Non-mutational neoantigens in disease.

The ability of mammals to mount adaptive immune responses culminating with the establishment of immunological memory is predicated on the ability of the mature T cell repertoire to recognize antigenic peptides presented by syngeneic MHC class I and II molecules. Although it is widely believed that mature T cells are highly skewed towards the recognition of antigenic peptides originating from genetically diverse (for example, foreign or mutated) protein-coding regions, preclinical and clinical data rather demonstrate that novel antigenic determinants efficiently recognized by mature T cells can emerge from a variety of non-mutational mechanisms. In this Review, we describe various mechanisms that underlie the formation of bona fide non-mutational neoantigens, such as epitope mimicry, upregulation of cryptic epitopes, usage of non-canonical initiation codons, alternative RNA splicing, and defective ribosomal RNA processing, as well as both enzymatic and non-enzymatic post-translational protein modifications. Moreover, we discuss the implications of the immune recognition of non-mutational neoantigens for human disease.

Zika Virus Persistence in the Central Nervous System and Lymph Nodes of Rhesus Monkeys.

Zika virus (ZIKV) is associated with severe neuropathology in neonates as well as Guillain-Barré syndrome and other neurologic disorders in adults. Prolonged viral shedding has been reported in semen, suggesting the presence of anatomic viral reservoirs. Here we show that ZIKV can persist in cerebrospinal fluid (CSF) and lymph nodes (LN) of infected rhesus monkeys for weeks after virus has been cleared from peripheral blood, urine, and mucosal secretions. ZIKV-specific neutralizing antibodies correlated with rapid clearance of virus in peripheral blood but remained undetectable in CSF for the duration of the study. Viral persistence in both CSF and LN correlated with upregulation of mechanistic target of rapamycin (mTOR), proinflammatory, and anti-apoptotic signaling pathways, as well as downregulation of extracellular matrix signaling pathways. These data raise the possibility that persistent or occult neurologic and lymphoid disease may occur following clearance of peripheral virus in ZIKV-infected individuals.

A temporal thymic selection switch and ligand binding kinetics constrain neonatal Foxp3+ Treg cell development.

The neonatal thymus generates Foxp3+ regulatory T (tTreg) cells that are critical in controlling immune homeostasis and preventing multiorgan autoimmunity. The role of antigen specificity on neonatal tTreg cell selection is unresolved. Here we identify 17 self-peptides recognized by neonatal tTreg cells, and reveal ligand specificity patterns that include self-antigens presented in an age- and inflammation-dependent manner. Fate-mapping studies of neonatal peptidyl arginine deiminase type IV (Padi4)-specific thymocytes reveal disparate fate choices. Neonatal thymocytes expressing T cell receptors that engage IAb-Padi4 with moderate dwell times within a conventional docking orientation are exported as tTreg cells. In contrast, Padi4-specific T cell receptors with short dwell times are expressed on CD4+ T cells, while long dwell times induce negative selection. Temporally, Padi4-specific thymocytes are subject to a developmental stage-specific change in negative selection, which precludes tTreg cell development. Thus, a temporal switch in negative selection and ligand binding kinetics constrains the neonatal tTreg selection window.

Pleiotropic consequences of metabolic stress for the major histocompatibility complex class II molecule antigen processing and presentation machinery.

Hyperglycemia and hyperlipidemia are often observed in individuals with type II diabetes (T2D) and related mouse models. One dysmetabolic biochemical consequence is the non-enzymatic reaction between sugars, lipids, and proteins, favoring protein glycation, glycoxidation, and lipoxidation. Here, we identified oxidative alterations in key components of the major histocompatibility complex (MHC) class II molecule antigen processing and presentation machinery in vivo under conditions of hyperglycemia-induced metabolic stress. These modifications were linked to epitope-specific changes in endosomal processing efficiency, MHC class II-peptide binding, and DM editing activity. Moreover, we observed some quantitative and qualitative changes in the MHC class II immunopeptidome of Ob/Ob mice on a high-fat diet compared with controls, including changes in the presentation of an apolipoprotein B100 peptide associated previously with T2D and metabolic syndrome-related clinical complications. These findings highlight a link between glycation reactions and altered MHC class II antigen presentation that may contribute to T2D complications.

Heterogeneous melting near the Thwaites Glacier grounding line.

