Colchicine and aspirin in community patients with COVID-19 (ACT): an open-label, factorial, randomised, controlled trial.

BACKGROUND: The large number of patients worldwide infected with the SARS-CoV-2 virus has overwhelmed health-care systems globally. The Anti-Coronavirus Therapies (ACT) outpatient trial aimed to evaluate anti-inflammatory therapy with colchicine and antithrombotic therapy with aspirin for prevention of disease progression in community patients with COVID-19. METHODS: The ACT outpatient, open-label, 2 × 2 factorial, randomised, controlled trial, was done at 48 clinical sites in 11 countries. Patients in the community aged 30 years and older with symptomatic, laboratory confirmed COVID-19 who were within 7 days of diagnosis and at high risk of disease progression were randomly assigned (1:1) to receive colchicine 0·6 mg twice daily for 3 days and then 0·6 mg once daily for 25 days versus usual care, and in a second (1:1) randomisation to receive aspirin 100 mg once daily for 28 days versus usual care. Investigators and patients were not masked to treatment allocation. The primary outcome was assessed at 45 days in the intention-to-treat population; for the colchicine randomisation it was hospitalisation or death, and for the aspirin randomisation it was major thrombosis, hospitalisation, or death. The ACT outpatient trial is registered at ClinicalTrials.gov, NCT04324463 and is ongoing. FINDINGS: Between Aug 27, 2020, and Feb 10, 2022, 3917 patients were randomly assigned to colchicine or control and to aspirin or control; after excluding 36 patients due to administrative reasons 3881 individuals were included in the analysis (n=1939 colchicine vs n=1942 control; n=1945 aspirin vs 1936 control). Follow-up was more than 99% complete. Overall event rates were 5 (0·1%) of 3881 for major thrombosis, 123 (3·2%) of 3881 for hospitalisation, and 23 (0·6%) of 3881 for death; 66 (3·4%) of 1939 patients allocated to colchicine and 65 (3·3%) of 1942 patients allocated to control experienced hospitalisation or death (hazard ratio [HR] 1·02, 95% CI 0·72-1·43, p=0·93); and 59 (3·0%) of 1945 of patients allocated to aspirin and 73 (3·8%) of 1936 patients allocated to control experienced major thrombosis, hospitalisation, or death (HR 0·80, 95% CI 0·57-1·13, p=0·21). Results for the primary outcome were consistent in all prespecified subgroups, including according to baseline vaccination status, timing of randomisation in relation to onset of symptoms (post-hoc analysis), and timing of enrolment according to the phase of the pandemic (post-hoc analysis). There were more serious adverse events with colchicine than with control (34 patients [1·8%] of 1939 vs 27 [1·4%] of 1942) but none in either group that led to discontinuation of study interventions. There was no increase in serious adverse events with aspirin versus control (31 [1·6%] vs 31 [1·6%]) and none that led to discontinuation of study interventions. INTERPRETATION: The results provide no support for the use of colchicine or aspirin to prevent disease progression or death in outpatients with COVID-19. FUNDING: Canadian Institutes for Health Research, Bayer, Population Health Research Institute, Hamilton Health Sciences Research Institute, and Thistledown Foundation. TRANSLATIONS: For the Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

Colchicine and the combination of rivaroxaban and aspirin in patients hospitalised with COVID-19 (ACT): an open-label, factorial, randomised, controlled trial.

