Hôpital Maisonneuve-Rosemont

BACKGROUND: Patients with diffuse large B-cell lymphoma that is refractory to primary and second-line therapies or that has relapsed after stem-cell transplantation have a poor prognosis. The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study. METHODS: We conducted an international, phase 2, pivotal study of centrally manufactured tisagenlecleucel involving adult patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for or had disease progression after autologous hematopoietic stem-cell transplantation. The primary end point was the best overall response rate (i.e., the percentage of patients who had a complete or partial response), as judged by an independent review committee. RESULTS: A total of 93 patients received an infusion and were included in the evaluation of efficacy. The median time from infusion to data cutoff was 14 months (range, 0.1 to 26). The best overall response rate was 52% (95% confidence interval, 41 to 62); 40% of the patients had complete responses, and 12% had partial responses. Response rates were consistent across prognostic subgroups. At 12 months after the initial response, the rate of relapse-free survival was estimated to be 65% (79% among patients with a complete response). The most common grade 3 or 4 adverse events of special interest included cytokine release syndrome (22%), neurologic events (12%), cytopenias lasting more than 28 days (32%), infections (20%), and febrile neutropenia (14%). Three patients died from disease progression within 30 days after infusion. No deaths were attributed to tisagenlecleucel, cytokine release syndrome, or cerebral edema. No differences between response groups in tumor expression of CD19 or immune checkpoint-related proteins were found. CONCLUSIONS: In this international study of CAR T-cell therapy in relapsed or refractory diffuse large B-cell lymphoma in adults, high rates of durable responses were produced with the use of tisagenlecleucel. (Funded by Novartis; JULIET ClinicalTrials.gov number, NCT02445248 .).

The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.

BACKGROUND: In March 2003, several hospitals in Quebec, Canada, noted a marked increase in the incidence of Clostridium difficile-associated diarrhea. METHODS: In 2004 we conducted a prospective study at 12 Quebec hospitals to determine the incidence of nosocomial C. difficile-associated diarrhea and its complications and a case-control study to identify risk factors for the disease. Isolates of C. difficile were typed by pulsed-field gel electrophoresis and analyzed for binary toxin genes and partial deletions in the toxin A and B repressor gene tcdC. Antimicrobial susceptibility was evaluated in a subgroup of isolates. RESULTS: A total of 1703 patients with 1719 episodes of nosocomial C. difficile-associated diarrhea were identified. The incidence was 22.5 per 1000 admissions. The 30-day attributable mortality rate was 6.9 percent. Case patients were more likely than matched controls to have received fluoroquinolones (odds ratio, 3.9; 95 percent confidence interval, 2.3 to 6.6) or cephalosporins (odds ratio, 3.8; 95 percent confidence interval, 2.2 to 6.6). A predominant strain, resistant to fluoroquinolones, was found in 129 of 157 isolates (82.2 percent), and the binary toxin genes and partial deletions in the tcdC gene were present in 132 isolates (84.1 percent). CONCLUSIONS: A strain of C. difficile that was resistant to fluoroquinolones and had binary toxin and a partial deletion of the tcdC gene was responsible for this outbreak of C. difficile-associated diarrhea. Exposure to fluoroquinolones or cephalosporins was a risk factor.

BACKGROUND: Cholinergic deficits are prominent in patients who have dementia associated with Parkinson's disease. We investigated the effects of the dual cholinesterase inhibitor rivastigmine in such patients. METHODS: Patients in whom mild-to-moderate dementia developed at least 2 years after they received a clinical diagnosis of Parkinson's disease were randomly assigned to receive placebo or 3 to 12 mg of rivastigmine per day for 24 weeks. Primary efficacy variables were the scores for the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC). Secondary clinical outcomes were the scores for the Alzheimer's Disease Cooperative Study-Activities of Daily Living, the 10-item Neuropsychiatric Inventory, the Mini-Mental State Examination, Cognitive Drug Research power of attention tests, the Verbal Fluency test, and the Ten Point Clock-Drawing test. RESULTS: A total of 541 patients were enrolled, and 410 completed the study. The outcomes were better among patients treated with rivastigmine than among those who received placebo; however, the differences between these two groups were moderate and similar to those reported in trials of rivastigmine for Alzheimer's disease. Rivastigmine-treated patients had a mean improvement of 2.1 points in the score for the 70-point ADAS-cog, from a baseline score of 23.8, as compared with a 0.7-point worsening in the placebo group, from a baseline score of 24.3 (P<0.001). Clinically meaningful improvements in the scores for the ADCS-CGIC were observed in 19.8 percent of patients in the rivastigmine group and 14.5 percent of those in the placebo group, and clinically meaningful worsening was observed in 13.0 percent and 23.1 percent, respectively (mean score at 24 weeks, 3.8 and 4.3, respectively; P=0.007). Significantly better outcomes were seen with rivastigmine with respect to all secondary efficacy variables. The most frequent adverse events were nausea (affecting 29.0 percent of patients in the rivastigmine group and 11.2 percent of those in the placebo group, P<0.001), vomiting (16.6 and 1.7 percent, P<0.001), and tremor (10.2 and 3.9 percent, P=0.01). CONCLUSIONS: In this placebo-controlled study, rivastigmine was associated with moderate improvements in dementia associated with Parkinson's disease but also with higher rates of nausea, vomiting, and tremor.

