Longitudinal Changes in Kidney Solute Clearance in a Prospective Cohort of Patients Initiating Chronic Hemodialysis.

Introduction: Longitudinal changes in residual kidney function have not been well-examined in patients starting chronic hemodialysis (HD). Methods: We analyzed urine volume and kidney solute clearances from timed urine collections and corresponding plasma samples from 42 patients randomized to incremental HD (n = 21) and conventional HD (n = 21) in the TwoPlus pilot study. Samples were collected before HD initiation (baseline); and at 6, 12, 24, and 48 weeks. We assessed temporal trends in urine volume, kidney urea and creatinine clearance, and correlations between urine volume and kidney solute clearance. Results: Residual kidney function parameters in all patients declined over time; the pattern of decline differed between urine volume and kidney solute clearances. Urine volume declined at a steady rate with median (quartile 1, quartile 3) percentage change relative to baseline of -10% (-36 to 29) at week 6 and -47% (-76 to 5) by week 48. Kidney urea and creatinine clearances exhibited a larger decline than urine volume at week 6, -32% (-61 to 8) and -47% (-57 to -20), respectively. The rate of decline subsequently slowed, reaching about 61% decline for both solutes by week 48. Conventional HD demonstrated larger declines in urine volume and kidney urea clearance than incremental HD at week 6. Urine volume showed moderate correlation with urea (R = 0.47) and weaker correlation with creatinine (R = 0.34). Conclusion: Despite gradual decrement in urine volume and kidney solute clearances, residual kidney function persists nearly 1 year after HD initiation. This knowledge could motivate increased practice of individualizing HD prescriptions by incorporating residual kidney function.

The DIAPH3 linker specifies a ß-actin network that maintains RhoA and Myosin-II at the cytokinetic furrow.

Cytokinesis is the final step of the cell division cycle that leads to the formation of two new cells. Successful cytokinesis requires significant remodelling of the plasma membrane by spatially distinct ß- and γ-actin networks. These networks are generated by the formin family of actin nucleators, DIAPH3 and DIAPH1 respectively. Here we show that ß- and γ-actin perform specialized and non-redundant roles in cytokinesis and cannot substitute for one another. Expression of hybrid DIAPH1 and DIAPH3 proteins with altered actin isoform specificity relocalized cytokinetic actin isoform networks within the cell, causing cytokinetic failure. Consistent with this we show that ß-actin networks, but not γ-actin networks, are required for the maintenance of non-muscle myosin II and RhoA at the cytokinetic furrow. These data suggest that independent and spatially distinct actin isoform networks form scaffolds of unique interactors that facilitate localized biochemical activities to ensure successful cell division.

Distinct host preconditioning regimens differentially impact the antitumor potency of adoptively transferred Th17 cells.

BACKGROUND: How distinct methods of host preconditioning impact the efficacy of adoptively transferred antitumor T helper cells is unknown. METHODS: CD4+ T cells with a transgenic T-cell receptor that recognize tyrosinase-related peptide (TRP)-1 melanoma antigen were polarized to the T helper 17 (Th17) phenotype and then transferred into melanoma-bearing mice preconditioned with either total body irradiation or chemotherapy. RESULTS: We found that preconditioning mice with a non-myeloablative dose of total body irradiation (TBI of 5 Gy) was more effective than using an equivalently dosed non-myeloablative chemotherapy (cyclophosphamide (CTX) of 200 mg/kg) at augmenting therapeutic activity of antitumor TRP-1 Th17 cells. Antitumor Th17 cells engrafted better following preconditioning with TBI and regressed large established melanoma in all animals. Conversely, only half of mice survived long-term when preconditioned with CTX and infused with anti-melanoma Th17 cells. Interleukin (IL)-17 and interferon-γ, produced by the infused Th17 cells, were detected in animals given either TBI or CTX preconditioning. Interestingly, inflammatory cytokines (granulocyte colony stimulating factor, IL-6, monocyte chemoattractant protein-1, IL-5, and keratinocyte chemoattractant) were significantly elevated in the serum of mice preconditioned with TBI versus CTX after Th17 therapy. The addition of fludarabine (FLU, 200 mg/kg) to CTX (200 mg/kg) improved the antitumor response to the same degree mediated by TBI, whereas FLU alone with Th17 therapy was ineffective. CONCLUSIONS: Our results indicate, for the first time, that the antitumor response, persistence, and cytokine profiles resulting from Th17 therapy are impacted by the specific regimen of host preconditioning. This work is important for understanding mechanisms that promote long-lived responses by adoptive cellular therapy, particularly as CD4+ based T-cell therapies are now emerging in the clinic.