BACKGROUND: COVID-19 disease is accompanied by a dysregulated immune response and hypercoagulability. The Anti-Coronavirus Therapies (ACT) inpatient trial aimed to evaluate anti-inflammatory therapy with colchicine and antithrombotic therapy with the combination of rivaroxaban and aspirin for prevention of disease progression in patients hospitalised with COVID-19. METHODS: The ACT inpatient, open-label, 2 × 2 factorial, randomised, controlled trial was done at 62 clinical centres in 11 countries. Patients aged at least 18 years with symptomatic, laboratory confirmed COVID-19 who were within 72 h of hospitalisation or worsening clinically if already hospitalised were randomly assigned (1:1) to receive colchicine 1·2 mg followed by 0·6 mg 2 h later and then 0·6 mg twice daily for 28 days versus usual care; and in a second (1:1) randomisation, to the combination of rivaroxaban 2·5 mg twice daily plus aspirin 100 mg once daily for 28 days versus usual care. Investigators and patients were not masked to treatment allocation. The primary outcome, assessed at 45 days in the intention-to-treat population, for the colchicine randomisation was the composite of the need for high-flow oxygen, mechanical ventilation, or death; and for the rivaroxaban plus aspirin randomisation was the composite of major thrombosis (myocardial infarction, stroke, acute limb ischaemia, or pulmonary embolism), the need for high-flow oxygen, mechanical ventilation, or death. The trial is registered at www. CLINICALTRIALS: gov, NCT04324463 and is ongoing. FINDINGS: Between Oct 2, 2020, and Feb 10, 2022, at 62 sites in 11 countries, 2749 patients were randomly assigned to colchicine or control and the combination of rivaroxaban and aspirin or to the control. 2611 patients were included in the analysis of colchicine (n=1304) versus control (n=1307); 2119 patients were included in the analysis of rivaroxaban and aspirin (n=1063) versus control (n=1056). Follow-up was more than 98% complete. Overall, 368 (28·2%) of 1304 patients allocated to colchicine and 356 (27·2%) of 1307 allocated to control had a primary outcome (hazard ratio [HR] 1·04, 95% CI 0·90-1·21, p=0·58); and 281 (26·4%) of 1063 patients allocated to the combination of rivaroxaban and aspirin and 300 (28·4%) of 1056 allocated to control had a primary outcome (HR 0·92, 95% CI 0·78-1·09, p=0·32). Results were consistent in subgroups defined by vaccination status, disease severity at baseline, and timing of randomisation in relation to onset of symptoms. There was no increase in the number of patients who had at least one serious adverse event for colchicine versus control groups (87 [6·7%] of 1304 vs 90 [6·9%] of 1307) or with rivaroxaban and aspirin versus control groups (85 [8·0%] vs 91 [8·6%]). Among patients assigned to colchicine, 8 (0·61%) had adverse events that led to discontinuation of study drug, mostly gastrointestinal in nature. 17 (1·6%) patients assigned to the combination of rivaroxaban and aspirin had bleeding compared with seven (0·66%) of those allocated to control (p=0·042); the number of serious bleeding events was two (0·19%) versus six (0·57%), respectively (p=0·18). No patients assigned to rivaroxaban and aspirin had serious adverse events that led to discontinuation of study drug. INTERPRETATION: Among patients hospitalised with COVID-19, neither colchicine nor the combination of rivaroxaban and aspirin prevent disease progression or death. FUNDING: Canadian Institutes for Health Research, Bayer, Population Health Research Institute, Hamilton Health Sciences Research Institute, Thistledown Foundation. TRANSLATIONS: For the Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

A Young Female With Thyroid Storm and Pulmonary Embolus: A Case Study.

Thyroid storm (TS) and pulmonary embolus (PE) are both dangerous conditions. We present a case of a 34-year-old woman suffering from both conditions concomitantly. She was given propranolol, propylthiouracil (PTU), potassium iodide (SSKI), hydrocortisone, and heparin, and improved gradually over the course of a 5-day hospitalization. The patient's presentation provided difficulties in diagnosis as well as management. Based on our experience with this case, we recommend that the practitioner refrains from prematurely anchoring on one diagnosis without a full workup for the other, as these conditions can be mutually causative. Also, if the patient meets the criteria for TS, it is important to treat them as such, even in the setting of "unimpressive" thyroid study abnormalities. Finally, it is important to administer a beta blocker in the setting of TS, even in the combined setting of PE, as long as the patient has no evidence of heart strain.

The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans.

Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, identification of the tissue-specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type-specific RNA splicing was discovered and analyzed across tissues within an individual.

The Anti-Coronavirus Therapies (ACT) Trials: Design, Baseline Characteristics, and Challenges.

