An interactive resource to identify cancer genetic and lineage dependencies targeted by small molecules.

The high rate of clinical response to protein-kinase-targeting drugs matched to cancer patients with specific genomic alterations has prompted efforts to use cancer cell line (CCL) profiling to identify additional biomarkers of small-molecule sensitivities. We have quantitatively measured the sensitivity of 242 genomically characterized CCLs to an Informer Set of 354 small molecules that target many nodes in cell circuitry, uncovering protein dependencies that: (1) associate with specific cancer-genomic alterations and (2) can be targeted by small molecules. We have created the Cancer Therapeutics Response Portal (http://www.broadinstitute.org/ctrp) to enable users to correlate genetic features to sensitivity in individual lineages and control for confounding factors of CCL profiling. We report a candidate dependency, associating activating mutations in the oncogene ß-catenin with sensitivity to the Bcl-2 family antagonist, navitoclax. The resource can be used to develop novel therapeutic hypotheses and to accelerate discovery of drugs matched to patients by their cancer genotype and lineage.

Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2.

Human transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causative pathogen of the COVID-19 pandemic, exerts a massive health and socioeconomic crisis. The virus infects alveolar epithelial type 2 cells (AT2s), leading to lung injury and impaired gas exchange, but the mechanisms driving infection and pathology are unclear. We performed a quantitative phosphoproteomic survey of induced pluripotent stem cell-derived AT2s (iAT2s) infected with SARS-CoV-2 at air-liquid interface (ALI). Time course analysis revealed rapid remodeling of diverse host systems, including signaling, RNA processing, translation, metabolism, nuclear integrity, protein trafficking, and cytoskeletal-microtubule organization, leading to cell cycle arrest, genotoxic stress, and innate immunity. Comparison to analogous data from transformed cell lines revealed respiratory-specific processes hijacked by SARS-CoV-2, highlighting potential novel therapeutic avenues that were validated by a high hit rate in a targeted small molecule screen in our iAT2 ALI system.

The COPD GWAS gene ADGRG6 instructs function and injury response in human iPSC-derived type II alveolar epithelial cells.

Emphysema and chronic obstructive pulmonary disease (COPD) most commonly result from the effects of environmental exposures in genetically susceptible individuals. Genome-wide association studies have implicated ADGRG6 in COPD and reduced lung function, and a limited number of studies have examined the role of ADGRG6 in cells representative of the airway. However, the ADGRG6 locus is also associated with DLCO/VA, an indicator of gas exchange efficiency and alveolar function. Here, we sought to evaluate the mechanistic contributions of ADGRG6 to homeostatic function and disease in type 2 alveolar epithelial cells. We applied an inducible CRISPR interference (CRISPRi) human induced pluripotent stem cell (iPSC) platform to explore ADGRG6 function in iPSC-derived AT2s (iAT2s). We demonstrate that ADGRG6 exerts pleiotropic effects on iAT2s including regulation of focal adhesions, cytoskeleton, tight junctions, and proliferation. Moreover, we find that ADGRG6 knockdown in cigarette smoke-exposed iAT2s alters cellular responses to injury, downregulating apical complexes in favor of proliferation. Our work functionally characterizes the COPD GWAS gene ADGRG6 in human alveolar epithelium.

LepR+ niche cell-derived AREG compromises hematopoietic stem cell maintenance under conditions of DNA repair deficiency and aging.

The cross talk between extrinsic niche-derived and intrinsic hematopoietic stem cell (HSC) factors controlling HSC maintenance remains elusive. Here, we demonstrated that amphiregulin (AREG) from bone marrow (BM) leptin receptor (LepR+) niche cells is an important factor that mediates the cross talk between the BM niche and HSCs in stem cell maintenance. Mice deficient of the DNA repair gene Brca2, specifically in LepR+ cells (LepR-Cre;Brca2fl/fl), exhibited increased frequencies of total and myeloid-biased HSCs. Furthermore, HSCs from LepR-Cre;Brca2fl/fl mice showed compromised repopulation, increased expansion of donor-derived, myeloid-biased HSCs, and increased myeloid output. Brca2-deficient BM LepR+ cells exhibited persistent DNA damage-inducible overproduction of AREG. Ex vivo treatment of wild-type HSCs or systemic treatment of C57BL/6 mice with recombinant AREG impaired repopulation, leading to HSC exhaustion. Conversely, inhibition of AREG by an anti-AREG-neutralizing antibody or deletion of the Areg gene in LepR-Cre;Brca2fl/fl mice rescued HSC defects caused by AREG. Mechanistically, AREG activated the phosphoinositide 3-kinases (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, promoted HSC cycling, and compromised HSC quiescence. Finally, we demonstrated that BM LepR+ niche cells from other DNA repair-deficient and aged mice also showed persistent DNA damage-associated overexpression of AREG, which exerts similar negative effects on HSC maintenance. Therefore, we identified an important factor that regulates HSCs function under conditions of DNA repair deficiency and aging.