Thwaites Glacier represents 15% of the ice discharge from the West Antarctic Ice Sheet and influences a wider catchment1-3. Because it is grounded below sea level4,5, Thwaites Glacier is thought to be susceptible to runaway retreat triggered at the grounding line (GL) at which the glacier reaches the ocean6,7. Recent ice-flow acceleration2,8 and retreat of the ice front8-10 and GL11,12 indicate that ice loss will continue. The relative impacts of mechanisms underlying recent retreat are however uncertain. Here we show sustained GL retreat from at least 2011 to 2020 and resolve mechanisms of ice-shelf melt at the submetre scale. Our conclusions are based on observations of the Thwaites Eastern Ice Shelf (TEIS) from an underwater vehicle, extending from the GL to 3 km oceanward and from the ice-ocean interface to the sea floor. These observations show a rough ice base above a sea floor sloping upward towards the GL and an ocean cavity in which the warmest water exceeds 2 °C above freezing. Data closest to the ice base show that enhanced melting occurs along sloped surfaces that initiate near the GL and evolve into steep-sided terraces. This pronounced melting along steep ice faces, including in crevasses, produces stratification that suppresses melt along flat interfaces. These data imply that slope-dependent melting sculpts the ice base and acts as an important response to ocean warming.

Resurrection genomics provides molecular and phenotypic evidence of rapid adaptation to salinization in a keystone aquatic species.

Ecologists and evolutionary biologists are increasingly cognizant of rapid adaptation in wild populations. Rapid adaptation to anthropogenic environmental change is critical for maintaining biodiversity and ecosystems services into the future. Anthropogenic salinization of freshwater ecosystems is quickly emerging as a primary threat, which is well documented in the northern temperate ecoregion. Specifically, many northern temperate lakes have undergone extensive salinization because of urbanization and the associated increase in impervious surfaces causing runoff, and the extensive use of road deicing salts (e.g., NaCl). It remains unclear whether increasing salinization will lead to extirpation of species from these systems. Using a "resurrection genomics" approach, we investigated whether the keystone aquatic herbivore, Daphnia pulicaria, has evolved increased salinity tolerance in a severely salinized lake located in Minnesota, USA. Whole-genome resequencing of 54 Daphnia clones from the lake and hatched from resting eggs that represent a 25-y temporal contrast demonstrates that many regions of the genome containing genes related to osmoregulation are under selection in the study population. Tolerance assays of clones revealed that the most recent clones are more tolerant to salinity than older clones; this pattern is concomitant with the temporal pattern of stabilizing salinity in this lake. Together, our results demonstrate that keystone species such as Daphnia can rapidly adapt to increasing freshwater salinization. Further, our results indicate that rapid adaptation to salinity may allow lake Daphnia populations to persist in the face of anthropogenic salinization maintaining the food webs and ecosystem services they support despite global environmental change.

Confinement plus myosin-II suppression maximizes heritable loss of chromosomes, as revealed by live-cell ChReporters.

The mechanical environment of a cell can have many effects, but whether it impacts the DNA sequence of a cell has remained unexamined. To investigate this, we developed a live-cell method to measure changes in chromosome numbers. We edited constitutive genes with GFP or RFP tags on single alleles and discovered that cells that lose Chromosome reporters (ChReporters) become non-fluorescent. We applied our new tools to confined mitosis and to inhibition of the putative tumor suppressor myosin-II. We quantified compression of mitotic chromatin in vivo and demonstrated that similar compression in vitro resulted in cell death, but also rare and heritable ChReptorter loss. Myosin-II suppression rescued lethal multipolar divisions and maximized ChReporter loss during three-dimensional (3D) compression and two-dimensional (2D) lateral confinement, but not in standard 2D culture. ChReporter loss was associated with chromosome mis-segregation, rather than just the number of divisions, and loss in vitro and in mice was selected against in subsequent 2D cultures. Inhibition of the spindle assembly checkpoint (SAC) caused ChReporter loss in 2D culture, as expected, but not during 3D compression, suggesting a SAC perturbation. Thus, ChReporters enable diverse studies of viable genetic changes, and show that confinement and myosin-II affect DNA sequence and mechano-evolution.

Early Outpatient Treatment for Covid-19 with Convalescent Plasma.

BACKGROUND: Polyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset Covid-19 is uncertain. METHODS: In this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19-related hospitalization within 28 days after transfusion. RESULTS: Participants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P = 0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized. CONCLUSIONS: In participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalization. (Funded by the Department of Defense and others; CSSC-004 ClinicalTrials.gov number, NCT04373460.).