Background: Effective treatments for COVID-19 are urgently needed, but conducting randomized trials during the pandemic has been challenging. Methods: The Anti-Coronavirus Therapy (ACT) trials are parallel factorial international trials that aimed to enroll 3500 outpatients and 2500 inpatients with symptomatic COVID-19. The outpatient trial is evaluating colchicine vs usual care, and aspirin vs usual care. The primary outcome for the colchicine randomization is hospitalization or death, and for the aspirin randomization, it is major thrombosis, hospitalization, or death. The inpatient trial is evaluating colchicine vs usual care, and the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily vs usual care. The primary outcome for the colchicine randomization is need for high-flow oxygen, need for mechanical ventilation, or death, and for the rivaroxaban plus aspirin randomization, it is major thrombotic events, need for high-flow oxygen, need for mechanical ventilation, or death. Results: At the completion of enrollment on February 10, 2022, the outpatient trial had enrolled 3917 patients, and the inpatient trial had enrolled 2611 patients. Challenges encountered included lack of preliminary data about the interventions under evaluation, uncertainties related to the expected event rates, delays in regulatory and ethics approvals, and in obtaining study interventions, as well as the changing pattern of the COVID-19 pandemic. Conclusions: The ACT trials will determine the efficacy of anti-inflammatory therapy with colchicine, and antithrombotic therapy with aspirin given alone or in combination with rivaroxaban, across the spectrum of mild, moderate, and severe COVID-19. Lessons learned from the conduct of these trials will inform planning of future trials.

Contexte: Il est urgent de mettre au point des traitements efficaces contre la COVID-19, mais il n'est pas facile de réaliser des essais à répartition aléatoire dans un contexte pandémique. Méthodologie: Les essais internationaux factoriels ACT (Anti-Coronavirus Therapy) avaient un objectif d'inscription de 3 500 patients externes et de 2 500 patients hospitalisés présentant une COVID-19 symptomatique. L'essai mené auprès de patients externes visait à évaluer la colchicine par rapport aux soins habituels, et l'aspirine par rapport aux soins habituels. Le paramètre d'évaluation principal au terme de la répartition aléatoire des patients était l'hospitalisation ou le décès dans le groupe traité par la colchicine, et la thrombose majeure, l'hospitalisation ou le décès dans le groupe traité par l'aspirine. L'essai mené auprès de patients hospitalisés visant à évaluer la colchicine par rapport aux soins habituels, et un traitement associant le rivaroxaban à 2,5 mg deux fois par jour et l'aspirine à 100 mg une fois par jour par rapport aux soins habituels. Le paramètre d'évaluation principal au terme de la répartition aléatoire des patients était le recours à l'oxygénothérapie à haut débit ou à la ventilation mécanique ou le décès dans le groupe traité par la colchicine, et la survenue de manifestations thrombotiques majeures, le recours à l'oxygénothérapie à haut débit ou à la ventilation mécanique ou le décès dans le groupe traité par l'association rivaroxaban-aspirine. Résultats: À la fin de la période d'inscription, le 10 février 2022, 3 917 patients externes et 2 611 patients hospitalisés formaient la population des essais. Certains aspects se sont révélés problématiques, notamment le manque de données préliminaires sur les interventions à évaluer, les incertitudes liées aux taux d'événements prévus, les retards touchant les approbations réglementaires et éthiques et les interventions de recherche, de même que l'évolution de la pandémie de COVID-19. Conclusions: Les essais ACT détermineront l'efficacité du traitement anti-inflammatoire par la colchicine et du traitement antithrombotique par l'aspirine, administrée seule ou en association avec le rivaroxaban, contre la COVID-19 légère, modérée ou sévère. Les leçons tirées de ces essais orienteront la planification d'essais ultérieurs.

Equity and Game-Theory Strategies to Promote Gender Diversity and Inclusion in an Academic Health Science Centre.

BACKGROUND: Achieving diversity, inclusion, and gender equity remains an elusive challenge for many institutions worldwide and is understudied in Canadian academic health science centres. METHODS: McMaster University's Department of Medicine undertook surveys and analyses to determine whether there was inequity in leadership positions and salaries, or unprofessional behaviour within the department. Measures of academic productivity in relation to gender for both educators and researchers were analyzed. The department began shifting policies to foster greater gender diversity and inclusion. A revision of the leadership selection process, incorporating tenets of equity and a new game theory-based strategy called Diversitive Agreement Versus Nash Equilibrium (DAvNE) was evaluated. RESULTS: The department's survey revealed underrepresentation of women and people of colour in leadership positions, with perceived barriers to their promotion. Both women and people of colour reported experiencing unprofessional behaviour directed toward them. A gender gap in base salary was observed, with female full professors being paid less. No difference in academic productivity was seen between male and female educators or researchers. The leadership competitions conducted under new selection processes emphasizing diversity resulted in 66% of participating women securing a leadership position, in comparison to 25% of participating men. People of colour made up 27% of members participating in these leadership competitions, but none was successful in obtaining a position. CONCLUSIONS: Diversity and inclusion disparities in the Department of Medicine at McMaster University indicate a need for further efforts and innovation to bring about greater gender and racial equity.

