Citations

Background: Immune checkpoint inhibitors (ICIs) are a first-line and perioperative treatment for lung cancer. Pneumonitis is a potentially life-threatening complication of ICI treatment in 2% to 5% of patients; however, risk factors for developing ICI pneumonitis (ICI-p) remain undefined. Methods: We conducted a retrospective cohort study of consecutive patients with lung cancer who received at least one dose of ICI from 2015 through 2020 at The Ohio State University. Pneumonitis cases were documented by the treating oncologist and retrospectively evaluated for agreement between an oncologist and a pulmonologist. Patient demographic and clinical characteristics were recorded and summarized between those with and without pneumonitis for the overall cohort. Univariate and multivariable survival analyses using the Fine-Gray competing risk model were used to examine the associations. Results: A total of 471 patients with lung cancer were included, of which 402 had non–small cell lung cancer and 69 had small cell lung cancer; 39 (8%) patients in the overall cohort developed ICI-p. Preexisting interstitial abnormalities and prior chest radiation were both significantly associated with ICI-p on univariate analysis (hazard ratio [HR], 8.91; 95% CI, 4.69–16.92; P<.001; and HR, 2.81; 95% CI, 1.50–5.28; P=.001). On multivariable analyses, interstitial abnormalities remained a strong independent risk factor for ICI-p when controlling for chest radiation and type of immunotherapy (HR, 9.77; 95% CI, 5.17–18.46; P<.001). Among patients with ICI-p (n=39), those with severe (grade 3–5) pneumonitis had worse overall survival compared with those with mild (grade 1 or 2) pneumonitis (P=.001). Abnormal pulmonary function test results at both 12 and 18 months prior to ICI initiation were not significantly associated with ICI-p. Conclusions: Preexisting interstitial abnormalities on chest CT and prior chest radiation are independent risk factors that are strongly associated with ICI-p in patients with lung cancer. These findings highlight a potential need for closer observation for ICI-p among patients with these risk factors.

Abstract The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs.

Abstract Zinc finger (ZNF) motifs are some of the most frequently occurring domains in the human genome. It was only recently that ZNF proteins emerged as key regulators of genome integrity in mammalian cells. In this study, we report a new role for the Krüppel-type ZNF-containing protein ZNF432 as a novel poly(ADP-ribose) (PAR) reader that regulates the DNA damage response. We show that ZNF432 is recruited to DNA lesions via DNA- and PAR-dependent mechanisms. Remarkably, ZNF432 stimulates PARP-1 activity in vitro and in cellulo. Knockdown of ZNF432 inhibits phospho-DNA-PKcs and increases RAD51 foci formation following irradiation. Moreover, purified ZNF432 preferentially binds single-stranded DNA and impairs EXO1-mediated DNA resection. Consequently, the loss of ZNF432 in a cellular system leads to resistance to PARP inhibitors while its overexpression results in sensitivity. Taken together, our results support the emerging concept that ZNF-containing proteins can modulate PARylation, which can be embodied by the pivotal role of ZNF432 to finely balance the outcome of PARPi response by regulating homologous recombination.

AbstractMagnetic resonance elastography (MRE) is an accurate noninvasive diagnostic tool for assessing the stiffness of parenchymal organs, including the spleen. However, this measurement may be biased due to postprandial changes in splenic stiffness. The aim of the current study was to evaluate postprandial changes in spleen stiffness assessed by MRE in a large sample of healthy volunteers. This was a prospective institutional research ethics board‐approved study. Healthy volunteers with no history of liver disease were recruited for an MRE test and blood draw from December 2018 to July 2019. Each participant underwent spleen MRE after at least 4 h of fasting and again 30 min after a 1000 kcal meal. Also, 14 randomly selected volunteers underwent additional MRE examinations at 1.5 and 2.5 h after food intake. The MRE data were acquired at 60 Hz using a 1.5‐T MRI scanner. The spleen stiffness was assessed using a weighted mean of stiffness values from regions of interest manually drawn on three to five spleen slices. Spearman's rank correlation, Wilcoxon signed‐rank, Friedman, and Mann–Whitney tests were used for statistical analysis. A total of 100 volunteers met the inclusion criteria and were eventually enrolled in this study (age 23 ± 2 years; 65 women). The mean spleen stiffness for the whole group increased by 7.9% (p < 0.001) from the mean ± SD value of 5.09 ± 0.63 (95% CI: 4.96–5.21) kPa in the fasting state to 5.47 ± 0.66 (95% CI 5.34–5.60) kPa 30 min after the meal and then gradually decreased. However, even 2 h 30 min after the meal, the spleen stiffness was higher than in the fasting state. This difference was statistically significant at p less than 0.001. It was concluded that meal intake results in a statistically significant elevation of spleen stiffness that persists for 2.5 h. This finding supports the recommendation for routine fasting for more than 2.5 h prior to assessing MRE‐based spleen stiffness.

