Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial.

OBJECTIVES: To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti-interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia. DESIGN: Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. SETTING: Hospitals in North America and Europe. PATIENTS: Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care. INTERVENTION: Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo. MEASUREMENTS AND MAIN RESULTS: Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomization) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Modeling in the placebo arm showed all candidate biomarkers except lactate dehydrogenase and d-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modeling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction, p = 0.03), mechanical ventilation (predictive interaction, p = 0.01), and clinical status (predictive interaction, p = 0.02) compared with placebo. CONCLUSIONS: Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28.

Congenital lipodystrophy induces severe osteosclerosis.

Berardinelli-Seip congenital generalized lipodystrophy is associated with increased bone mass suggesting that fat tissue regulates the skeleton. Because there is little mechanistic information regarding this issue, we generated "fat-free" (FF) mice completely lacking visible visceral, subcutaneous and brown fat. Due to robust osteoblastic activity, trabecular and cortical bone volume is markedly enhanced in these animals. FF mice, like Berardinelli-Seip patients, are diabetic but normalization of glucose tolerance and significant reduction in circulating insulin fails to alter their skeletal phenotype. Importantly, the skeletal phenotype of FF mice is completely rescued by transplantation of adipocyte precursors or white or brown fat depots, indicating that adipocyte derived products regulate bone mass. Confirming such is the case, transplantation of fat derived from adiponectin and leptin double knockout mice, unlike that obtained from their WT counterparts, fails to normalize FF bone. These observations suggest a paucity of leptin and adiponectin may contribute to the increased bone mass of Berardinelli-Seip patients.

Nurse Telephonic Triage Service for After-hour Patient Calls in Neurosurgery.

OBJECTIVE: The aim of this study was to report the utilization and experience of the nurse telephonic triage service for after-hour patient calls in Neurosurgery. BACKGROUND: It is challenging for patients to reach their clinicians after-hours in a timely manner. This may result in worse health outcomes for the patients, or inappropriate utilization of emergency rooms and urgent care facilities. Physicians continue to remain overwhelmed with frequent after-hours calls in addition to other clinical responsibilities while on-call. METHODS: In August 2015, our institution launched the Clinical Advice Service (CAS) to provide a patient-centric, nurse-run telephone triage service for after-hour calls from Neurosurgery patients. Clinical protocols were created for use by CAS staff by Neurosurgery clinicians. RESULTS: Between July 2016 and June 2017, CAS has accepted 1021 after-hours calls from Neurosurgery patients. A total of 71.4% of these calls were clinical, and the remaining nonclinical (directions, appointments, general information). CAS escalated 37.3% of the calls to the on-call Neurosurgery physician; 4.8% Neurosurgery patients were triaged to the emergency room by CAS. CONCLUSION: CAS has been able to provide well-coordinated care to Neurosurgery patients while reducing physician workload.

Surgical Comanagement by Hospitalists Improves Patient Outcomes: A Propensity Score Analysis.

OBJECTIVE: The aim of the study was to examine the impact of a surgical comanagement (SCM) hospitalist program on patient outcomes at an academic institution. BACKGROUND: Prior studies may have underestimated the impact of SCM due to methodological shortcomings. METHODS: This is a retrospective study utilizing a propensity score-weighted intervention (n = 16,930) and control group (n = 3695). Patients were admitted between January 2009 to July 2012 (pre-SCM) and September 2012 to September 2013 (post-SCM) to Orthopedic or Neurosurgery at our institution. Using propensity score methods, linear regression, and a difference-in-difference approach, we estimated changes in outcomes between pre and post periods, while adjusting for confounding patient characteristics. RESULTS: The SCM intervention was associated with a significant differential decrease in the proportion of patients with at least 1 medical complication [odds ratio (OR) 0.86; 95% confidence interval (CI), 0.74-0.96; P = 0.008), the proportion of patients with length of stay at least 5 days (OR 0.75; 95% CI, 0.67-0.84; P < 0.001), 30-day readmission rate for medical cause (OR 0.67; 95% CI, 0.52-0.81; P < 0.001), and the proportion of patients with at least 2 medical consultants (OR 0.55; 95% CI, 0.49-0.63; P < 0.001). There was no significant change in patient satisfaction (OR 1.08; 95% CI, 0.87-1.33; P = 0.507). We estimated average savings of $2642 to $4303 per patient in the post-SCM group. The overall provider satisfaction with SCM was 88.3%. CONCLUSIONS: The SCM intervention reduces medical complications, length of stay, 30-day readmissions, number of consultants, and cost of care.