CONTEXTE: La mise en place des conditions nécessaires à la diversité, à l'inclusion et à l'équité des genres demeure un défi difficile à relever pour de nombreux établissements dans le monde entier. C'est une démarche peu étudiée dans les centres universitaires canadiens des sciences de la santé. MÉTHODOLOGIE: Le département de médecine de l'Université McMaster a mené des sondages et des analyses en vue de déterminer s'il existait en son sein même des iniquités en matière d'attribution des postes de direction et de fixation des salaires, ou des comportements non professionnels. Des mesures de la productivité universitaire des éducateurs et des chercheurs ont été analysées en fonction des genres. Le département a entrepris une réforme de ses politiques afin de favoriser une plus grande diversité et inclusion des genres. Une révision du processus de sélection des candidats aux postes de direction, intégrant les principes d'équité et une nouvelle stratégie fondée sur la théorie des jeux appelée Diversitive Agreement Versus Nash Equilibrium (DAvNE [accord de diversité vs équilibre de Nash]), a été évaluée. RÉSULTATS: Le sondage du département a révélé qu'il existait une sous-représentation des femmes et des personnes de couleur parmi les titulaires des postes de direction, ainsi que des obstacles perçus à leur promotion. Tant les femmes que les personnes de couleur ont fait état de comportements non professionnels à leur endroit. Un écart entre les genres a été observé au chapitre de la rémunération de base, les professeurs titulaires de sexe féminin étant moins rémunérées. Aucune différence n'a été observée sur le plan de la productivité universitaire entre les femmes et les hommes au sein de l'effectif des éducateurs et des chercheurs. Les concours pour les postes de direction ont été organisés en fonction de nouveaux processus de sélection mettant l'accent sur la diversité. Au final, 66 % des candidats qui ont vu leur candidature retenue étaient des femmes et 25 %, des hommes. Dans le cadre de ces concours, 27 % des candidats étaient des personnes de couleur, mais aucun n'a réussi à obtenir un poste. CONCLUSIONS: Les disparités notées en matière de diversité et d'inclusion au sein du département de médecine de l'Université McMaster montrent que l'atteinte d'une plus grande équité des genres et des races passe par des efforts et une innovation soutenus.

Accelerometer and GPS Data to Analyze Built Environments and Physical Activity.

Purpose: Most built environment studies have quantified characteristics of the areas around participants' homes. However, the environmental exposures for physical activity (PA) are spatially dynamic rather than static. Thus, merged accelerometer and global positioning system (GPS) data were utilized to estimate associations between the built environment and PA among adults. Methods: Participants (N = 142) were recruited on trails in Massachusetts and wore an accelerometer and GPS unit for 1-4 days. Two binary outcomes were created: moderate-to-vigorous PA (MVPA vs. light PA-to-sedentary); and light-to-vigorous PA (LVPA vs. sedentary). Five built environment variables were created within 50-meter buffers around GPS points: population density, street density, land use mix (LUM), greenness, and walkability index. Generalized linear mixed models were fit to examine associations between environmental variables and both outcomes, adjusting for demographic covariates. Results: Overall, in the fully adjusted models, greenness was positively associated with MVPA and LVPA (odds ratios [ORs] = 1.15, 95% confidence interval [CI] = 1.03, 1.30 and 1.25, 95% CI = 1.12, 1.41, respectively). In contrast, street density and LUM were negatively associated with MVPA (ORs = 0.69, 95% CI = 0.67, 0.71 and 0.87, 95% CI = 0.78, 0.97, respectively) and LVPA (ORs = 0.79, 95% CI = 0.77, 0.81 and 0.81, 95% CI = 0.74, 0.90, respectively). Negative associations of population density and walkability with both outcomes reached statistical significance, yet the effect sizes were small. Conclusions: Concurrent monitoring of activity with accelerometers and GPS units allowed us to investigate relationships between objectively measured built environment around GPS points and minute-by-minute PA. Negative relationships between street density and LUM and PA contrast evidence from most built environment studies in adults. However, direct comparisons should be made with caution since most previous studies have focused on spatially fixed buffers around home locations, rather than the precise locations where PA occurs.

Patient-provider communications about pharmacogenomic results increase patient recall of medication changes.