Single-beam velocimetry with dual frequency comb absorption spectroscopy.

Laser absorption Doppler velocimeters use a crossed-beam configuration to cancel errors due to laser frequency drift and absorption model uncertainty. This configuration complicates the spatial interpretation of the measurement since the two beams sample different volumes of gas. Here, we achieve single-beam velocimetry with a portable dual comb spectrometer (DCS) with high frequency accuracy and stability enabled by GPS-referencing, and a new high-temperature water vapor absorption database. We measure the inlet flow in a supersonic ramjet engine and demonstrate single-beam measurements that are on average within 19 m/s of concurrent crossed-beam measurements. We estimate that the DCS and the new database contribute 1.6 and 13 m/s to this difference respectively.

Pulse interaction induced systematic errors in dual comb spectroscopy.

Systematic errors are observed in dual comb spectroscopy when pulses from the two sources travel in a common fiber before interrogating the sample of interest. When sounding a molecular gas, these errors distort both the line shapes and retrieved concentrations. Simulations of dual comb interferograms based on a generalized nonlinear Schrodinger equation highlight two processes for these systematic errors. Self-phase modulation changes the spectral content of the field interrogating the molecular response but affects the recorded spectral baseline and absorption features differently, leading to line intensity errors. Cross-phase modulation modifies the relative inter-pulse delay, thus introducing interferogram sampling errors and creating a characteristic asymmetric distortion on spectral lines. Simulations capture the shape and amplitude of experimental errors which are around 0.1% on spectral transmittance residuals for 10 mW of total average power in 10 meters of common fiber, scaling up to above 0.6% for 20 mW and 60 m.

Analysis of practice patterns and changes for ACL surgery document the past and present, but high quality data should inform the future.

Trends in practice patterns for ACL surgery can give us a real world look at what surgeons are actually doing. When large institutional studies show changing practice patterns over time, we can use that data to help benchmark our own practices. Innovations are inspired by colleagues, published literature, and industry, and not all innovation is positive. A return to independent drilling of the femoral and tibial tunnels reverses a single-incision trend that was less anatomic. While hamstring tendon grafts (HT) are a popular graft choice, HT shows higher revision rates, and high volume surgeons prefer bone-patellar tendon-bone and quadriceps tendon (QT) and autografts in general. Additional data is required to determine the benefit of QT and of lateral extra-articular tenodesis augmentation of ACL reconstruction. While a first step is to identify current practice patterns, the most important step is to study high quality data, to inform surgeons so they can individualize and optimize surgery for their patients.

Disruption of Transmembrane Phosphatidylserine Asymmetry by HIV-1 Incorporated SERINC5 Is Not Responsible for Virus Restriction.

Host restriction factor SERINC5 (SER5) incorporates into the HIV-1 membrane and inhibits infectivity by a poorly understood mechanism. Recently, SER5 was found to exhibit scramblase-like activity leading to the externalization of phosphatidylserine (PS) on the viral surface, which has been proposed to be responsible for SER5's antiviral activity. This and other reports that document modulation of HIV-1 infectivity by viral lipid composition prompted us to investigate the role of PS in regulating SER5-mediated HIV-1 restriction. First, we show that the level of SER5 incorporation into virions correlates with an increase in PS levels in the outer leaflet of the viral membrane. We developed an assay to estimate the PS distribution across the viral membrane and found that SER5, but not SER2, which lacks antiviral activity, abrogates PS asymmetry by externalizing this lipid. Second, SER5 incorporation diminished the infectivity of pseudoviruses produced from cells lacking a flippase subunit CDC50a and, therefore, exhibited a higher baseline level of surface-accessible PS. Finally, exogenous manipulation of the viral PS levels utilizing methyl-alpha-cyclodextrin revealed a lack of correlation between external PS and virion infectivity. Taken together, our study implies that the increased PS exposure to SER5-containing virions itself is not directly linked to HIV-1 restriction.

Development of a novel, concentric micro-ECoG array enabling simultaneous detection of a single location by multiple electrode sizes.