Correlating RANK ligand/RANK binding kinetics with osteoclast formation and function.

The interaction between Receptor Activator of NF-κB Ligand (RANKL) and its receptor RANK is essential for the differentiation and bone resorbing capacity of the osteoclast. Osteoprotegerin (OPG), a soluble homodimer, acts as a decoy receptor for RANKL and thus inhibits osteoclastogenesis. An imbalance in the RANKL/RANK/OPG axis, with decreased OPG and/or increased RANKL, is associated with diseases that favor bone loss, including osteoporosis. Recently, we established a yeast surface display system and screened libraries of randomly mutated RANKL proteins to identify mutations that abolish binding to OPG while preserving recognition of RANK. These efforts yielded several RANKL variants possessing substantially higher affinity for RANK compared to their wild-type (WT) counterpart. Using recombinant RANKL mutant proteins, we find those with increased affinity for RANK produce more robust signaling in osteoclast lineage cells and have greater osteoclastogenic potential. Our results are the first to document gain of function RANKL mutations. They indicate that the physiological RANKL/RANK interaction is not optimized for maximal signaling and function, perhaps reflecting the need to maintain receptor specificity within the tumor necrosis factor superfamily (TNFSF). Instead, we find, a biphasic relationship exists between RANKL/RANK affinity and osteoclastogenic capacity. In our panel of RANKL variants, this relationship is driven entirely by manipulation of the kinetic off-rate. Our structure-based and yeast surface display-derived insights into manipulating this critical signaling axis may aid in the design of novel anti-resorptive therapies as well as provide a paradigm for design of other receptor-specific TNF superfamily ligand variants.

Tmem178 Negatively Regulates IL-1ß Production Through Inhibition of the NLRP3 Inflammasome.

OBJECTIVE: Inflammasomes modulate the release of bioactive interleukin (IL)-1ß. Excessive IL-1ß levels are detected in patients with systemic juvenile idiopathic arthritis (sJIA) and cytokine storm syndrome (CSS) with mutated and unmutated inflammasome components, raising questions on the mechanisms of IL-1ß regulation in these disorders. METHODS: To investigate how the NLRP3 inflammasome is modulated in sJIA, we focused on Transmembrane protein 178 (Tmem178), a negative regulator of calcium levels in macrophages, and measured IL-1ß and caspase-1 activation in wild-type (WT) and Tmem178-/- macrophages after calcium chelators, silencing of Stim1, a component of store-operated calcium entry (SOCE), or by expressing a Tmem178 mutant lacking the Stromal Interaction Molecule 1 (Stim1) binding site. Mitochondrial function in both genotypes was assessed by measuring oxidative respiration, mitochondrial reactive oxygen species (mtROS), and mitochondrial damage. CSS development was analyzed in Perforin-/- /Tmem178-/- mice infected with lymphocytic choriomeningitis virus (LCMV) in which inflammasome or IL-1ß signaling was pharmacologically inhibited. Human TMEM178 and IL1B transcripts were analyzed in data sets of whole blood and peripheral blood monocytes from healthy controls and patients with active sJIA. RESULTS: TMEM178 levels are reduced in whole blood and monocytes from patients with sJIA while IL1B levels are increased. Accordingly, Tmem178-/- macrophages produce elevated IL-1ß compared with WT cells. The elevated intracellular calcium levels after SOCE activation in Tmem178-/- macrophages induce mitochondrial damage, release mtROS, and ultimately promote NLRP3 inflammasome activation. In vivo, inhibition of inflammasome or IL-1ß neutralization prolongs Tmem178-/- mouse survival in LCMV-induced CSS. CONCLUSION: Down-regulation of TMEM178 levels may represent a marker of disease activity and help identify patients who could benefit from inflammasome targeting.

Adapted large language models can outperform medical experts in clinical text summarization.