Quantum-enhanced sensing of a single-ion mechanical oscillator.

Special quantum states are used in metrology to achieve sensitivities below the limits established by classically behaving states1,2. In bosonic interferometers, squeezed states3, number states4,5 and 'Schrödinger cat' states5 have been implemented on various platforms and have demonstrated improved measurement precision over interferometers using coherent states6,7. Another metrologically useful state is an equal superposition of two eigenstates with maximally different energies; this state ideally reaches the full interferometric sensitivity allowed by quantum mechanics8,9. Here we demonstrate the enhanced sensitivity of these quantum states in the case of a harmonic oscillator. We extend an existing experimental technique10 to create number states of order up to n = 100 and to generate superpositions of a harmonic oscillator ground state and a number state of the form [Formula: see text] with n up to 18 in the motion of a single trapped ion. Although experimental imperfections prevent us from reaching the ideal Heisenberg limit, we observe enhanced sensitivity to changes in the frequency of the mechanical oscillator. This sensitivity initially increases linearly with n and reaches a maximum at n = 12, where we observe a metrological enhancement of 6.4(4) decibels (the uncertainty is one standard deviation of the mean) compared to an ideal measurement on a coherent state with the same average occupation number. Such measurements should provide improved characterization of motional decoherence, which is an important source of error in quantum information processing with trapped ions11,12. It should also be possible to use the quantum advantage from number-state superpositions to achieve precision measurements in other harmonic oscillator systems.

Biophysical and structural analyses of the interaction between the SHANK1 PDZ domain and an internal SLiM.

The PDZ (Postsynaptic density protein-95[PSD-95]/Discs-large) domain, prevalent as a recognition module, has attracted significant attention given its ability to specifically recognize ligands with consensus motifs (also termed PDZ binding motifs [PBMs]). PBMs typically bear a C-terminal carboxylate as a recognition handle and have been extensively characterized, whilst internal ligands are less well known. Here we characterize a short linear motif (SLiM) - EESTSFQGP - as an internal PBM based on its strong binding affinity towards the SHANK1 PDZ domain (SHANK1656-762 hereafter referred to as SHANK1). Using the acetylated analogue Ac-EESTSFQGP-CONH2 as a competitor for the interaction of SHANK1 with FAM-Ahx-EESTSFQGP-CONH2 or a typical fluorophore-labelled C-terminal PBM - GKAP - FITC-Ahx-EAQTRL-COOH - the internal SLiM was demonstrated to show comparable low-micromolar IC50 by competition fluorescent anisotropy. To gain further insight into the internal ligand interaction at the molecular level, we obtained the X-ray co-crystal structure of the Ac-EESTSFQGP-CONH2/SHANK1 complex and compared this to the Ac-EAQTRL-COOH/SHANK1 complex. The crystallographic studies reveal that the SHANK1 backbones for the two interactions overlap significantly. The main structural differences were shown to result from the flexible loops which reorganize to accommodate the two PBMs with distinct lengths and terminal groups. In addition, the two C-terminal residues Gly and Pro in Ac-EESTSFQGP-CONH2 were shown not to participate in interaction with the target protein, implying further truncation and structural modification using peptidomimetic approaches on this sequence may be feasible. Taken together, the SLiM Ac-EESTSFQGP-CONH2 holds potential as an internal ligand for targeting SHANK1.

Harnessing interpretable and unsupervised machine learning to address big data from modern X-ray diffraction.