Immunopeptidome profiling of human coronavirus OC43-infected cells identifies CD4 T-cell epitopes specific to seasonal coronaviruses or cross-reactive with SARS-CoV-2.

Seasonal "common-cold" human coronaviruses are widely spread throughout the world and are mainly associated with mild upper respiratory tract infections. The emergence of highly pathogenic coronaviruses MERS-CoV, SARS-CoV, and most recently SARS-CoV-2 has prompted increased attention to coronavirus biology and immunopathology, but the T-cell response to seasonal coronaviruses remains largely uncharacterized. Here we report the repertoire of viral peptides that are naturally processed and presented upon infection of a model cell line with seasonal coronavirus OC43. We identified MHC-bound peptides derived from each of the viral structural proteins (spike, nucleoprotein, hemagglutinin-esterase, membrane, and envelope) as well as non-structural proteins nsp3, nsp5, nsp6, and nsp12. Eighty MHC-II bound peptides corresponding to 14 distinct OC43-derived epitopes were identified, including many at very high abundance within the overall MHC-II peptidome. Fewer and less abundant MHC-I bound OC43-derived peptides were observed, possibly due to MHC-I downregulation induced by OC43 infection. The MHC-II peptides elicited low-abundance recall T-cell responses in most donors tested. In vitro assays confirmed that the peptides were recognized by CD4+ T cells and identified the presenting HLA alleles. T-cell responses cross-reactive between OC43, SARS-CoV-2, and the other seasonal coronaviruses were confirmed in samples of peripheral blood and peptide-expanded T-cell lines. Among the validated epitopes, spike protein S903-917 presented by DPA1*01:03/DPB1*04:01 and S1085-1099 presented by DRB1*15:01 shared substantial homology to other human coronaviruses, including SARS-CoV-2, and were targeted by cross-reactive CD4 T cells. Nucleoprotein N54-68 and hemagglutinin-esterase HE128-142 presented by DRB1*15:01 and HE259-273 presented by DPA1*01:03/DPB1*04:01 are immunodominant epitopes with low coronavirus homology that are not cross-reactive with SARS-CoV-2. Overall, the set of naturally processed and presented OC43 epitopes comprise both OC43-specific and human coronavirus cross-reactive epitopes, which can be used to follow CD4 T-cell cross-reactivity after infection or vaccination, and to guide selection of epitopes for inclusion in pan-coronavirus vaccines.

Chemoproteomic identification of a DPP4 homolog in Bacteroides thetaiotaomicron.

Serine hydrolases have important roles in signaling and human metabolism, yet little is known about their functions in gut commensal bacteria. Using bioinformatics and chemoproteomics, we identify serine hydrolases in the gut commensal Bacteroides thetaiotaomicron that are specific to the Bacteroidetes phylum. Two are predicted homologs of the human dipeptidyl peptidase 4 (hDPP4), a key enzyme that regulates insulin signaling. Our functional studies reveal that BT4193 is a true homolog of hDPP4 that can be inhibited by FDA-approved type 2 diabetes medications targeting hDPP4, while the other is a misannotated proline-specific triaminopeptidase. We demonstrate that BT4193 is important for envelope integrity and that loss of BT4193 reduces B. thetaiotaomicron fitness during in vitro growth within a diverse community. However, neither function is dependent on BT4193 proteolytic activity, suggesting a scaffolding or signaling function for this bacterial protease.

CD4 Effector TCR Avidity for Peptide on APC Determines the Level of Memory Generated.

Initial TCR affinity for peptide Ag is known to impact the generation of memory; however, its contributions later, when effectors must again recognize Ag at 5-8 d postinfection to become memory, is unclear. We examined whether the effector TCR affinity for peptide at this "effector checkpoint" dictates the extent of memory and degree of protection against rechallenge. We made an influenza A virus nucleoprotein (NP)-specific TCR transgenic mouse strain, FluNP, and generated NP-peptide variants that are presented by MHC class II to bind to the FluNP TCR over a broad range of avidity. To evaluate the impact of avidity in vivo, we primed naive donor FluNP in influenza A virus-infected host mice, purified donor effectors at the checkpoint, and cotransferred them with the range of peptides pulsed on activated APCs into second uninfected hosts. Higher-avidity peptides yielded higher numbers of FluNP memory cells in spleen and most dramatically in lung and draining lymph nodes and induced better protection against lethal influenza infection. Avidity determined memory cell number, not cytokine profile, and already impacted donor cell number within several days of transfer. We previously found that autocrine IL-2 production at the checkpoint prevents default effector apoptosis and supports memory formation. Here, we find that peptide avidity determines the level of IL-2 produced by these effectors and that IL-2Rα expression by the APCs enhances memory formation, suggesting that transpresentation of IL-2 by APCs further amplifies IL-2 availability. Secondary memory generation was also avidity dependent. We propose that this regulatory pathway selects CD4 effectors of highest affinity to progress to memory.