Effective doctor-patient communication is critical for disease management, especially when considering genetic information. We studied patient-provider communications after implementing a point-of-care pharmacogenomic results delivery system to understand whether pharmacogenomic results are discussed and whether medication recall is impacted. Outpatients undergoing preemptive pharmacogenomic testing (cases), non-genotyped controls, and study providers were surveyed from October 2012-May 2017. Patient responses were compared between visits where pharmacogenomic results guided prescribing versus visits where pharmacogenomics did not guide prescribing. Provider knowledge of pharmacogenomics, before and during study participation, was also analyzed. Both providers and case patients frequently reported discussions of genetic results after visits where pharmacogenomic information guided prescribing. Importantly, medication changes from visits where pharmacogenomics influenced prescribing were more often recalled than non-pharmacogenomic guided medication changes (OR = 3.3 [1.6-6.7], p = 0.001). Case patients who had separate visits where pharmacogenomics did and did not, respectively, influence prescribing more often remembered medication changes from visits where genomic-based guidance was used (OR = 3.4 [1.2-9.3], p = 0.02). Providers also displayed dramatic increases in personal genomic understanding through program participation (94% felt at least somewhat informed about pharmacogenomics post-participation, compared to 61% at baseline, p = 0.04). Using genomic information during prescribing increases patient-provider communications, patient medication recall, and provider understanding of genomics, important ancillary benefits to clinical use of pharmacogenomics.

Accelerometer and GPS Analysis of Trail Use and Associations With Physical Activity.

BACKGROUND: Concurrent use of accelerometers and global positioning system (GPS) data can be used to quantify physical activity (PA) occurring on trails. This study examined associations of trail use with PA and sedentary behavior (SB) and quantified on trail PA using a combination of accelerometer and GPS data. METHODS: Adults (N = 142) wore accelerometer and GPS units for 1-4 days. Trail use was defined as a minimum of 2 consecutive minutes occurring on a trail, based on GPS data. We examined associations between trail use and PA and SB. On trail minutes of light-intensity, moderate-intensity, and vigorous-intensity PA, and SB were quantified in 2 ways, using accelerometer counts only and with a combination of GPS speed and accelerometer data. RESULTS: Trail use was positively associated with total PA, moderate-intensity PA, and light-intensity PA (P < .05). On trail vigorous-intensity PA minutes were 346% higher when classified with the combination versus accelerometer only. Light-intensity PA, moderate-intensity PA, and SB minutes were 15%, 91%, and 85% lower with the combination, respectively. CONCLUSIONS: Adult trail users accumulated more PA on trail use days than on nontrail use days, indicating the importance of these facilities for supporting regular PA. The combination of GPS and accelerometer data for quantifying on trail activity may be more accurate than accelerometer data alone and is useful for classifying intensity of activities such as bicycling.

Prehospital Modified HEART Score Predictive of 30-Day Adverse Cardiac Events.

Introduction The History, Electrocardiogram (ECG), Age, Risk Factors, and Troponin (HEART) score is a decision aid designed to risk stratify emergency department (ED) patients with acute chest pain. It has been validated for ED use, but it has yet to be evaluated in a prehospital setting. Hypothesis A prehospital modified HEART score can predict major adverse cardiac events (MACE) among undifferentiated chest pain patients transported to the ED. METHODS: A retrospective cohort study of patients with chest pain transported by two county-based Emergency Medical Service (EMS) agencies to a tertiary care center was conducted. Adults without ST-elevation myocardial infarction (STEMI) were included. Inter-facility transfers and those without a prehospital 12-lead ECG or an ED troponin measurement were excluded. Modified HEART scores were calculated by study investigators using a standardized data collection tool for each patient. All MACE (death, myocardial infarction [MI], or coronary revascularization) were determined by record review at 30 days. The sensitivity and negative predictive values (NPVs) for MACE at 30 days were calculated. RESULTS: Over the study period, 794 patients met inclusion criteria. A MACE at 30 days was present in 10.7% (85/794) of patients with 12 deaths (1.5%), 66 MIs (8.3%), and 12 coronary revascularizations without MI (1.5%). The modified HEART score identified 33.2% (264/794) of patients as low risk. Among low-risk patients, 1.9% (5/264) had MACE (two MIs and three revascularizations without MI). The sensitivity and NPV for 30-day MACE was 94.1% (95% CI, 86.8-98.1) and 98.1% (95% CI, 95.6-99.4), respectively. CONCLUSIONS: Prehospital modified HEART scores have a high NPV for MACE at 30 days. A study in which prehospital providers prospectively apply this decision aid is warranted. Stopyra JP , Harper WS , Higgins TJ , Prokesova JV , Winslow JE , Nelson RD , Alson RL , Davis CA , Russell GB , Miller CD , Mahler SA . Prehospital modified HEART score predictive of 30-day adverse cardiac events. Prehosp Disaster Med. 2018;33(1):58-62.