The information content of crystalline materials becomes astronomical when collective electronic behavior and their fluctuations are taken into account. In the past decade, improvements in source brightness and detector technology at modern X-ray facilities have allowed a dramatically increased fraction of this information to be captured. Now, the primary challenge is to understand and discover scientific principles from big datasets when a comprehensive analysis is beyond human reach. We report the development of an unsupervised machine learning approach, X-ray diffraction (XRD) temperature clustering (X-TEC), that can automatically extract charge density wave order parameters and detect intraunit cell ordering and its fluctuations from a series of high-volume X-ray diffraction measurements taken at multiple temperatures. We benchmark X-TEC with diffraction data on a quasi-skutterudite family of materials, (CaxSr[Formula: see text])3Rh4Sn13, where a quantum critical point is observed as a function of Ca concentration. We apply X-TEC to XRD data on the pyrochlore metal, Cd2Re2O7, to investigate its two much-debated structural phase transitions and uncover the Goldstone mode accompanying them. We demonstrate how unprecedented atomic-scale knowledge can be gained when human researchers connect the X-TEC results to physical principles. Specifically, we extract from the X-TEC-revealed selection rules that the Cd and Re displacements are approximately equal in amplitude but out of phase. This discovery reveals a previously unknown involvement of [Formula: see text] Re, supporting the idea of an electronic origin to the structural order. Our approach can radically transform XRD experiments by allowing in operando data analysis and enabling researchers to refine experiments by discovering interesting regions of phase space on the fly.

Clinical utility of investigations in triple-negative thrombocytosis: A real-world, multicentre evaluation of UK practice.

Diagnosis of essential thrombocythaemia (ET) is challenging in patients lacking JAK2/CALR/MPL mutations. In a retrospective evaluation of 320 patients with 'triple-negative thrombocytosis', we assessed utility of bone marrow histology (90.9% of patients) and myeloid gene panel (MGP, 55.6%). Supportive histology ('myeloproliferative neoplasm-definite/probable', 36.8%) was associated with higher platelet counts and varied between centres. 14.6% MGP revealed significant variants: 3.4% JAK2/CALR/MPL and 11.2% other myeloid genes. Final clinical diagnosis was strongly predicted by histology, not MGP. 23.7% received cytoreduction (17.6% under 60 years). Real-world 'triple-negative' ET diagnosis currently depends heavily on histology; we advocate caution in MGP-negative cases and that specific guidelines are needed.

Inhibition of Aurora-A/N-Myc Protein-Protein Interaction Using Peptidomimetics: Understanding the Role of Peptide Cyclization.

Using N-Myc61-89 as a starting template we showcase the systematic use of truncation and maleimide constraining to develop peptidomimetic inhibitors of the N-Myc/Aurora-A protein-protein interaction (PPI); a potential anticancer drug discovery target. The most promising of these - N-Myc73-94-N85C/G89C-mal - is shown to favour a more Aurora-A compliant binding ensemble in comparison to the linear wild-type sequence as observed through fluorescence anisotropy competition assays, circular dichroism (CD) and nuclear magnetic resonance (NMR) experiments. Further in silico investigation of this peptide in its Aurora-A bound state, by molecular dynamics (MD) simulations, imply (i) the bound conformation is more stable as a consequence of the constraint, which likely suppresses dissociation and (ii) the constraint may make further stabilizing interactions with the Aurora-A surface. Taken together this work unveils the first orthosteric N-Myc/Aurora-A inhibitor and provides useful insights on the biophysical properties and thus design of constrained peptides, an attractive therapeutic modality.

Correction: Recombinant Lloviu virus as a tool to study viral replication and host responses.

[This corrects the article DOI: 10.1371/journal.ppat.1010268.].

Recombinant Lloviu virus as a tool to study viral replication and host responses.

