Effect of testing for cancer on cancer- or venous thromboembolism (VTE)-related mortality and morbidity in people with unprovoked VTE

BACKGROUND: Venous thromboembolism (VTE) is a collective term for two conditions: deep vein thrombosis (DVT) and pulmonary embolism (PE). A proportion of people with VTE have no underlying or immediately predisposing risk factors and the VTE is referred to as unprovoked. Unprovoked VTE can often be the first clinical manifestation of an underlying malignancy. This has raised the question of whether people with an unprovoked VTE should be investigated for an underlying cancer. Treatment for VTE is different in cancer and non‐cancer patients and a correct diagnosis would ensure that people received the optimal treatment for VTE to prevent recurrence and further morbidity. Furthermore, an appropriate cancer diagnosis at an earlier stage could avoid the risk of cancer progression and lead to improvements in cancer‐related mortality and morbidity. This is the third update of the review first published in 2015. OBJECTIVES: To determine whether testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT of the lower limb or PE) is effective in reducing cancer‐ or VTE‐related mortality and morbidity and to determine which tests for cancer are best at identifying treatable cancers early. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 5 May 2021. We also undertook reference checking to identify additional studies. SELECTION CRITERIA: Randomised and quasi‐randomised trials in which people with an unprovoked VTE were allocated to receive specific tests for identifying cancer or clinically indicated tests only were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias and extracted data. We assessed the certainty of the evidence using GRADE criteria. We resolved any disagreements by discussion. The main outcomes of interest were all‐cause mortality, cancer‐related mortality and VTE‐related mortality. MAIN RESULTS: No new studies were identified for this 2021 update. In total, four studies with 1644 participants are included. Two studies assessed the effect of extensive tests including computed tomography (CT) scanning versus tests at the physician's discretion, while the other two studies assessed the effect of standard testing plus positron emission tomography (PET)/CT scanning versus standard testing alone. For extensive tests including CT versus tests at the physician's discretion, the certainty of the evidence, as assessed according to GRADE, was low due to risk of bias (early termination of the studies). When comparing standard testing plus PET/CT scanning versus standard testing alone, the certainty of evidence was moderate due to a risk of detection bias. The certainty of the evidence was downgraded further as detection bias was present in one study with a low number of events. When comparing extensive tests including CT versus tests at the physician's discretion, pooled analysis on two studies showed that testing for cancer was consistent with either benefit or no benefit on cancer‐related mortality (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.15 to 1.67; 396 participants; 2 studies; low‐certainty evidence). One study (201 participants) showed that, overall, malignancies were less advanced at diagnosis in extensively tested participants than in participants in the control group. In total, 9/13 participants diagnosed with cancer in the extensively tested group had a T1 or T2 stage malignancy compared to 2/10 participants diagnosed with cancer in the control group (OR 5.00, 95% CI 1.05 to 23.76; low‐certainty evidence). There was no clear difference in detection of advanced stages between extensive tests versus tests at the physician's discretion: one participant in the extensively tested group had stage T3 compared with four participants in the control group (OR 0.25, 95% CI 0.03 to 2.28; low‐certainty evidence). In addition, extensively tested participants were diagnosed earlier than control group (mean: 1 month with extensive tests versus 11.6 months with tests at physician's discretion to cancer diagnosis from the time of diagnosis of VTE). Extensive testing did not increase the frequency of an underlying cancer diagnosis (OR 1.32, 95% CI 0.59 to 2.93; 396 participants; 2 studies; low‐certainty evidence). Neither study measured all‐cause mortality, VTE‐related morbidity and mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life. When comparing standard testing plus PET/CT screening versus standard testing alone, standard testing plus PET/CT screening was consistent with either benefit or no benefit on all‐cause mortality (OR 1.22, 95% CI 0.49 to 3.04; 1248 participants; 2 studies; moderate‐certainty evidence), cancer‐related mortality (OR 0.55, 95% CI 0.20 to 1.52; 1248 participants; 2 studies; moderate‐certainty evidence) or VTE‐related morbidity (OR 1.02, 95% CI 0.48 to 2.17; 854 participants; 1 study; moderate‐certainty evidence). Regarding stage of cancer, there was no clear difference for detection of early (OR 1.78, 95% 0.51 to 6.17; 394 participants; 1 study; low‐certainty evidence) or advanced (OR 1.00, 95% CI 0.14 to 7.17; 394 participants; 1 study; low‐certainty evidence) stages of cancer. There was also no clear difference in the frequency of an underlying cancer diagnosis (OR 1.71, 95% CI 0.91 to 3.20; 1248 participants; 2 studies; moderate‐certainty evidence). Time to cancer diagnosis was 4.2 months in the standard testing group and 4.0 months in the standard testing plus PET/CT group (P = 0.88). Neither study measured VTE‐related mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life. AUTHORS' CONCLUSIONS: Specific testing for cancer in people with unprovoked VTE may lead to earlier diagnosis of cancer at an earlier stage of the disease. However, there is currently insufficient evidence to draw definitive conclusions concerning the effectiveness of testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT or PE) in reducing cancer‐ or VTE‐related morbidity and mortality. The results could be consistent with either benefit or no benefit. Further good‐quality large‐scale randomised controlled trials are required before firm conclusions can be made