Simple synthesis of soft, tough, and cytocompatible biohybrid composites.

Collagen is the most abundant component of mammalian extracellular matrices. As such, the development of materials that mimic the biological and mechanical properties of collagenous tissues is an enduring goal of the biomaterials community. Despite the development of molded and 3D printed collagen hydrogel platforms, their use as biomaterials and tissue engineering scaffolds is hindered by either low stiffness and toughness or processing complexity. Here, we demonstrate the development of stiff and tough biohybrid composites by combining collagen with a zwitterionic hydrogel through simple mixing. This combination led to the self-assembly of a nanostructured fibrillar network of collagen that was ionically linked to the surrounding zwitterionic hydrogel matrix, leading to a composite microstructure reminiscent of soft biological tissues. The addition of 5-15 mg mL-1 collagen and the formation of nanostructured fibrils increased the elastic modulus of the composite system by 40% compared to the base zwitterionic matrix. Most notably, the addition of collagen increased the fracture energy nearly 11-fold ([Formula: see text] 180 J m-2) and clearly delayed crack initiation and propagation. These composites exhibit elastic modulus ([Formula: see text] 0.180 MJ) and toughness ([Formula: see text]0.617 MJ m-3) approaching that of biological tissues such as articular cartilage. Maintenance of the fibrillar structure of collagen also greatly enhanced cytocompatibility, improving cell adhesion more than 100-fold with >90% cell viability.

Effect of Isocaloric, Time-Restricted Eating on Body Weight in Adults With Obesity : A Randomized Controlled Trial.

BACKGROUND: Time-restricted eating (TRE) lowers body weight in many studies. Whether TRE induces weight loss independent of reductions in calorie intake, as seen in rodent studies, is unknown. OBJECTIVE: To determine the effect of TRE versus a usual eating pattern (UEP) on body weight in the setting of stable caloric intake. DESIGN: Randomized, isocaloric feeding study. (ClinicalTrials.gov: NCT03527368). SETTING: Clinical research unit. PARTICIPANTS: Adults with obesity and prediabetes or diet-controlled diabetes. INTERVENTION: Participants were randomly assigned 1:1 to TRE (10-hour eating window, 80% of calories before 1 p.m.) or UEP (≤16-hour window, ≥50% of calories after 5 p.m.) for 12 weeks. Both groups had the same nutrient content and were isocaloric with total calories determined at baseline. MEASUREMENTS: Primary outcome was change in body weight at 12 weeks. Secondary outcomes were fasting glucose, homeostatic model assessment for insulin resistance (HOMA-IR), glucose area under the curve by oral glucose tolerance test, and glycated albumin. We used linear mixed models to evaluate the effect of interventions on outcomes. RESULTS: All 41 randomly assigned participants (mean age, 59 years; 93% women; 93% Black race; mean BMI, 36 kg/m2) completed the intervention. Baseline weight was 95.6 kg (95% CI, 89.6 to 101.6 kg) in the TRE group and 103.7 kg (CI, 95.3 to 112.0 kg) in the UEP group. At 12 weeks, weight decreased by 2.3 kg (CI, 1.0 to 3.5 kg) in the TRE group and by 2.6 kg (CI, 1.5 to 3.7 kg) in the UEP group (average difference TRE vs. UEP, 0.3 kg [CI, -1.2 to 1.9 kg]). Change in glycemic measures did not differ between groups. LIMITATION: Small, single-site study; baseline differences in weight by group. CONCLUSION: In the setting of isocaloric eating, TRE did not decrease weight or improve glucose homeostasis relative to a UEP, suggesting that any effects of TRE on weight in prior studies may be due to reductions in caloric intake. PRIMARY FUNDING SOURCE: American Heart Association.