Objective.Detection of the epileptogenic zone is critical, especially for patients with drug-resistant epilepsy. Accurately mapping cortical regions exhibiting high activity during spontaneous seizure events while detecting neural activity up to 500 Hz can assist clinicians' surgical decisions and improve patient outcomes.Approach.We designed, fabricated, and tested a novel hybrid, multi-scale micro-electrocorticography (micro-ECoG) array with a unique embedded configuration. This array was compared to a commercially available microelectrode array (Neuronexus) for recording neural activity in rodent sensory cortex elicited by somatosensory evoked potentials and pilocarpine-induced seizures.Main results.Evoked potentials and spatial maps recorded by the multi-scale array ('micros', 'mesos', and 'macros' refering to the relative electrode sizes, 40 micron, 1 mm, and 4 mm respectively) were comparable to the Neuronexus array. The SSEPs recorded with the micros had higher peak amplitudes and greater signal power than those recorded by the larger mesos and macro. Seizure onset events and high-frequency oscillations (∼450 Hz) were detected on the multi-scale, similar to the commercially available array. The micros had greater SNR than the mesos and macro over the 5-1000 Hz frequency range during seizure monitoring. During cortical stimulation experimentation, the mesos successfully elicited motor effects.Significance.Previous studies have compared macro- and microelectrodes for localizing seizure activity in adjacent regions. The multi-scale design validated here is the first to simultaneously measure macro- and microelectrode signals from the same overlapping cortical area. This enables direct comparison of microelectrode recordings to the macroelectrode recordings used in standard neurosurgical practice. Previous studies have also shown that cortical regions generating high-frequency oscillations are at an increased risk for becoming epileptogenic zones. More accurate mapping of these micro seizures may improve surgical outcomes for epilepsy patients.

Mitochondria regulate proliferation in adult cardiac myocytes.

Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation but loses mitotic capacity. We tested whether forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype would restore proliferative capacity. We deleted Uqcrfs1 (mitochondrial Rieske iron-sulfur protein, RISP) in hearts of adult mice. As RISP protein decreased, heart mitochondrial function declined, and glucose utilization increased. Simultaneously, the hearts underwent hyperplastic remodeling during which cardiomyocyte number doubled without cellular hypertrophy. Cellular energy supply was preserved, AMPK activation was absent, and mTOR activation was evident. In ischemic hearts with RISP deletion, new cardiomyocytes migrated into the infarcted region, suggesting the potential for therapeutic cardiac regeneration. RNA sequencing revealed upregulation of genes associated with cardiac development and proliferation. Metabolomic analysis revealed a decrease in α-ketoglutarate (required for TET-mediated demethylation) and an increase in S-adenosylmethionine (required for methyltransferase activity). Analysis revealed an increase in methylated CpGs near gene transcriptional start sites. Genes that were both differentially expressed and differentially methylated were linked to upregulated cardiac developmental pathways. We conclude that decreased mitochondrial function and increased glucose utilization can restore mitotic capacity in adult cardiomyocytes, resulting in the generation of new heart cells, potentially through the modification of substrates that regulate epigenetic modification of genes required for proliferation.

Venus water loss is dominated by HCO+ dissociative recombination.

Despite its Earth-like size and source material1,2, Venus is extremely dry3,4, indicating near-total water loss to space by means of hydrogen outflow from an ancient, steam-dominated atmosphere5,6. Such hydrodynamic escape likely removed most of an initial Earth-like 3-km global equivalent layer (GEL) of water but cannot deplete the atmosphere to the observed 3-cm GEL because it shuts down below about 10-100 m GEL5,7. To complete Venus water loss, and to produce the observed bulk atmospheric enrichment in deuterium of about 120 times Earth8,9, nonthermal H escape mechanisms still operating today are required10,11. Early studies identified these as resonant charge exchange12-14, hot oxygen impact15,16 and ion outflow17,18, establishing a consensus view of H escape10,19 that has since received only minimal updates20. Here we show that this consensus omits the most important present-day H loss process, HCO+ dissociative recombination. This process nearly doubles the Venus H escape rate and, consequently, doubles the amount of present-day volcanic water outgassing and/or impactor infall required to maintain a steady-state atmospheric water abundance. These higher loss rates resolve long-standing difficulties in simultaneously explaining the measured abundance and isotope ratio of Venusian water21,22 and would enable faster desiccation in the wake of speculative late ocean scenarios23. Design limitations prevented past Venus missions from measuring both HCO+ and the escaping hydrogen produced by its recombination; future spacecraft measurements are imperative.