Exploring the failing right ventricle in pulmonary hypertension by cardiac magnetic resonance: an in vivo study utilizing Macitentan

Cardiac magnetic resonance (CMR) imaging is used to assess the right ventricle (RV) of pulmonary hypertensive (PH) patients and more recently to track changes in response to therapy. We wished to investigate if repeat CMRs could be used to assess ventricular changes in the Sugen 5416 hypoxic (Su/Hx) rat model of PH treated with the dual endothelin receptor antagonist Macitentan. Male Sprague Dawley Su/Hx rats were dosed for 3 weeks with either vehicle or Macitentan (30 mg/kg) daily, control rats received only vehicle. All rats underwent three CMR scans; before treatment, 2 weeks into treatment, and end of the study. A separate group of Su/Hx and control rats, treated as above, underwent terminal hemodynamic measurements. Using terminal and CMR measurements, Macitentan was found to lower RV systolic pressure pulmonary artery remodeling and increase RV ejection fraction but not change RV hypertrophy (RVH). Repeat CMRs determined that Su/Hx rats treated with Macitentan had significantly reversed RVH via reducing RV mass as well as reducing elevated left ventricular eccentricity index; reductions in RV mass were also observed in Su/Hx vehicle rats exposed to normoxic conditions. We have demonstrated that repeat CMRs can be used to assess the volume and structural changes in the ventricles of the Su/Hx rat model. Using repeat CMRs has allowed us to build a more complete picture of the response of the RV and the left ventricle to treatment. It is unknown if these effects are a consequence of direct action on the RV or secondary to improvements in the lung vasculature

Pharmacological treatment of vascular risk factors for reducing mortality and cardiovascular events in patients with abdominal aortic aneurysm

Background: Pharmacological prophylaxis has been proven to reduce the risk of cardiovascular events in individuals with atherosclerotic occlusive arterial disease. However, the role of prophylaxis in individuals with abdominal aortic aneurysm (AAA) remains unclear. Several studies have shown that despite successful repair, those people with AAA have a poorer rate of survival than healthy controls. People with AAA have an increased prevalence of coronary heart disease and risk of cardiovascular events. Despite this association, little is known about the effectiveness of pharmacological prophylaxis in reducing cardiovascular risk in people with AAA. This is an update of a Cochrane review first published in 2014. Objectives: To determine the long-term effectiveness of antiplatelet, antihypertensive or lipid-lowering medication in reducing mortality and cardiovascular events in people with abdominal aortic aneurysm (AAA). Search methods: For this update the Cochrane Vascular Information Specialist (CIS) searched the Cochrane Vascular Specialised Register (14 April 2016). In addition, the CIS searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 3) and trials registries (14 April 2016) and We also searched the reference lists of relevant articles. Selection criteria: Randomised controlled trials in which people with AAA were randomly allocated to one prophylactic treatment versus another, a different regimen of the same treatment, a placebo, or no treatment were eligible for inclusion in this review. Primary outcomes included all-cause mortality and cardiovascular mortality. Data collection and analysis: Two review authors independently selected studies for inclusion, and completed quality assessment and data extraction. We resolved any disagreements by discussion. Only one study met the inclusion criteria of the review, therefore we were unable to perform meta-analysis. Main results: No new studies met the inclusion criteria for this update. We included one randomised controlled trial in the review. A subgroup of 227 participants with AAA received either metoprolol (N = 111) or placebo (N = 116). There was no clear evidence that metoprolol reduced all-cause mortality (odds ratio (OR) 0.17, 95% confidence interval (CI) 0.02 to 1.41), cardiovascular death (OR 0.20, 95% CI 0.02 to 1.76), AAA-related death (OR 1.05, 95% CI 0.06 to 16.92) or increased nonfatal cardiovascular events (OR 1.44, 95% CI 0.58 to 3.57) 30 days postoperatively. Furthermore, at six months postoperatively, estimated effects were compatible with benefit and harm for all-cause mortality (OR 0.71, 95% CI 0.26 to 1.95), cardiovascular death (OR 0.73, 95% CI 0.23 to 2.39) and nonfatal cardiovascular events (OR 1.41, 95% CI 0.59 to 3.35). Adverse drug effects were reported for the whole study population and were not available for the subgroup of participants with AAA. We considered the study to be at a generally low risk of bias. We downgraded the quality of the evidence for all outcomes to low. We downgraded the quality of evidence for imprecision as only one study with a small number of participants was available, the number of events was small and the result was consistent with benefit and harm. Authors' conclusions: Due to the limited number of included trials, there is insufficient evidence to draw any conclusions about the effectiveness of cardiovascular prophylaxis in reducing mortality and cardiovascular events in people with AAA. Further good-quality randomised controlled trials that examine many types of prophylaxis with long-term follow-up are required before firm conclusions can be made