MTNR1B genotype and effects of carbohydrate quantity and dietary glycaemic index on glycaemic response to an oral glucose load: the OmniCarb trial.

AIMS/HYPOTHESIS: A type 2 diabetes-risk-increasing variant, MTNR1B (melatonin receptor 1B) rs10830963, regulates the circadian function and may influence the variability in metabolic responses to dietary carbohydrates. We investigated whether the effects of carbohydrate quantity and dietary glycaemic index (GI) on glycaemic response during OGTTs varied by the risk G allele of MTNR1B-rs10830963. METHODS: This study included participants (n=150) of a randomised crossover-controlled feeding trial of four diets with high/low GI levels and high/low carbohydrate content for 5 weeks. The MTNR1B-rs10830963 (C/G) variant was genotyped. Glucose response during 2 h OGTT was measured at baseline and the end of each diet intervention. RESULTS: Among the four study diets, carrying the risk G allele (CG/GG vs CC genotype) of MTNR1B-rs10830963 was associated with the largest AUC of glucose during 2 h OGTT after consuming a high-carbohydrate/high-GI diet (ß 134.32 [SE 45.69] mmol/l × min; p=0.004). The risk G-allele carriers showed greater increment of glucose during 0-60 min (ß 1.26 [0.47] mmol/l; p=0.008) or 0-90 min (ß 1.10 [0.50] mmol/l; p=0.028) after the high-carbohydrate/high-GI diet intervention, but not after consuming the other three diets. At high carbohydrate content, reducing GI levels decreased 60 min post-OGTT glucose (mean -0.67 [95% CI: -1.18, -0.17] mmol/l) and the increment of glucose during 0-60 min (mean -1.00 [95% CI: -1.67, -0.33] mmol/l) and 0-90 min, particularly in the risk G-allele carriers (pinteraction <0.05 for all). CONCLUSIONS/INTERPRETATION: Our study shows that carrying the risk G allele of MTNR1B-rs10830963 is associated with greater glycaemic responses after consuming a diet with high carbohydrates and high GI levels. Reducing GI in a high-carbohydrate diet may decrease post-OGTT glucose concentrations among the risk G-allele carriers.

The peroxidation-derived DNA adduct, 6-oxo-M1dG, is a strong block to replication by human DNA polymerase η.

The DNA adduct 6-oxo-M1dG, (3-(2'-deoxy-ß-D-erythro-pentofuranosyl)-6-oxo-pyrimido(1,2alpha)purin-10(3H)-one) is formed in the genome via oxidation of the peroxidation-derived adduct M1dG. However, the effect of 6-oxo-M1dG adducts on subsequent DNA replication is unclear. Here we investigated the ability of the human Y-family polymerase hPol η to bypass 6-oxo-M1dG. Using steady-state kinetics and analysis of DNA extension products by liquid chromatography-tandem mass spectrometry, we found hPol η preferentially inserts a dAMP or dGMP nucleotide into primer-templates across from the 6-oxo-M1dG adduct, with dGMP being slightly preferred. We also show primer-templates with a 3'-terminal dGMP or dAMP across from 6-oxo-M1dG were extended to a greater degree than primers with a dCMP or dTMP across from the adduct. In addition, we explored the structural basis for bypass of 6-oxo-M1dG by hPol η using X-ray crystallography of both an insertion-stage and an extension-stage complex. In the insertion-stage complex, we observed that the incoming dCTP opposite 6-oxo-M1dG, although present during crystallization, was not present in the active site. We found the adduct does not interact with residues in the hPol η active site but rather forms stacking interactions with the base pair immediately 3' to the adduct. In the extension-stage complex, we observed the 3' hydroxyl group of the primer strand dGMP across from 6-oxo-M1dG is not positioned correctly to form a phosphodiester bond with the incoming dCTP. Taken together, these results indicate 6-oxo-M1dG forms a strong block to DNA replication by hPol η and provide a structural basis for its blocking ability.

IDEAL Phase 2a Results: Posterior Rectus Sheath Flap for Hiatal Augmentation in Complex Paraesophageal Hernias.