Directed assembly of defined oligomeric photosynthetic reaction centres through adaptation with programmable extra-membrane coiled-coil interfaces.

A challenge associated with the utilisation of bioenergetic proteins in new, synthetic energy transducing systems is achieving efficient and predictable self-assembly of individual components, both natural and man-made, into a functioning macromolecular system. Despite progress with water-soluble proteins, the challenge of programming self-assembly of integral membrane proteins into non-native macromolecular architectures remains largely unexplored. In this work it is shown that the assembly of dimers, trimers or tetramers of the naturally monomeric purple bacterial reaction centre can be directed by augmentation with an α-helical peptide that self-associates into extra-membrane coiled-coil bundle. Despite this induced oligomerisation the assembled reaction centres displayed normal spectroscopic properties, implying preserved structural and functional integrity. Mixing of two reaction centres modified with mutually complementary α-helical peptides enabled the assembly of heterodimers in vitro, pointing to a generic strategy for assembling hetero-oligomeric complexes from diverse modified or synthetic components. Addition of two coiled-coil peptides per reaction centre monomer was also tolerated despite the challenge presented to the pigment-protein assembly machinery of introducing multiple self-associating sequences. These findings point to a generalised approach where oligomers or longer range assemblies of multiple light harvesting and/or redox proteins can be constructed in a manner that can be genetically-encoded, enabling the construction of new, designed bioenergetic systems in vivo or in vitro.

Adoption of a clinical pharmacogenomics implementation program during outpatient care--initial results of the University of Chicago "1,200 Patients Project".

Pharmacogenomic testing is viewed as an integral part of precision medicine. To achieve this, we originated The 1,200 Patients Project which offers broad, preemptive pharmacogenomic testing to patients at our institution. We analyzed enrollment, genotype, and encounter-level data from the first year of implementation to assess utility of providing pharmacogenomic results. Results were delivered via a genomic prescribing system (GPS) in the form of traffic lights: green (favorable), yellow (caution), and red (high risk). Additional supporting information was provided as a virtual pharmacogenomic consult, including citation to relevant publications. Currently, 812 patients have participated, representing 90% of those approached; 608 have been successfully genotyped across a custom array. A total of 268 clinic encounters have occurred at which results were accessible via the GPS. At 86% of visits, physicians accessed the GPS, receiving 367 result signals for medications patients were taking: 57% green lights, 41% yellow lights, and 1.4% red lights. Physician click frequencies to obtain clinical details about alerts varied according to color severity (100% of red were clicked, 72% yellow, 20% green). For 85% of visits, clinical pharmacogenomic information was available for at least one drug the patient was taking, suggesting relevance of the delivered information. We successfully implemented an individualized health care model of preemptive pharmacogenomic testing, delivering results along with pharmacogenomic decision support. Patient interest was robust, physician adoption of information was high, and results were routinely utilized. Ongoing examination of a larger number of clinic encounters and inclusion of more physicians and patients is warranted.

Long-term efficacy of modified-release recombinant human thyrotropin augmented radioiodine therapy for benign multinodular goiter: results from a multicenter, international, randomized, placebo-controlled, dose-selection study.