Seasonal Variability in Near-bed Environmental Conditions in the Vazella pourtalesii Glass Sponge Grounds of the Scotian Shelf

The Scotian Shelf harbors unique aggregations of the glass sponge Vazella pourtalesii that provides an important habitat for benthic and pelagic fauna. Recent studies have shown that these sponge grounds have persisted in the face of strong inter-annual and multi-decadal variability in temperature and salinity. However, little is known of these environmental characteristics on hourly-seasonal time scales. This study presents the first hydrodynamic observations and associated (food) particle supply mechanisms for the Vazella sponge grounds, highlighting the influence of natural variability in environmental conditions on sponge growth and resilience. Near-bottom environmental conditions were characterized by high temporal resolution data collected with a benthic lander, deployed during a period of 10 months in the Sambro Bank Sponge Conservation Area. The lander was equipped with temperature and oxygen sensors, a current meter, a sediment trap and a video camera. In addition, water column profiles of temperature and salinity were collected in an array across the sponge grounds from high to lower sponge presence probability. Over the course of the lander deployment, temperature fluctuated between 8.8–12°C with an average of 10.6 ± 0.4°C. Dissolved oxygen concentration was on average 6.3 mg l–1, and near-bottom current speed was on average 0.12 m s–1, with peaks up to 0.47 m s–1. Semi-diurnal tidal currents promoted constant resuspension of particulate matter in the benthic boundary layer. Surface storm events episodically caused extremely turbid conditions on the seafloor that persisted for several days, with particles being resuspended to more than 13 m above the seabed. The carbon flux in the near-bottom sediment trap peaked during storm events and also after a spring bloom in April, when fresh phytodetritus was observed in the bottom boundary layer. While resuspension events can represent a major stressor for sponges, limiting their filtration capability and remobilizing them, episodes of strong currents and lateral particle transport likely play an important role in food supply and the replenishment of nutrients and oxygen. Our results contextualize human-induced threats such as bottom fishing and climate change by providing more knowledge of the natural environmental conditions under which sponge grounds persist.publishedVersio

A Cryptic Polyene Biosynthetic Gene Cluster in Streptomyces calvus Is Expressed upon Complementation with a Functional bldA Gene

SummaryStreptomyces calvus is best known as the producer of the fluorinated natural product nucleocidin. This strain of Streptomycetes is also unusual for displaying a “bald” phenotype that is deficient in the formation of aerial mycelium and spores. Genome sequencing of this organism revealed a point mutation in the bldA gene that is predicted to encode a misfolded Leu-tRNAUUA molecule. Complementation of S. calvus with a correct copy of bldA restored sporulation and additionally promoted production of a polyeneoic acid amide, 4-Z-annimycin, and a minor amount of the isomer, 4-E-annimycin. Bioassays reveal that these compounds inhibit morphological differentiation in other Actinobacteria. The annimycin gene cluster encoding a type 1 polyketide synthase was identified and verified through disruption studies. This study underscores the importance of the bldA gene in regulating the expression of cryptic biosynthetic genes

Effect of testing for cancer on cancer- or venous thromboembolism (VTE)-related mortality and morbidity in people with unprovoked VTE