OBJECTIVE: To report the developmental phase results of posterior rectus sheath hiatal flap augmentation (PoRSHA), a promising surgical innovation for large and recurrent paraesophageal hernias. BACKGROUND: Durable hernia repair for large paraesophageal hernias continues to be a surgical challenge. PoRSHA addresses the challenges of current and historical approaches to complex paraesophageal hernias and demonstrates significant promise as a successful alternative approach. METHODS: Using the IDEAL framework, we outline the technical modifications made over the first 27 consecutive cases using PoRSHA. Outcomes measured included hernia recurrence on routine imaging at 6 months and 2 years, development of a postoperative abdominal wall eventration and incidence of solid food dysphagia. RESULTS: Twenty-seven patients at our single institution with type III (n=12), type IV (n=7), or recurrent (n=8) paraesophageal hernias underwent PoRSHA. Surgery was safely and successfully carried out in all cases. Stability of the technique was reached after 16 cases, resulting in 4 main repair types. At an average follow-up of 11 months, we observed no radiologic recurrences, no abdominal eventrations or hernias at the donor site, and 1 patient with occasional solid food dysphagia that resolved with dilation. CONCLUSIONS: PoRSHA can not only be safely added to conventional hiatal hernia repair with appropriate training but also demonstrates excellent short-term outcomes. While the long-term durability with 5-year follow-up is still needed, here we provide cautious optimism that PoRSHA may represent a novel solution to the long-standing high recurrence rates observed with current complex PEH repair.

Final Report of a Trial of Intensive versus Standard Blood-Pressure Control.

BACKGROUND: In a previously reported randomized trial of standard and intensive systolic blood-pressure control, data on some outcome events had yet to be adjudicated and post-trial follow-up data had not yet been collected. METHODS: We randomly assigned 9361 participants who were at increased risk for cardiovascular disease but did not have diabetes or previous stroke to adhere to an intensive treatment target (systolic blood pressure, <120 mm Hg) or a standard treatment target (systolic blood pressure, <140 mm Hg). The primary outcome was a composite of myocardial infarction, other acute coronary syndromes, stroke, acute decompensated heart failure, or death from cardiovascular causes. Additional primary outcome events occurring through the end of the intervention period (August 20, 2015) were adjudicated after data lock for the primary analysis. We also analyzed post-trial observational follow-up data through July 29, 2016. RESULTS: At a median of 3.33 years of follow-up, the rate of the primary outcome and all-cause mortality during the trial were significantly lower in the intensive-treatment group than in the standard-treatment group (rate of the primary outcome, 1.77% per year vs. 2.40% per year; hazard ratio, 0.73; 95% confidence interval [CI], 0.63 to 0.86; all-cause mortality, 1.06% per year vs. 1.41% per year; hazard ratio, 0.75; 95% CI, 0.61 to 0.92). Serious adverse events of hypotension, electrolyte abnormalities, acute kidney injury or failure, and syncope were significantly more frequent in the intensive-treatment group. When trial and post-trial follow-up data were combined (3.88 years in total), similar patterns were found for treatment benefit and adverse events; however, rates of heart failure no longer differed between the groups. CONCLUSIONS: Among patients who were at increased cardiovascular risk, targeting a systolic blood pressure of less than 120 mm Hg resulted in lower rates of major adverse cardiovascular events and lower all-cause mortality than targeting a systolic blood pressure of less than 140 mm Hg, both during receipt of the randomly assigned therapy and after the trial. Rates of some adverse events were higher in the intensive-treatment group. (Funded by the National Institutes of Health; SPRINT ClinicalTrials.gov number, NCT01206062.).

Randomized Trial of Patient Outreach Approaches to De-implement Outdated Colonoscopy Surveillance Intervals.