VPAC2 Receptor Signaling Promotes Growth and Immunosuppression in Pancreatic Cancer.

Pancreatic cancer (PDAC) harbors a complex tumor microenvironment (TME), and crosstalk between cells in the TME can contribute to drug resistance and relapse. Vasoactive intestinal peptide (VIP) is overexpressed in PDAC, and VIP receptors expressed on T cells are a targetable pathway that sensitizes PDAC to immunotherapy. In this study, we showed that pancreatic cancer cells engage in autocrine VIP signaling through VIP receptor 2 (VPAC2). High co-expression of VIP with VPAC2 correlated with reduced relapse-free survival in PDAC patients. VPAC2 activation in PDAC cells upregulated piwi-like RNA-mediated gene silencing 2 (Piwil2), which stimulated cancer cell clonogenic growth. In addition, VPAC2 signaling increased expression of TGF-ß1 to inhibit T cell function. Loss of VPAC2 on PDAC cells led to reduced tumor growth and increased sensitivity to anti-PD1 immunotherapy in mouse models of PDAC. Overall, these findings expand our understanding of the role of VIP/VPAC2 signaling in PDAC and provide the rationale for developing potent VPAC2-specific antagonists for treating PDAC patients.

Identifying and Responding to Lead in Drinking Water in a University Setting.

Lead is an established neurotoxicant, and it has known associations with adverse neurodevelopmental and reproductive outcomes. Exposure to lead at any level is unsafe, and the United States (US) has enacted various federal and state legislations to regulate lead levels in drinking water in K-12 schools and childcare facilities; however, no regulations exist for higher education settings. Upon the discovery of lead in drinking water fixtures in the University of North Carolina at Chapel Hill (UNC-CH) campus, a cross-campus water testing network and sampling plan was developed and deployed. The campaign was based on the US Environmental Protection Agency's (EPA) 3Ts (Training, Testing, and Taking Action) guidance. The seven-month campaign involved 5954 tests on 3825 drinking water fixtures across 265 buildings. A total of 502 (8.43%) tests showed lead above the limit of detection (1 part per billion, ppb), which represented 422 (11.03%) fixtures. Fewer than 1.5% of the tests were above the EPA action level for public water systems (15 ppb). In conclusion, systematic testing of all the fixtures across campus was required to identify localized contamination, and each entity in the cross-campus network undertook necessary roles to generate a successful testing campaign. UNC-CH established preventative measures to test drinking water fixtures every three years, which provide a framework for other higher education institutions in responding to lead contamination.

Stray Magnetic Field Variations and Micromagnetic Simulations: Models for Ni0.8Fe0.2 Disks Used for Microparticle Trapping.

Patterned micro-scale thin-film magnetic structures, in conjunction with weak (~few tens of Oe) applied magnetic fields, can create energy landscapes capable of trapping and transporting fluid-borne magnetic microparticles. These energy landscapes arise from magnetic field magnitude variations that arise in the vicinity of the magnetic structures. In this study, we examine means of calculating magnetic fields in the local vicinity of permalloy (Ni0.8Fe0.2) microdisks in weak (~tens of Oe) external magnetic fields. To do this, we employ micromagnetic simulations and the resulting calculations of fields. Because field calculation from micromagnetic simulations is computationally time-intensive, we discuss a method for fitting simulated results to improve calculation speed. Resulting stray fields vary dramatically based on variations in micromagnetic simulations-vortex vs. non-vortex micromagnetic results-which can each appear despite identical simulation final conditions, resulting in field strengths that differ by about a factor of two.

Effects of flavoring additives on feed intake, growth performance, temperament, and markers of immune function for newly received feedlot cattle.