Background: Venous thromboembolism (VTE) is a collective term for two conditions: deep vein thrombosis (DVT) and pulmonary embolism (PE). A proportion of people with VTE have no underlying or immediately predisposing risk factors and the VTE is referred to as unprovoked. Unprovoked VTE can often be the first clinical manifestation of an underlying malignancy. This has raised the question of whether people with an unprovoked VTE should be investigated for an underlying cancer. Treatment for VTE is different in cancer and non-cancer patients and a correct diagnosis would ensure that people received the optimal treatment for VTE to prevent recurrence and further morbidity. Furthermore, an appropriate cancer diagnosis at an earlier stage could avoid the risk of cancer progression and lead to improvements in cancer-related mortality and morbidity. This is an update of a review first published in 2015. Objectives: To determine whether testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT of the lower limb or PE) is effective in reducing cancer or VTE-related mortality and morbidity and to determine which tests for cancer are best at identifying treatable cancers early. Search methods: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 11 July 2018. We also undertook reference checking to identify additional studies. Selection criteria: Randomised and quasi-randomised trials in which people with an unprovoked VTE were allocated to receive specific tests for identifying cancer or clinically indicated tests only were eligible for inclusion. Primary outcomes included all-cause mortality, cancer-related mortality and VTE-related mortality. Data collection and analysis: Two review authors independently selected studies, assessed risk of bias and extracted data. We resolved any disagreements by discussion. Main results: No new studies were identified for this 2018 update. In total, four studies with 1644 participants are included. Two studies assessed the effect of extensive tests including computed tomography (CT) scanning versus tests at the physician's discretion, while the other two studies assessed the effect of standard testing plus positron emission tomography (PET)/CT scanning versus standard testing alone. For extensive tests including CT versus tests at the physician's discretion, the quality of the evidence, as assessed according to GRADE, was low due to risk of bias (early termination of the studies). When comparing standard testing plus PET/CT scanning versus standard testing alone, the quality of evidence was moderate due to a risk of detection bias. The quality of the evidence was downgraded further as detection bias was present in one study with a low number of events. When comparing extensive tests including CT versus tests at the physician's discretion, pooled analysis on two studies showed that testing for cancer was consistent with either benefit or no benefit on cancer-related mortality (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.15 to 1.67; 396 participants; 2 studies; P = 0.26; low-quality evidence). One study (201 participants) showed that, overall, malignancies were less advanced at diagnosis in extensively tested participants than in participants in the control group. In total, 9/13 participants diagnosed with cancer in the extensively tested group had a T1 or T2 stage malignancy compared to 2/10 participants diagnosed with cancer in the control group (OR 5.00, 95% CI 1.05 to 23.76; P = 0.04; low-quality evidence). There was no clear difference in detection of advanced stages between extensive tests versus tests at the physician's discretion: one participant in the extensively tested group had stage T3 compared with four participants in the control group (OR 0.25, 95% CI 0.03 to 2.28; P = 0.22; low-quality evidence). In addition, extensively tested participants were diagnosed earlier than control group (mean: 1 month with extensive tests versus 11.6 months with tests at physician's discretion to cancer diagnosis from the time of diagnosis of VTE). Extensive testing did not increase the frequency of an underlying cancer diagnosis (OR 1.32, 95% CI 0.59 to 2.93; 396 participants; 2 studies; P = 0.50; low-quality evidence). Neither study measured all-cause mortality, VTE-related morbidity and mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life. When comparing standard testing plus PET/CT screening versus standard testing alone, standard testing plus PET/CT screening was consistent with either benefit or no benefit on all-cause mortality (OR 1.22, 95% CI 0.49 to 3.04; 1248 participants; 2 studies; P = 0.66; moderate-quality evidence), cancer-related mortality (OR 0.55, 95% CI 0.20 to 1.52; 1248 participants; 2 studies; P = 0.25; moderate-quality evidence) or VTE-related morbidity (OR 1.02, 95% CI 0.48 to 2.17; 854 participants; 1 study; P = 0.96; moderate-quality evidence). Regarding stage of cancer, there was no clear difference for detection of early (OR 1.78, 95% 0.51 to 6.17; 394 participants; 1 study; P = 0.37; low-quality evidence) or advanced (OR 1.00, 95% CI 0.14 to 7.17; 394 participants; 1 study; P = 1.00; low-quality evidence) stages of cancer. There was also no clear difference in the frequency of an underlying cancer diagnosis (OR 1.71, 95% CI 0.91 to 3.20; 1248 participants; 2 studies; P = 0.09; moderate-quality evidence). Time to cancer diagnosis was 4.2 months in the standard testing group and 4.0 months in the standard testing plus PET/CT group (P = 0.88). Neither study measured VTE-related mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life. Authors' conclusions: Specific testing for cancer in people with unprovoked VTE may lead to earlier diagnosis of cancer at an earlier stage of the disease. However, there is currently insufficient evidence to draw definitive conclusions concerning the effectiveness of testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT or PE) in reducing cancer- or VTE-related morbidity and mortality. The results could be consistent with either benefit or no benefit. Further good-quality large-scale randomised controlled trials are required before firm conclusions can be made