Analyzing vast textual data and summarizing key information from electronic health records imposes a substantial burden on how clinicians allocate their time. Although large language models (LLMs) have shown promise in natural language processing (NLP) tasks, their effectiveness on a diverse range of clinical summarization tasks remains unproven. Here we applied adaptation methods to eight LLMs, spanning four distinct clinical summarization tasks: radiology reports, patient questions, progress notes and doctor-patient dialogue. Quantitative assessments with syntactic, semantic and conceptual NLP metrics reveal trade-offs between models and adaptation methods. A clinical reader study with 10 physicians evaluated summary completeness, correctness and conciseness; in most cases, summaries from our best-adapted LLMs were deemed either equivalent (45%) or superior (36%) compared with summaries from medical experts. The ensuing safety analysis highlights challenges faced by both LLMs and medical experts, as we connect errors to potential medical harm and categorize types of fabricated information. Our research provides evidence of LLMs outperforming medical experts in clinical text summarization across multiple tasks. This suggests that integrating LLMs into clinical workflows could alleviate documentation burden, allowing clinicians to focus more on patient care.

JMIR Perioperative Medicine: A Global Journal for Publishing Interdisciplinary Innovations, Research, and Perspectives.

JMIR Perioperative Medicine supports the dissemination of technological and data science-driven innovative research conducted by interdisciplinary teams in perioperative medicine. We invite contributions on a broad range of topics from clinicians, scientists, and allied health professionals from across the globe.

Tmem178 negatively regulates IL-1ß production through inhibition of the NLRP3 inflammasome.

Objective: Inflammasomes modulate the release of bioactive IL-1ß. Excessive IL-1ß levels are detected in patients with systemic juvenile idiopathic arthritis (sJIA) and cytokine storm syndrome (CSS) with mutated and unmutated inflammasome components, raising questions on the mechanisms of IL-1ß regulation in these disorders. Methods: To investigate how the NLRP3 inflammasome is modulated in sJIA, we focused on Tmem178, a negative regulator of calcium levels in macrophages, and measured IL-1ß and caspase-1 activation in wild-type (WT) and Tmem178 -/- macrophages following calcium chelators, silencing of Stim1, a component of store-operated calcium entry (SOCE), or by expressing a Tmem178 mutant lacking Stim1 binding site. Mitochondrial function in both genotypes was assessed by measuring oxidative respiration, mitochondrial reactive oxygen species (mtROS), and mitochondrial damage. CSS development was analyzed in Perforin -/- /Tmem178 -/- mice infected with LCMV in which inflammasome or IL-1 signaling was pharmacologically inhibited. Human TMEM178 and IL-1B transcripts were analyzed in a dataset of peripheral blood monocytes from healthy controls and active sJIA patients. Results: TMEM178 levels are reduced in monocytes from sJIA patients while IL-1B show increased levels. Accordingly, Tmem178 -/- macrophages produce elevated IL-1ß compared to WT cells. The elevated intracellular calcium levels following SOCE activation in Tmem178 -/- macrophages induce mitochondrial damage, release mtROS, and ultimately, promote NLRP3 inflammasome activation. In vivo , inhibition of inflammasome or IL-1 neutralization prolongs Tmem178 -/- mouse survival to LCMV-induced CSS. Conclusion: Downregulation of Tmem178 levels may represent a new biomarker to identify sJIA/CSS patients that could benefit from receiving drugs targeting inflammasome signaling.

Characteristics associated with diagnostic yield of imaging for deep venous thrombosis and pulmonary embolism in the emergency department, hospital, and office settings: An Optum Clinformatics claims database study (2015-2019).

BACKGROUND: Different patient characteristics influence the decision to order diagnostic imaging for deep venous thrombosis (DVT) and pulmonary embolism (PE) in different settings (emergency department (ED), hospital, and office). Diagnostic yield is defined as the proportion of tests that report positive results. We hypothesize different patient characteristics are associated with higher or lower diagnostic yield of imaging for DVT and PE in different settings. METHODS: We used Optum Clinformatics™ national claims database (2015-2019) to assess the diagnostic yield of imaging for DVT and PE in three settings: (a) ED discharge, (b) Hospitalized, and (c) Office. We studied the patient characteristics associated with diagnostic yield using logistic regression. RESULTS: Diagnostic imaging for DVT and PE was performed in 1,502,417 and 710,263 visits, respectively. Diagnostic yield for DVT and PE was 9.8 ± 0.1 % and 12.7 ± 0.1 %, respectively in the overall cohort. In the ED discharge, hospitalized, and office settings, diagnostic yield for DVT was 10.4 ± 0.1 %, 16.9 ± 0.1 %, and 6.5 ± 0.1 %, respectively, and that for PE 6.4 ± 0.1 %, 18.7 ± 0.1 %, and 8.8 ± 0.2 %, respectively. Of the patients who underwent imaging for DVT, higher diagnostic yield was more likely with thrombophilia, central venous access, and cancer. Of the patients who underwent imaging for PE, higher diagnostic yield was most likely with thrombophilia, respiratory failure, and heart failure or acute myocardial infarction. CONCLUSIONS: In each setting, different patient characteristics influence the diagnostic yield of imaging for DVT and PE and can inform clinical practice. Judicious use of imaging for DVT and PE could reduce costs and avoid exposure to radiation and contrast.