BACKGROUND AND AIMS: Guidelines now recommend patients with low-risk adenomas receive colonoscopy surveillance in 7-10 years and those with the previously recommended 5-year interval be re-evaluated. We tested 3 outreach approaches for transitioning patients to the 10-year interval recommendation. METHODS: This was a 3-arm pragmatic randomized trial comparing telephone, secure messaging, and mailed letter outreach. The setting was Kaiser Permanente Northern California, a large integrated healthcare system. Participants were patients 54-70 years of age with 1-2 small (<10 mm) tubular adenomas at baseline colonoscopy, due for 5-year surveillance in 2022, without high-risk conditions, and with access to all 3 outreach modalities. Patients were randomly assigned to the outreach arm (telephone [n = 200], secure message [n = 203], and mailed letter [n = 201]) stratified by age, sex, and race/ethnicity. Outreach in each arm was performed by trained medical assistants (unblinded) communicating in English with 1 reminder attempt at 2-4 weeks. Participants could change their assigned interval to 10 years or continue their planned 5-year interval. RESULTS: Sixty-day response rates were higher for telephone (64.5%) and secure messaging outreach (51.7%) vs mailed letter (31.3%). Also, more patients adopted the 10-year surveillance interval in the telephone (37.0%) and secure messaging arms (32.0%) compared with mailed letter (18.9%) and rate differences were significant for telephone (18.1%; 97.5% confidence interval: 8.3%-27.9%) and secure message outreach (13.1%; 97.5% confidence interval: 3.5%-22.7%) vs mailed letter outreach. CONCLUSIONS: Telephone and secure messaging were more effective than mailed letter outreach for de-implementing outdated colonoscopy surveillance recommendations among individuals with a history of low-risk adenomas in an integrated healthcare setting. (ClinicalTrials.gov, Number: NCT05389397).

Adiposity associates with lower plasma resolvin E1 (Rve1): a population study.

BACKGROUND: Inadequate inflammation resolution may contribute to persistent low-grade inflammation that accompanies many chronic conditions. Resolution of inflammation is an active process driven by Specialized Pro-resolving Mediators (SPM) that derive from long chain n-3 and n-6 fatty acids. This study examined plasma SPM in relation to sex differences, lifestyle and a broad range cardiovascular disease (CVD) risk factors in 978, 27-year olds from the Australian Raine Study. METHODS: Plasma SPM pathway intermediates (18-HEPE, 17-HDHA and 14-HDHA), and SPM (E- and D-series resolvins, PD1, MaR1) and LTB4 were measured by liquid chromatography-tandem mass spectrometry (LCMSMS). Pearson correlations and multiple regression analyses assessed relationships between SPM and CVD risk factors. Unpaired t-tests or ANOVA assessed the effect of sex, smoking, unhealthy alcohol consumption and obesity on SPM. RESULTS: Women had higher 17-HDHA (p = 0.01) and lower RvE1 (p < 0.0001) and RvD1 (p = 0.05) levels compared with men. In univariate analysis, obesity associated with lower RvE1 (p = 0.002), whereas smoking (p < 0.001) and higher alcohol consumption (p < 0.001) associated with increased RvE1. In multiple regression analysis, plasma RvE1 was negatively associated with a range of measures of adiposity including BMI, waist circumference, waist-to-height ratio, abdominal subcutaneous fat volume, and skinfold thicknesses in both men and women. CONCLUSION: This population study suggests that a deficiency in plasma RvE1 may occur in response to increasing adiposity. This observation could be relevant to ongoing inflammation that associates with CVD and other chronic diseases.

Longitudinal study of the impact of the COVID-19 pandemic on diet and physical activity among Latinos of Mexican ancestry.

BACKGROUND: The COVID-19 pandemic caused societal disruption in the United States and most of the world, affecting many aspects of life, including healthcare and health-related behaviors such as diet, food security, and physical activity. Communities with economic and health disparities may have been particularly affected. This study was undertaken to determine how conditions in the early pandemic (January, 2021-February, 2022) affected Latino patients of Mexican Ancestry at high risk of type 2 diabetes mellitus who participated in El Banco por Salud biobank project in Tucson, Arizona. METHODS: Baseline, prepandemic measurements were available in 17, 21, and 60 patients with normal hemoglobin A1c (HbA1c), prediabetes, and type 2 diabetes, respectively. RESULTS: People with healthy HbA1c were significantly younger, less obese, and had higher HDL cholesterol. HbA1c was unaffected by the pandemic in any group. Triglycerides, total and HDL cholesterol levels fell in all groups during the pandemic. Physical activity levels in all groups were remarkably low, with most reporting no engagement in any voluntary physical activity. Engagement in physical activity or its enjoyment was lower in patients with diabetes and prediabetes than in younger, less obese patients. Major diet differences were between men and women and were present before the pandemic. Women consumed significantly more vegetables, fruit, and salad than men. The only pandemic-related change in diet was a drop in egg consumption, possibly explaining the fall in total cholesterol. CONCLUSION: Societal disruption during the COVID-19 pandemic had minimal effects on adverse health-related behaviors, cardiometabolic risk, or changes in glycemic control in a Latino community with diabetes and healthcare disparities in the Southwest US.