Next generation sequencing has revealed the presence of numerous RNA viruses in animal reservoir hosts, including many closely related to known human pathogens. Despite their zoonotic potential, most of these viruses remain understudied due to not yet being cultured. While reverse genetic systems can facilitate virus rescue, this is often hindered by missing viral genome ends. A prime example is Lloviu virus (LLOV), an uncultured filovirus that is closely related to the highly pathogenic Ebola virus. Using minigenome systems, we complemented the missing LLOV genomic ends and identified cis-acting elements required for LLOV replication that were lacking in the published sequence. We leveraged these data to generate recombinant full-length LLOV clones and rescue infectious virus. Similar to other filoviruses, recombinant LLOV (rLLOV) forms filamentous virions and induces the formation of characteristic inclusions in the cytoplasm of the infected cells, as shown by electron microscopy. Known target cells of Ebola virus, including macrophages and hepatocytes, are permissive to rLLOV infection, suggesting that humans could be potential hosts. However, inflammatory responses in human macrophages, a hallmark of Ebola virus disease, are not induced by rLLOV. Additional tropism testing identified pneumocytes as capable of robust rLLOV and Ebola virus infection. We also used rLLOV to test antivirals targeting multiple facets of the replication cycle. Rescue of uncultured viruses of pathogenic concern represents a valuable tool in our arsenal for pandemic preparedness.

Visible-Light Driven Control Over Triply and Quadruply Hydrogen-Bonded Supramolecular Assemblies.

Supramolecular polymers offer tremendous potential to produce new "smart" materials, however, there remains a need to develop systems that are responsive to external stimuli. In this work, visible-light responsive hydrogen-bonded supramolecular polymers comprising photoresponsive supramolecular synthons (I-III) consisting of two hydrogen bonding motifs (HBMs) connected by a central ortho-tetrafluorinated azobenzene have been characterized by DOSY NMR and viscometry. Comparison of different hydrogen-bonding motifs reveals that assembly in the low and high concentration regimes is strongly influenced by the strength of association between the HBMs. I, Incorporating a triply hydrogen-bonded heterodimer, was found to exhibit concentration dependent switching between a monomeric pseudo-cycle and supramolecular oligomer through intermolecular hydrogen bonding interactions between the HBMs. II, Based on the same photoresponsive scaffold, and incorporating a quadruply hydrogen-bonded homodimer was found to form a supramolecular polymer which was dependent upon the ring-chain equilibrium and thus dependent upon both concentration and photochemical stimulus. Finally, III, incorporating a quadruply hydrogen-bonded heterodimer represents the first photoswitchable AB type hydrogen-bonded supramolecular polymer. Depending on the concentration and photostationary state, four different assemblies dominate for both monomers II and III, demonstrating the ability to control supramolecular assembly and physical properties triggered by light.

Oxycodone initiation in Australia (2014-2018): Sociodemographic factors and preceding health service use.

AIMS: Oxycodone is the most commonly prescribed strong opioid in Australia. This study describes health service antecedents and sociodemographic factors associated with oxycodone initiation. METHODS: Population-based new user cohort study linking medicine dispensings, hospitalizations, emergency department visits, medical services and cancer notifications from New South Wales (NSW) for 2014-2018. New users had no dispensings of any opioid in the preceding year. We analysed health service use in the 5 days preceding initiation and proportion of people on treatment over 1 year and fitted an area-based, multivariable initiation model with sociodemographic covariates. RESULTS: Oxycodone accounted for 30% of opioid initiations. Annually, 3% of the NSW population initiated oxycodone, and 5-6% were prevalent users; the new user cohort comprised 830 963 people. Discharge from hospital (39.3%), therapeutic procedures (21.4%) and emergency department visits (19.7%) were common; a hospital admission for injury (6.0%) or a past-year history of cancer (7.2%) were less common. At 1 year after initiation, 4.6% of people were using oxycodone. In the multivariable model, new use of oxycodone increased with age and was higher for people outside major cities, for example, an incidence rate ratio of 1.43 (95% confidence interval 1.36-1.51) for inner regional areas relative to major cities; there was no evidence of variation in rates of new use by social disadvantage. CONCLUSION: About half of new oxycodone use in NSW was preceded by a recent episode of hospital care or a therapeutic procedure. Higher rates of oxycodone initiation in rural and regional areas were not explained by sociodemographic factors.

The cost of respiratory hospitalizations in children with cerebral palsy.