Association of mitochondrial variants and haplogroups identified by whole exome sequencing with Alzheimer's disease

Introduction: Findings regarding the association between mitochondrial DNA (mtDNA) variants and Alzheimer's disease (AD) are inconsistent. Methods: We developed a pipeline for accurate assembly and variant calling in mitochondrial genomes embedded within whole exome sequences (WES) from 10,831 participants from the Alzheimer's Disease Sequencing Project (ADSP). Association of AD risk was evaluated with each mtDNA variant and variants located in 1158 nuclear genes related to mitochondrial function using the SCORE test. Gene-based tests were performed using SKAT-O. Results: Analysis of 4220 mtDNA variants revealed study-wide significant association of AD with a rare MT-ND4L variant (rs28709356 C&gt;T; minor allele frequency = 0.002; P = 7.3 × 10 −5) as well as with MT-ND4L in a gene-based test (P = 6.71 × 10 −5). Significant association was also observed with a MT-related nuclear gene, TAMM41, in a gene-based test (P = 2.7 × 10 −5). The expression of TAMM41 was lower in AD cases than controls (P =.00046) or mild cognitive impairment cases (P =.03). Discussion: Significant findings in MT-ND4L and TAMM41 provide evidence for a role of mitochondria in AD.</p

Analysis of brain region-specific co-expression networks reveals clustering of established and novel genes associated with Alzheimer disease

BACKGROUND: Identifying and understanding the functional role of genetic risk factors for Alzheimer disease (AD) has been complicated by the variability of genetic influences across brain regions and confounding with age-related neurodegeneration. METHODS: A gene co-expression network was constructed using data obtained from the Allen Brain Atlas for multiple brain regions (cerebral cortex, cerebellum, and brain stem) in six individuals. Gene network analyses were seeded with 52 reproducible (i.e., established) AD (RAD) genes. Genome-wide association study summary data were integrated with the gene co-expression results and phenotypic information (i.e., memory and aging-related outcomes) from gene knockout studies in Drosophila to generate rankings for other genes that may have a role in AD. RESULTS: We found that co-expression of the RAD genes is strongest in the cortical regions where neurodegeneration due to AD is most severe. There was significant evidence for two novel AD-related genes including EPS8 (FDR p = 8.77 × 10−3) and HSPA2 (FDR p = 0.245). CONCLUSIONS: Our findings indicate that AD-related risk factors are potentially associated with brain region-specific effects on gene expression that can be detected using a gene network approach.Published versio

Linkage analyses in Caribbean Hispanic families identify novel loci associated with familial late-onset Alzheimer's disease

INTRODUCTION: We performed linkage analyses in Caribbean Hispanic families with multiple late-onset Alzheimer's disease (LOAD) cases to identify regions that may contain disease causative variants. METHODS: We selected 67 LOAD families to perform genome-wide linkage scan. Analysis of the linked regions was repeated using the entire sample of 282 families. Validated chromosomal regions were analyzed using joint linkage and association. RESULTS: We identified 26 regions linked to LOAD (HLOD ≥3.6). We validated 13 of the regions (HLOD ≥2.5) using the entire family sample. The strongest signal was at 11q12.3 (rs2232932: HLODmax = 4.7, Pjoint = 6.6 × 10(-6)), a locus located ∼2 Mb upstream of the membrane-spanning 4A gene cluster. We additionally identified a locus at 7p14.3 (rs10255835: HLODmax = 4.9, Pjoint = 1.2 × 10(-5)), a region harboring genes associated with the nervous system (GARS, GHRHR, and NEUROD6). DISCUSSION: Future sequencing efforts should focus on these regions because they may harbor familial LOAD causative mutations