Ninety Angus × Hereford steers (259.9 ±â€…36.18 kg body weight [BW]) were used in a 56-d experiment to assess the effects of flavoring additives on feed intake, and stress and immune response of newly received feedlot cattle. Steers were homogenously distributed by BW into six pens equipped with an individual feed intake monitoring system, and pen was randomly assigned to one of three treatments (15 heads per pen; 30 heads per treatment): a standard feedlot receiving diet (CT), or the same diet with a flavoring additive comprised of either sweeteners (Luctarom Feedlot, SW) or a mix of basic tastes (Luctarom Feedlot Mix, MX) at 1 kg/mT. Pens were equipped with a feed intake monitoring system, while BW, chute behavior, flight speed, blood and saliva samples were collected bi-weekly, and hair samples were collected at 4-wk intervals during the study. Data were analyzed using a mixed-effects model for a pen study using individual animal records with repeated measures. There was a treatment × week interaction (P < 0.01) where meal duration was greater in SW steers than MX and CT on week 3, and then CT on weeks 7 and 8. A trend for treatment × week interaction (P = 0.06) showed that the number of visits per day tended to be greater in SW than MX steers on weeks 4 and 5, and it tended to be greater in SW than MX and CT on week 5. The concentration of IL-6 was greater (P < 0.01) on days 1 and 28 than on day 14. The IgM concentration was greater (P < 0.01) on day 1 compared to days 14, 28, and 56. The concentration of haptoglobin was greater (P < 0.01) on 14 than days 28, 42, and 56, and it was greater (P < 0.01) on day 1 than days 42 and 56. The concentration of serum amyloid A was greater (P < 0.01) on day 1 compared to the rest of sampling days. Fibrinogen concentration was greater (P < 0.01) on day 1 compared to days 14 and 42. The neutrophil-to-lymphocyte ratio was greater (P < 0.01) on days 42 and 56 compared to days 1 and 28, and greater (P < 0.01) on day 14 compared to day 28. Hair and saliva cortisol concentrations were lower (P < 0.01) on day 56 compared to days 1 and 28, respectively. The use of flavoring additives, particularly when based on sweeteners (SW), caused some changes in the feeding pattern of newly received steers. These changes, however, were not consistent over the 56-d feeding period and were not accompanied by a change in growth performance, temperament, biomarkers of stress, inflammation, or immune function.

Feedlot-receiving calves are typically exposed to a series of stressful events, such as weaning, transportation, commingling, a change of environment, and illness, that have a negative impact on feed intake. The objective of this study was to assess the effects of feed flavors on feed intake, indicators of stress, and markers of the immune response for newly received feedlot cattle. Under the conditions of this study, the addition of flavoring agents showed some effects on the feeding pattern of newly arrived feedlot cattle, compatible with a positive hedonic response to the treatments. These effects, however, were limited to specific periods of time during the experiment and were not present when considering their performance over the whole 56-d feeding period. Furthermore, the addition of flavoring agents did not have a consistent effect on the concentration of inflammatory mediators, biomarkers of stress, or immune function. Future research should explore whether these or other flavoring agents, at different doses or used at different times, could cause biologically relevant effects to improve the resilience of calves during the feedlot receiving period.

Perivascular adipose tissue remodeling impairs vasoreactivity in thermoneutral-housed rats.

Objective: Vascular pathology, characterized by impaired vasoreactivity and mitochondrial respiration, differs between the sexes. Housing rats under thermoneutral (TN) conditions causes vascular dysfunction and perturbed metabolism. We hypothesized that perivascular adipose tissue (PVAT), a vasoregulatory adipose depot with brown adipose tissue (BAT) phenotype, remodels to a white adipose (WAT) phenotype in rats housed at TN, driving diminished vasoreactivity in a sex-dependent manner. Methods: Male and female Wistar rats were housed at either room temperature (RT) or TN. Endpoints included changes in PVAT morphology, vasoreactivity in vessels with intact PVAT or transferred to PVAT of the oppositely-housed animal, vessel stiffness, vessel mitochondrial respiration and cellular signaling. Results: Remodeling of PVAT was observed in rats housed at TN; animals in this environment showed PVAT whitening and displayed diminished aortae vasodilation (p<0.05), different between the sexes. Juxtaposing PVAT from RT rats onto aortae from TN rats in females corrected vasodilation (p<0.05); this did not occur in males. In aortae of all animals housed at TN, mitochondrial respiration was significantly diminished in lipid substrate experiments (p<0.05), and there was significantly less expression of peNOS (p<0.001). Conclusions: These data are consistent with TN-induced remodeling of PVAT, notably associated with sex-specific blunting of vasoreactivity, diminished mitochondrial respiration, and altered cellular signaling.

Production and use of dry-rolled hybrid rye grain as a replacement for barley grain on growth performance and carcass quality of feedlot steers.