AIM: To establish the burden of respiratory illness in cerebral palsy (CP) on the Western Australian health care system by quantifying the costs of respiratory hospitalizations in children with CP, compared with non-respiratory hospitalizations. METHOD: A 2-year (2014-2015) retrospective study using linked hospital data (excluding emergency department visits), in a population of children with CP in Western Australia aged 18 years and under (median age at hospitalization 7 years; interquartile range 5-12 years). RESULTS: In 671 individuals (57% male) there were 726 emergency hospitalizations, and 1631 elective hospitalizations. Although there were more elective hospitalizations, emergency hospitalizations were associated with longer stays in hospital, and more days in an intensive care unit, resulting in a higher total cost of emergency hospitalizations than elective hospitalizations (total costs: emergency AU$7 748 718 vs elective AU$6 738 187). 'Respiratory' was the leading cause of emergency hospitalizations, contributing to 36% of all emergency admission costs. For a group of high-cost inpatient users (top 5% of individuals with the highest total inpatient costs) the most common reason for hospitalization was 'respiratory'. Where non-respiratory admissions were complicated by an additional respiratory diagnosis, length of stay was greater. INTERPRETATION: Respiratory hospitalizations in CP are a significant driver of health care costs. In the paediatric group, they are a burden for a subgroup of children with CP. WHAT THIS PAPER ADDS: Respiratory illness is the most costly area for unplanned, emergency hospitalizations for children and young people with cerebral palsy. The top 5% of individuals with the highest total inpatient costs account for a disproportionate amount of health care costs.

The effect of older age on outcomes of rTMS treatment for treatment-resistant depression.

Clinical outcomes of repetitive transcranial magnetic stimulation (rTMS) for treatment of treatment-resistant depression (TRD) vary widely and there is no mood rating scale that is standard for assessing rTMS outcome. It remains unclear whether TMS is as efficacious in older adults with late-life depression (LLD) compared to younger adults with major depressive disorder (MDD). This study examined the effect of age on outcomes of rTMS treatment of adults with TRD. Self-report and observer mood ratings were measured weekly in 687 subjects ages 16-100 years undergoing rTMS treatment using the Inventory of Depressive Symptomatology 30-item Self-Report (IDS-SR), Patient Health Questionnaire 9-item (PHQ), Profile of Mood States 30-item, and Hamilton Depression Rating Scale 17-item (HDRS). All rating scales detected significant improvement with treatment; response and remission rates varied by scale but not by age (response/remission ≥ 60: 38%-57%/25%-33%; <60: 32%-49%/18%-25%). Proportional hazards models showed early improvement predicted later improvement across ages, though early improvements in PHQ and HDRS were more predictive of remission in those < 60 years (relative to those ≥ 60) and greater baseline IDS burden was more predictive of non-remission in those ≥ 60 years (relative to those < 60). These results indicate there is no significant effect of age on treatment outcomes in rTMS for TRD, though rating instruments may differ in assessment of symptom burden between younger and older adults during treatment.

Virtual Reality-Based Simulated Hallucinations to Enhance Empathy Toward Individuals With Schizophrenia.

ABSTRACT: Individuals affected by schizophrenia often relay frustration that persons in their life are unable to understand their symptoms. We sought to examine whether a brief virtual reality (VR) experience for students in an undergraduate psychopathology course entailing simulated hallucinations could increase empathy, decrease negative affect, and positively affect attitudes toward persons with schizophrenia. After the unit on schizophrenia, 41 participants engaged in a VR experience with simulated auditory and visual hallucinations. We sought to maximize fidelity and immersion by incorporating the actual classroom and course instructor into the virtual world. By collecting data at multiple points, we were able to isolate the impact of the simulation on affect and attitudes. Participants experienced an increase in empathy and favorable attitudes toward individuals with schizophrenia and reported the simulation to be highly educational. The favorable results are notable given the brevity of the simulation and the absence of any explicit (declarative) knowledge being conveyed.

Antibiotics for the treatment of lower respiratory tract infections in children with neurodisability: Systematic review.

AIM: Determine the optimal antibiotic choice for lower respiratory tract infection (LRTI) in children with neurodisability. METHODS: Embase, Ovid Emcare and MEDLINE were searched for studies from inception to January 2023. All studies, except case reports, focusing on the antibiotic treatment of LRTI in children, with neurodisabilities were included. Outcomes included length of stay, intensive care admission and mortality. RESULTS: Nine studies met the inclusion criteria (5115 patients). All the studies were of low quality. The shortest length of stay was with anaerobic and gram-positive cover. Five studies used anaerobic, gram-positive and gram-negative cover (e.g., amoxicillin-clavulanic acid), which was frequently adequate. In one large study, it was better than gram-positive and gram-negative cover alone (e.g. ceftriaxone). Those unresponsive or more unwell at presentation improved faster on Pseudomonas aeruginosa cover (e.g., piperacillin-tazobactam). CONCLUSION: In this context, anaerobic, gram-positive and gram-negative cover is just as effective as P. aeruginosa cover, supporting empiric treatment with amoxicillin-clavulanic acid. If there is a failure to improve, broadening to include P. aeruginosa could be considered. This is consistent with a consensus statement on the treatment of LRTI in children with neurodisability. An accepted definition for what constitutes LRTI in this cohort is required before designing prospective randomised trials.

