual tuberculosis units for the screening of new entrants into Europe. Semi-structured interviews were conducted with clinicians, nurses and administrators from a selected sample of European tuberculosis screening units. An outline of key themes to be addressed was forwarded to units ahead of scheduled interviews. Themes included the history of the unit, structure, processes and outputs involved in screening new entrants for tuberculosis. Considerable variation in screening services exists in the approaches studied. Units are sited in transit camps or as units within hospital facilities. Staff capacity and administration varies from one clinic per week with few dedicated staff to fully dedicated units. Only one site recorded symptoms; tuberculin testing was universal in children, but varied in adults; chest radiograph screening was universal except at one site where a positive tuberculin skin test or symptoms were required in those <35 yrs of age before ordering a radiograph. Few output data are routinely and systematically collected, which hinders comparison and determination of effectiveness and efficiency. Service models for screening new immigrants for tuberculosis appear to vary in Western Europe. The systematic collection of data would make international comparisons between units easier and help draw conclusions that might usefully inform service development.
Latent tuberculosis infection (LTBI) is characterised by the presence of immune responses to previously acquired Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis ...(TB). Here we report evidence-based guidelines from the World Health Organization for a public health approach to the management of LTBI in high risk individuals in countries with high or middle upper income and TB incidence of <100 per 100 000 per year. The guidelines strongly recommend systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematological transplantation, and patients with silicosis. In prisoners, healthcare workers, immigrants from high TB burden countries, homeless persons and illicit drug users, systematic testing and treatment of LTBI is conditionally recommended, according to TB epidemiology and resource availability. Either commercial interferon-gamma release assays or Mantoux tuberculin skin testing could be used to test for LTBI. Chest radiography should be performed before LTBI treatment to rule out active TB disease. Recommended treatment regimens for LTBI include: 6 or 9 month isoniazid; 12 week rifapentine plus isoniazid; 3-4 month isoniazid plus rifampicin; or 3-4 month rifampicin alone.
Coronary artery disease (CAD) plays an important role in diabetic patients because they have a very high cardiovascular mortality risk. Therefore the question arises if all diabetic patients should ...be screened for CAD. In patients with (a)typical angina or anginal equivalents (e.g. shortness of breath) an extended CAD evaluation is indicated. Unselected screening in diabetic patients, however, does not seem to make sense as the only large prospective randomized study in this field did not demonstrate a survival benefit in the screened patient population. It is noteworthy that preoperative risk stratification deserves special consideration in diabetic patients. If screening is considered there is the anatomic approach (calcium score, non-invasive coronary angiography) or the functional approach (stress testing, ischemia evaluation). In diabetic patients who in general should already have all the medication with respect to coronary prevention, functional rather than anatomic testing makes sense because revascularization can be considered in patients with extensive ischemia. In contrast, anatomic testing if positive would only be confirming that a medical preventive strategy is necessary. On the other hand a normal anatomic test has a very high negative predictive value. Therefore, CAD evaluation should follow an individual patient tailored approach as long as evidence-based guidelines are lacking.
Data on extra-intestinal manifestations EIM and their impact on the disease course of ulcerative colitis UC in population-based cohorts are scarce, particularly in paediatric- and elderly-onset UC ...patients. The aims of this population-based study were to assess: 1 the occurrence of EIM in paediatric- and elderly-onset UC; 2 the factors associated with EIM; and 3 their impact on long-term disease outcome.
Paediatric-onset < 17 years at diagnosis and elderly-onset UC patients > 60 years at diagnosis from a French prospective population-based registry EPIMAD were included. Data on EIM and other clinical factors at diagnosis and at maximal follow-up were collected.
In all, 158 paediatric- and 470 elderly-onset patients were included median age at diagnosis 14.5 and 68.8 years, median follow-up 11.2 and 6.2 years, respectively. EIM occurred in 8.9% of childhood- and 3% of elderly-onset patients at diagnosis and in 16.7% and 2.2% of individuals during follow-up p < 0.01, respectively. The most frequent EIM was joint involvement 15.8% of paediatric onset and 2.6% of elderly-onset. Presence of EIM at diagnosis was associated with more severe disease course need for immunosuppressants or biologic therapy or colectomy in both paediatric- and elderly-onset UC (hazard ratio HR = 2.0, 95% confidence interval CI: 1.0-4.2; and HR = 2.8, 0.9-7.9, respectively). Extensive colitis was another independent risk factor in both age groups.
Elderly-onset UC patients had lower risk of EIM either at diagnosis or during follow-up than paediatric-onset individuals. EIM at diagnosis predicted more severe disease outcome, including need for immunosuppressive or biologic therapy or surgery, in both paediatric- and elderly-onset UC.
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