State of research in adult Hospital Medicine: Updated results of a national survey and longitudinal analysis of national data.

We sought to understand the current state of research in adult Hospital Medicine by repeating a 2018 survey of leaders in Hospital Medicine with changes to improve the response rate of surveyed programs. We also analyzed the public sources of federal research funding and MEDLINE-indexed publications from 2010 through 2019 among members of the Society of Hospital Medicine (SHM). Of the 102 contacted leaders of Hospital Medicine groups across the country, 49 responded, for a total response rate of 48%. Among the 3397 faculty members represented in responding programs, 72 (2%) of faculty were identified as conducting research for more than 50% of their time. Respondents noted difficulties at every stage of the research development pipeline, from a lack of mentors to running a fellowship program to a lack of applicants seeking further research training. Improvements to our research training pipeline will be essential to the long-term improvement of our profession.

BAP1 promotes osteoclast function by metabolic reprogramming.

Treatment of osteoporosis commonly diminishes osteoclast number which suppresses bone formation thus compromising fracture prevention. Bone formation is not suppressed, however, when bone degradation is reduced by retarding osteoclast functional resorptive capacity, rather than differentiation. We find deletion of deubiquitinase, BRCA1-associated protein 1 (Bap1), in myeloid cells (Bap1∆LysM), arrests osteoclast function but not formation. Bap1∆LysM osteoclasts fail to organize their cytoskeleton which is essential for bone degradation consequently increasing bone mass in both male and female mice. The deubiquitinase activity of BAP1 modifies osteoclast function by metabolic reprogramming. Bap1 deficient osteoclast upregulate the cystine transporter, Slc7a11, by enhanced H2Aub occupancy of its promoter. SLC7A11 controls cellular reactive oxygen species levels and redirects the mitochondrial metabolites away from the tricarboxylic acid cycle, both being necessary for osteoclast function. Thus, in osteoclasts BAP1 appears to regulate the epigenetic-metabolic axis and is a potential target to reduce bone degradation while maintaining osteogenesis in osteoporotic patients.

Clinical Text Summarization: Adapting Large Language Models Can Outperform Human Experts.

Sifting through vast textual data and summarizing key information from electronic health records (EHR) imposes a substantial burden on how clinicians allocate their time. Although large language models (LLMs) have shown immense promise in natural language processing (NLP) tasks, their efficacy on a diverse range of clinical summarization tasks has not yet been rigorously demonstrated. In this work, we apply domain adaptation methods to eight LLMs, spanning six datasets and four distinct clinical summarization tasks: radiology reports, patient questions, progress notes, and doctor-patient dialogue. Our thorough quantitative assessment reveals trade-offs between models and adaptation methods in addition to instances where recent advances in LLMs may not improve results. Further, in a clinical reader study with ten physicians, we show that summaries from our best-adapted LLMs are preferable to human summaries in terms of completeness and correctness. Our ensuing qualitative analysis highlights challenges faced by both LLMs and human experts. Lastly, we correlate traditional quantitative NLP metrics with reader study scores to enhance our understanding of how these metrics align with physician preferences. Our research marks the first evidence of LLMs outperforming human experts in clinical text summarization across multiple tasks. This implies that integrating LLMs into clinical workflows could alleviate documentation burden, empowering clinicians to focus more on personalized patient care and the inherently human aspects of medicine.

ThPOK Inhibits Osteoclast Formation Via NFATc1 Transcription and Function.