Aberrant epithelial polarity cues drive the development of precancerous airway lesions.

Molecular events that drive the development of precancerous lesions in the bronchial epithelium, which are precursors of lung squamous cell carcinoma (LUSC), are poorly understood. We demonstrate that disruption of epithelial cellular polarity, via the conditional deletion of the apical determinant Crumbs3 (Crb3), initiates and sustains precancerous airway pathology. The loss of Crb3 in adult luminal airway epithelium promotes the uncontrolled activation of the transcriptional regulators YAP and TAZ, which stimulate intrinsic signals that promote epithelial cell plasticity and paracrine signals that induce basal-like cell growth. We show that aberrant polarity and YAP/TAZ-regulated gene expression associates with human bronchial precancer pathology and disease progression. Analyses of YAP/TAZ-regulated genes further identified the ERBB receptor ligand Neuregulin-1 (NRG1) as a key transcriptional target and therapeutic targeting of ERBB receptors as a means of preventing and treating precancerous cell growth. Our observations offer important molecular insight into the etiology of LUSC and provides directions for potential interception strategies of lung cancer.

Bisoprolol in Patients With Chronic Obstructive Pulmonary Disease at High Risk of Exacerbation: The BICS Randomized Clinical Trial.

Importance: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Observational studies report that ß-blocker use may be associated with reduced risk of COPD exacerbations. However, a recent trial reported that metoprolol did not reduce COPD exacerbations and increased COPD exacerbations requiring hospital admission. Objective: To test whether bisoprolol decreased COPD exacerbations in people with COPD at high risk of exacerbations. Design, Setting, and Participants: The Bisoprolol in COPD Study (BICS) was a double-blind placebo-controlled randomized clinical trial conducted in 76 UK sites (45 primary care clinics and 31 secondary clinics). Patients with COPD who had at least moderate airflow obstruction on spirometry (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity <0.7; FEV1 <80% predicted) and at least 2 COPD exacerbations treated with oral corticosteroids, antibiotics, or both in the prior 12 months were enrolled from October 17, 2018, to May 31, 2022. Follow-up concluded on April 18, 2023. Interventions: Patients were randomly assigned to bisoprolol (n = 261) or placebo (n = 258). Bisoprolol was started at 1.25 mg orally daily and was titrated as tolerated during 4 sessions to a maximum dose of 5 mg/d, using a standardized protocol. Main Outcomes and Measures: The primary clinical outcome was the number of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both during the 1-year treatment period. Safety outcomes included serious adverse events and adverse reactions. Results: Although the trial planned to enroll 1574 patients, recruitment was suspended from March 16, 2020, to July 31, 2021, due to the COVID-19 pandemic. Two patients in each group were excluded postrandomization. Among the 515 patients (mean [SD] age, 68 [7.9] years; 274 men [53%]; mean FEV1, 50.1%), primary outcome data were available for 514 patients (99.8%) and 371 (72.0%) continued taking the study drug. The primary outcome of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both was 526 in the bisoprolol group, with a mean exacerbation rate of 2.03/y, vs 513 exacerbations in the placebo group, with a mean exacerbation rate of 2.01/y. The adjusted incidence rate ratio was 0.97 (95% CI, 0.84-1.13; P = .72). Serious adverse events occurred in 37 of 255 patients in the bisoprolol group (14.5%) vs 36 of 251 in the placebo group (14.3%; relative risk, 1.01; 95% CI, 0.62-1.66; P = .96). Conclusions and Relevance: Among people with COPD at high risk of exacerbation, treatment with bisoprolol did not reduce the number of self-reported COPD exacerbations requiring treatment with oral corticosteroids, antibiotics, or both. Trial Registration: isrctn.org Identifier: ISRCTN10497306.