The objectives were to compare cereal grain and straw yield between barley and hybrid rye (HR) and to evaluate whether the inclusion of dry-rolled HR grain as a replacement for barley grain affected feed intake and growth for growing cattle, and feed intake, growth, and carcass characteristics for finishing cattle. Crop yield was measured by directly weighing harvested grain and straw bales (n = 3 plots/grain type). Three-hundred sixty steers with an initial body weight (BW) of 348 ±â€…40 kg were stratified by BW and randomly assigned to 1 of the 24 pens during the growing phase (n = 8; 65 d). The control diet (BCON) included 60.22% barley grain with HR included by replacing 50 (BMID) or 100% (BHIGH) of the barley grain on a dry matter (DM) basis. Steers were re-randomized for the finishing phase (n = 6; 118 d) and treatments included a control diet containing 88.60% barley grain (FCON) with HR replacing 33 (FLOW), 67 (FMED), or 100% (FHIGH) of the barley grain (DM basis). The grain yield was greater (P = 0.04) and straw yield tended (P = 0.06) to be less for HR than barley. There were no effects of HR inclusion on DM intake (DMI) or G:F during the growing phase, but average daily gain (ADG) responded quadratically (P = 0.02) with cattle fed 50% HR having the greatest gain. During finishing, DMI decreased linearly as HR grain inclusion increased (P < 0.01). ADG initially increased from FCON to FLOW followed by a decrease with increasing HR inclusion (quadratic, P < 0.01), but G:F was not affected. Hot carcass weight was greatest for FCON with the magnitude of difference between FCON and the HR treatments increasing with increasing inclusion of HR (quadratic, P = 0.02). There was a linear increase in dressing percentage (P = 0.02) and a linear reduction in back fat thickness (P = 0.04) with increasing inclusion of HR. Increasing the inclusion of HR during finishing cubically (P < 0.01) affected the proportion of minor and severe liver abscesses with an average of 34.60% severely abscessed livers when HR was included compared to 11.11% for BCON. HR may have greater grain yield than barley, and partial replacement of barley grain with HR may improve ADG without affecting DMI or G:F during the growing phase. However, replacing barley grain in finishing diets with HR decreases DMI, and increases the risk of minor and severe liver abscesses, but does not affect feed conversion, suggesting HR should not replace more than 33% of the barley grain to maintain ADG.

Invasive vs. conservative management of older patients with non-ST-elevation acute coronary syndrome: individual patient data meta-analysis.

BACKGROUND AND AIMS: Older patients with non-ST-elevation acute coronary syndrome (NSTEACS) are less likely to receive guideline-recommended care including coronary angiography and revascularization. Evidence-based recommendations regarding interventional management strategies in this patient cohort are scarce. This meta-analysis aimed to assess the impact of routine invasive vs. conservative management of NSTEACS by using individual patient data (IPD) from all available randomized controlled trials (RCTs) including older patients. METHODS: MEDLINE, Web of Science and Scopus were searched between 1 January 2010 and 11 September 2023. RCTs investigating routine invasive and conservative strategies in persons >70 years old with NSTEACS were included. Observational studies or trials involving populations outside the target range were excluded. The primary endpoint was a composite of all-cause mortality and myocardial infarction (MI) at 1 year. One-stage IPD meta-analyses were adopted by use of random-effects and fixed-effect Cox models. This meta-analysis is registered with PROSPERO (CRD42023379819). RESULTS: Six eligible studies were identified including 1479 participants. The primary endpoint occurred in 181 of 736 (24.5%) participants in the invasive management group compared with 215 of 743 (28.9%) participants in the conservative management group with a hazard ratio (HR) from random-effects model of 0.87 (95% CI 0.63-1.22; P = .43). The hazard for MI at 1 year was significantly lower in the invasive group compared with the conservative group (HR from random-effects model 0.62, 95% CI 0.44-0.87; P = .006). Similar results were seen for urgent revascularization (HR from random-effects model 0.41, 95% CI 0.18-0.95; P = .037). There was no significant difference in mortality. CONCLUSIONS: No evidence was found that routine invasive treatment for NSTEACS in older patients reduces the risk of a composite of all-cause mortality and MI within 1 year compared with conservative management. However, there is convincing evidence that invasive treatment significantly lowers the risk of repeat MI or urgent revascularisation. Further evidence is needed from ongoing larger clinical trials.