ABSTRACT Some marine bacteria can swim at speeds exceeding 50× their body length per second as they actively seek out fleeting microscale nutrient patches. Yet, even in vast marine environments, most micro-organisms live in surface-associated biofilm communities. Such astonishing speeds can pose a serious challenge to initiating biofilm formation, and our understanding of the mechanisms that regulate deceleration is lacking. Calcium, a major constituent of marine ecosystems, promotes biofilm formation in the marine bacterium and opportunistic human pathogen Vibrio vulnificus by increasing cellular levels of the key secondary signaling molecule bis-(3´-5´)-cyclic dimeric guanosine monophosphate (c-di-GMP). Here, we show that elevated c-di-GMP levels inhibit V. vulnificus swimming motility and identify a PilZ domain protein, PlzD, that mediates this effect. PlzD is localized at the flagellar pole in slow-moving, initially adherent, and mature biofilm cells. This positioning was partly dependent on the flagellar stator protein PomA and was regulated by c-di-GMP. Mutating the conserved RXXXR c-di-GMP binding motif of the PilZ domain abrogated PlzD activity. Single-cell tracking of bacterial swimming trajectories revealed that PlzD altered the foraging behavior of cells by slowing swimming speed and by decreasing the number of directional changes, ultimately limiting exploration of the surrounding 3D space. The cumulative effects were increased biofilm formation, aggregation, oyster colonization, and attenuated virulence in mice, phenotypes underpinning the evolution of V. vulnificus as a resilient environmental organism and potent human pathogen. IMPORTANCE Many free-swimming bacteria propel themselves through liquid using rotary flagella, and mounting evidence suggests that the inhibition of flagellar rotation initiates biofilm formation, a sessile lifestyle that is a nearly universal surface colonization paradigm in bacteria. In general, motility and biofilm formation are inversely regulated by the intracellular second messenger bis-(3´-5´)-cyclic dimeric guanosine monophosphate (c-di-GMP). Here, we identify a protein, PlzD, bearing a conserved c-di-GMP binding PilZ domain that localizes to the flagellar pole in a c-di-GMP-dependent manner and alters the foraging behavior, biofilm, and virulence characteristics of the opportunistic human pathogen, Vibrio vulnificus . Our data suggest that PlzD interacts with components of the flagellar stator to decrease bacterial swimming speed and changes in swimming direction, and these activities are enhanced when cellular c-di-GMP levels are elevated. These results reveal a physical link between a second messenger (c-di-GMP) and an effector (PlzD) that promotes transition from a motile to a sessile state in V. vulnificus .

Perioperative cardiac arrest (POCA) is a catastrophic complication that requires immediate recognition and correction of the underlying cause to improve patient outcomes. While the hypoxia, hypovolemia, hydrogen ions (acidosis), hypo-/hyperkalemia, and hypothermia (Hs) and toxins, tamponade (cardiac), tension pneumothorax, thrombosis (pulmonary), and thrombosis (coronary) (Ts) mnemonic is a valuable tool for rapid differential diagnosis, it does not cover all possible causes leading to POCA. To address this limitation, we propose using the preload-contractility-afterload-rate and rhythm (PCARR) construct to categorize POCA, which is comprehensive, systemic, and physiologically logical. We provide evidence for each component in the PCARR construct and emphasize that it complements the Hs and Ts mnemonic rather than replacing it. Furthermore, we discuss the significance of utilizing monitored variables such as electrocardiography, pulse oxygen saturation, end-tidal carbon dioxide, and blood pressure to identify clues to the underlying cause of POCA. To aid in investigating POCA causes, we suggest the Anesthetic care, Surgery, Echocardiography, Relevant Check and History (A-SERCH) list of actions. We recommend combining the Hs and Ts mnemonic, the PCARR construct, monitoring, and the A-SERCH list of actions in a rational manner to investigate POCA causes. These proposals require real-world testing to assess their feasibility.