Both LRF (Zbtb7a) and ThPOK (Zbtb7b) belong to the POK (BTB/POZ and Kruppel) family of transcription repressors that participate in development, differentiation, and oncogenesis. Although LRF mediates osteoclast differentiation by regulating NFATc1 expression, the principal established function of ThPOK is transcriptional control of T-cell lineage commitment. Whether ThPOK affects osteoclast formation or function is not known. We find that marrow macrophage ThPOK expression diminishes with exposure to receptor activator of NF-kB ligand (RANKL), but ThPOK deficiency does not affect osteoclast differentiation. On the other hand, enhanced ThPOK, in macrophages, substantially impairs osteoclastogenesis. Excess ThPOK binds the NFATc1 promoter and suppresses its transcription, suggesting a mechanism for its osteoclast inhibitory effect. Despite suppression of osteoclastogenesis by excess ThPOK being associated with diminished NFATc1, osteoclast formation is not rescued by NFATc1 overexpression. Thus, ThPOK appears to inhibit NFATc1 transcription and its osteoclastogenic capacity, while its depletion has no effect on the bone-resorptive cell. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Conditional loss of IKKα in Osterix + cells has no effect on bone but leads to age-related loss of peripheral fat.

NF-κB has been reported to both promote and inhibit bone formation. To explore its role in osteolineage cells, we conditionally deleted IKKα, an upstream kinase required for non-canonical NF-κB activation, using Osterix (Osx)-Cre. Surprisingly, we found no effect on either cancellous or cortical bone, even following mechanical loading. However, we noted that IKKα conditional knockout (cKO) mice began to lose body weight after 6 months of age with severe reductions in fat mass and lower adipocyte size in geriatric animals. qPCR analysis of adipogenic markers in fat pads of cKO mice indicated no difference in early differentiation, but instead markedly lower leptin with age. We challenged young mice with a high fat diet finding that cKO mice gained less weight and showed improved glucose metabolism. Low levels of recombination at the IKKα locus were detected in fat pads isolated from old cKO mice. To determine whether recombination occurs in adipocytes, we examined fat pads in Osx-Cre;TdT reporter mice; these showed increasing Osx-Cre-mediated expression in peripheral adipocytes from 6 weeks to 18 months. Since Osx-Cre drives recombination in peripheral adipocytes with age, we conclude that fat loss in cKO mice is most likely caused by progressive deficits of IKKα in adipocytes.

Utilization of a National Writing Challenge to Promote Scholarly Work: A Pilot Study.

Background Hospitalists value mentorship and scholarly work, yet often struggle to find time and mentors amid busy clinical workloads. Objective To help catalyze writing for hospitalists nationally, we created a Writing Challenge, where we asked hospitalists to commit to the goal of writing 400 words a day, four days a week, for four weeks. Methods Prospective, programmatic evaluation with daily logs followed by a survey at the completion of the project. The four-week Writing Challenge occurred between June 7 and July 5, 2021. Email invitations to participate in the challenge were disseminated to peer networks, and the challenge was promoted using social media. Participants agreed to attempt to write 400 words per day, four days per week, for four weeks. Results Seventy-four individuals from 28 institutions registered for the Writing Challenge, with 36 (49%) participating in the challenge by logging their writing. Participants wrote an average of 4,372 +/- 4,324 words during the challenge. Sixty-eight percent of the participants reported that their amount of writing increased during the challenge and 50% of the participants stated they planned to publish their work, though many participants (46%) reported struggling to write each day. Conclusions The Writing Challenge is one way to generate increased writing and may result in increased scholarly output for academic hospitalists.

Association between Obesity and Length of COVID-19 Hospitalization: Unexpected Insights from the American Heart Association National COVID-19 Registry.

Background: The mechanism for possible association between obesity and poor clinical outcomes from Coronavirus Disease 2019 (COVID-19) remains unclear. Methods: We analyzed 22,915 adult COVID-19 patients hospitalized from March 2020 to April 2021 to non-intensive care using the American Heart Association National COVID Registry. A multivariable Poisson model adjusted for age, sex, medical history, admission respiratory status, hospitalization characteristics, and laboratory findings was used to calculate length of stay (LOS) as a function of body mass index (BMI). We similarly analyzed 5,327 patients admitted to intensive care for comparison. Results: Relative to normal BMI subjects, overweight, class I obese, and class II obese patients had approximately half-day reductions in LOS (-0.469 days, P<0.01; -0.480 days, P<0.01; -0.578 days, P<0.01, respectively). Conclusion: The model identified a dose-dependent, inverse relationship between BMI category and LOS for COVID-19, which was not seen when the model was applied to critically ill patients.