BACKGROUND: Enhanced reduction of multinodular goiter (MNG) can be achieved by stimulation with recombinant human thyrotropin (rhTSH) before radioiodine ((131)I) therapy. The objective was to compare the long-term efficacy and safety of two low doses of modified release rhTSH (MRrhTSH) in combination with (131)I therapy. METHODS: In this phase II, single-blinded, placebo-controlled study, 95 patients (57.2 ± 9.6 years old, 85% women, 83% Caucasians) with MNG (median size 96.0 mL; range 31.9-242.2 mL) were randomized to receive placebo (n=32), 0.01 mg MRrhTSH (n=30), or 0.03 mg MRrhTSH (n=33) 24 hours before a calculated (131)I activity. Thyroid volume (TV) and smallest cross-sectional area of trachea (SCAT) were measured (by computed tomography scan) at baseline, six months, and 36 months. Thyroid function and quality of life (QoL) was evaluated at three-month and yearly intervals respectively. RESULTS: At six months, TV reduction was enhanced in the 0.03 mg MRrhTSH group (32.9% vs. 23.1% in the placebo group; p=0.03) but not in the 0.01 mg MRrhTSH group. At 36 months, the mean percent TV reduction from baseline was 44 ± 12.7% (SD) in the placebo group, 41 ± 21.0% in the 0.01 mg MRrhTSH group, and 53 ± 18.6% in the 0.03 mg MRrhTSH group, with no statistically significant differences among the groups, p=0.105. In the 0.03 mg MRrhTSH group, the subset of patients with basal (131)I uptake <20% had a 24% greater TV reduction at 36 months than the corresponding subset of patients in the placebo group (p=0.01). At 36 months, the largest relative increase in SCAT was observed in the 0.03 mg MRrhTSH group (13.4 ± 23.2%), but this was not statistically different from the increases observed in the placebo or the 0.01 mg MRrhTSH group (p=0.15). Goiter-related symptoms were reduced and QoL improved, without any enhanced benefit from using MRrhTSH. At three years, the prevalence of permanent hypothyroidism was 13%, 33%, and 45% in the placebo, 0.01 mg, and 0.03 mg MRrhTSH groups respectively. The overall safety profile of the study was favorable. CONCLUSIONS: When used as adjuvant to (131)I, enhanced MNG reduction could not be demonstrated with MRrhTSH doses ≤ 0.03 mg, indicating that the lower threshold for efficacy is around this level.

Long-term survival of proximal humerus allografts for reconstruction following resection of malignant bone tumours.

We previously reported early favourable results concerning allograft use in proximal humerus reconstruction following malignancy. We now present the long-term follow-up of patients who underwent tumour resection with massive humeral allograft reconstruction. This is a retrospective review of 8 consecutive patients who underwent massive proximal humeral allograft for primary or secondary bone tumours. The median age at first surgery was 41 years; the median followup is 11.1 years. The overall revision rate of the allografts was 75%. A total of 10 revision procedures were required in this cohort. Five-year survival for implants was 44%; at ten years no implants were intact. Five-year survival for patients was 88%; it was 60% at ten years. In our experience, proximal humerus allograft reconstruction was associated with a high complication rate and resulted in multiple revision procedures in the long-term. We no longer perform or recommend this procedure.

A multi-institutional study exploring the impact of positive mental health on medical students' professionalism in an era of high burnout.

PURPOSE: Although burnout is associated with erosion of professionalism and serious personal consequences, whether positive mental health can enhance professionalism and how it shapes personal experience remain poorly understood. The study simultaneously explores the relationship between positive mental health and burnout with professionalism and personal experience. METHOD: The authors surveyed 4,400 medical students at seven U.S. medical schools in 2009 to assess mental health (categorized as languishing, moderate, and flourishing) and burnout. Additional items explored professional behaviors, beliefs, suicidal ideation, and serious thoughts of dropping out. RESULTS: A total of 2,682/4,400 (61%) responded. Prevalence of suicidal ideation (55/114 [48.2%], 281/1,128 [24.9%], and 127/1,409 [9.1%]) and serious thoughts of dropping out (15/114 [13.2%], 30/1,128 [2.7%], and 14/1,409 [1.0%]) decreased as mental health improved from languishing, moderate, and flourishing, respectively (all P < .0001); this relationship between personal experience and mental health persisted independent of burnout (all P < .001). As mental health improved, the prevalence of unprofessional behaviors (i.e., cheating and dishonest behaviors) also declined, whereas students' altruistic beliefs regarding physicians' responsibility toward society improved. For example, 33/113 (29.2%), 426/1,120 (38.0%), and 718/1,391 (51.6%) of students with languishing, moderate, and flourishing mental health endorsed all five altruistic professional beliefs (P < .0001). The relationship between professional beliefs and mental health persisted among students with burnout, whereas fewer relationships were found among students without burnout. CONCLUSIONS: Findings suggest that positive mental health attenuates some adverse consequences of burnout. Medical student wellness programs should aspire to prevent burnout and promote mental health.