ObjectiveTo develop evidence‐based consensus recommendations for the optimal timing of hip and knee arthroplasty to improve patient‐important outcomes including, but not limited to, pain, function, infection, hospitalization, and death at 1 year for patients with symptomatic and radiographic moderate‐to‐severe osteoarthritis or advanced symptomatic osteonecrosis with secondary arthritis of the hip or knee who have previously attempted nonoperative therapy, and for whom nonoperative therapy was ineffective, and who have chosen to undergo elective hip or knee arthroplasty (collectively referred to as TJA).MethodsWe developed 13 clinically relevant population, intervention, comparator, outcomes (PICO) questions. After a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the quality of evidence (high, moderate, low, or very low), and evidence tables were created. A Voting Panel, including 13 physicians and patients, discussed the PICO questions until consensus was achieved on the direction (for/against) and strength (strong/conditional) of the recommendations.ResultsThe panel conditionally recommended against delaying TJA to pursue additional nonoperative treatment including physical therapy, nonsteroidal antiinflammatory drugs, ambulatory aids, and intraarticular injections. It conditionally recommended delaying TJA for nicotine reduction or cessation. The panel conditionally recommended delay for better glycemic control for patients who have diabetes mellitus, although no specific measure or level was identified. There was consensus that obesity by itself was not a reason for delay, but that weight loss should be strongly encouraged, and the increase in operative risk should be discussed. The panel conditionally recommended against delay in patients who have severe deformity or bone loss, or in patients who have a neuropathic joint. Evidence for all recommendations was graded as low or very low quality.ConclusionThis guideline provides evidence‐based recommendations regarding the optimal timing of TJA in patients who have symptomatic and radiographic moderate‐to‐severe osteoarthritis or advanced symptomatic osteonecrosis with secondary arthritis for whom nonoperative therapy was ineffective to improve patient‐important outcomes, including pain, function, infection, hospitalization, and death at 1 year. We acknowledge that the evidence is of low quality primarily due to indirectness and hope future research will allow for further refinement of the recommendations.

ObjectiveTo develop evidence‐based consensus recommendations for the optimal timing of hip and knee arthroplasty to improve patient‐important outcomes including, but not limited to, pain, function, infection, hospitalization, and death at 1 year for patients with symptomatic and radiographic moderate‐to‐severe osteoarthritis or advanced symptomatic osteonecrosis with secondary arthritis of the hip or knee who have previously attempted nonoperative therapy, and for whom nonoperative therapy was ineffective, and who have chosen to undergo elective hip or knee arthroplasty (collectively referred to as TJA).MethodsWe developed 13 clinically relevant population, intervention, comparator, outcomes (PICO) questions. After a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the quality of evidence (high, moderate, low, or very low), and evidence tables were created. A Voting Panel, including 13 physicians and patients, discussed the PICO questions until consensus was achieved on the direction (for/against) and strength (strong/conditional) of the recommendations.ResultsThe panel conditionally recommended against delaying TJA to pursue additional nonoperative treatment including physical therapy, nonsteroidal antiinflammatory drugs, ambulatory aids, and intraarticular injections. It conditionally recommended delaying TJA for nicotine reduction or cessation. The panel conditionally recommended delay for better glycemic control for patients who have diabetes mellitus, although no specific measure or level was identified. There was consensus that obesity by itself was not a reason for delay, but that weight loss should be strongly encouraged, and the increase in operative risk should be discussed. The panel conditionally recommended against delay in patients who have severe deformity or bone loss, or in patients who have a neuropathic joint. Evidence for all recommendations was graded as low or very low quality.ConclusionThis guideline provides evidence‐based recommendations regarding the optimal timing of TJA in patients who have symptomatic and radiographic moderate‐to‐severe osteoarthritis or advanced symptomatic osteonecrosis with secondary arthritis for whom nonoperative therapy was ineffective to improve patient‐important outcomes, including pain, function, infection, hospitalization, and death at 1 year. We acknowledge that the evidence is of low quality primarily due to indirectness and hope future research will allow for further refinement of the recommendations.

AbstractBackgroundParticipation in colonoscopies is an essential aspect of endoscopic training. The purpose of this study was to explore the impact of fellow/trainee participation on colonoscopy outcomes.MethodsThis meta‐analysis was registered on the International Prospective Register of Systematic Reviews (PROSPERO). From database inception to July 2022, studies investigating fellow involvement and colonoscopy outcomes were searched across Cochrane library, PubMed, and other databases. The random‐effects model was applied to generate more conservative estimates. Sensitive analysis was conducted to explore whether the result would depend on a particular study. Egger's test and Begg's test were used to estimate the potential for publication bias.ResultsSeventeen studies including 30,062 participants were included. We found that fellow/trainee involvement enhanced the overall rates of adenoma detection and polyp detection (OR = 1.26, 95% CI = 1.14–1.40, p < 0.001; OR = 1.29, 95% CI = 1.02–1.63, p = 0.020, respectively). The mean number of adenoma/polyps per colonoscopy was also higher with fellow/trainee participation (MD = 0.12, 95% CI = 0.08–0.17, p < 0.001; MD = 0.15, 95% CI = 0.02–0.28, p = 0.020, respectively).ConclusionIn addition to its educational purpose, fellow or trainee involvement is associated with beneficial effects on colonoscopy outcomes.