OBJECTIVE: To examine mortality rates in the largest systemic lupus erythematosus (SLE) cohort ever assembled. METHODS: Our sample was a multisite international SLE cohort (23 centers, 9,547 patients). Deaths were ascertained by vital statistics registry linkage. Standardized mortality ratio (SMR; ratio of deaths observed to deaths expected) estimates were calculated for all deaths and by cause. The effects of sex, age, SLE duration, race, and calendar-year periods were determined. RESULTS: The overall SMR was 2.4 (95% confidence interval 2.3-2.5). Particularly high mortality was seen for circulatory disease, infections, renal disease, non-Hodgkin's lymphoma, and lung cancer. The highest SMR estimates were seen in patient groups characterized by female sex, younger age, SLE duration <1 year, or black/African American race. There was a dramatic decrease in total SMR estimates across calendar-year periods, which was demonstrable for specific causes including death due to infections and death due to renal disorders. However, the SMR due to circulatory diseases tended to increase slightly from the 1970s to the year 2001. CONCLUSION: Our data from a very large multicenter international cohort emphasize what has been demonstrated previously in smaller samples. These results highlight the increased mortality rate in SLE patients compared with the general population, and they suggest particular risk associated with female sex, younger age, shorter SLE duration, and black/African American race. The risk for certain types of deaths, primarily related to lupus activity (such as renal disease), has decreased over time, while the risk for deaths due to circulatory disease does not appear to have diminished.

BACKGROUND: Clostridium difficile infection is the leading cause of health care-associated diarrhea, and the bacterium can also be carried asymptomatically. The objective of this study was to identify host and bacterial factors associated with health care-associated acquisition of C. difficile infection and colonization. METHODS: We conducted a 15-month prospective study in six Canadian hospitals in Quebec and Ontario. Demographic information, known risk factors, potential confounding factors, and weekly stool samples or rectal swabs were collected. Pulsed-field gel electrophoresis (PFGE) was performed on C. difficile isolates to determine the genotype. Levels of serum antibodies against C. difficile toxins A and B were measured. RESULTS: A total of 4143 patients were included in the study; 117 (2.8%) and 123 (3.0%) had health care-associated C. difficile infection and colonization, respectively. Older age and use of antibiotics and proton-pump inhibitors were significantly associated with health care-associated C. difficile infection. Hospitalization in the previous 2 months; use of chemotherapy, proton-pump inhibitors, and H(2) blockers; and antibodies against toxin B were associated with health care-associated C. difficile colonization. Among patients with health care-associated C. difficile infection and those with colonization, 62.7% and 36.1%, respectively, had the North American PFGE type 1 (NAP1) strain. CONCLUSIONS: In this study, health care-associated C. difficile infection and colonization were differentially associated with defined host and pathogen variables. The NAP1 strain was predominant among patients with C. difficile infection, whereas asymptomatic patients were more likely to be colonized with other strains. (Funded by the Consortium de Recherche sur le Clostridium difficile.).

Azoles are the mainstay of oral therapy for aspergillosis. Azole resistance in Aspergillus has been reported infrequently. The first resistant isolate was detected in 1999 in Manchester, UK. In a clinical collection of 519 A. fumigatus isolates, the frequency of itraconazole resistance was 5%, a significant increase since 2004 (p<0.001). Of the 34 itraconazole-resistant isolates we studied, 65% (22) were cross-resistant to voriconazole and 74% (25) were cross-resistant to posaconazole. Thirteen of 14 evaluable patients in our study had prior azole exposure; 8 infections failed therapy (progressed), and 5 failed to improve (remained stable). Eighteen amino acid alterations were found in the target enzyme, Cyp51A, 4 of which were novel. A population genetic analysis of microsatellites showed the existence of resistant mutants that evolved from originally susceptible strains, different cyp51A mutations in the same strain, and microalterations in microsatellite repeat number. Azole resistance in A. fumigatus is an emerging problem and may develop during azole therapy.

OBJECTIVE: To evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk. DESIGN: Network meta-analysis. DATA SOURCES: Medline, Embase, and Cochrane CENTRAL up to 11 August 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials comparing SGLT-2 inhibitors or GLP-1 receptor agonists with placebo, standard care, or other glucose lowering treatment in adults with type 2 diabetes with follow up of 24 weeks or longer. Studies were screened independently by two reviewers for eligibility, extracted data, and assessed risk of bias. MAIN OUTCOME MEASURES: Frequentist random effects network meta-analysis was carried out and GRADE (grading of recommendations assessment, development, and evaluation) used to assess evidence certainty. Results included estimated absolute effects of treatment per 1000 patients treated for five years for patients at very low risk (no cardiovascular risk factors), low risk (three or more cardiovascular risk factors), moderate risk (cardiovascular disease), high risk (chronic kidney disease), and very high risk (cardiovascular disease and kidney disease). A guideline panel provided oversight of the systematic review. RESULTS: 764 trials including 421 346 patients proved eligible. All results refer to the addition of SGLT-2 inhibitors and GLP-1 receptor agonists to existing diabetes treatment. Both classes of drugs lowered all cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence). Notable differences were found between the two agents: SGLT-2 inhibitors reduced admission to hospital for heart failure more than GLP-1 receptor agonists, and GLP-1 receptor agonists reduced non-fatal stroke more than SGLT-2 inhibitors (which appeared to have no effect). SGLT-2 inhibitors caused genital infection (high certainty), whereas GLP-1 receptor agonists might cause severe gastrointestinal events (low certainty). Low certainty evidence suggested that SGLT-2 inhibitors and GLP-1 receptor agonists might lower body weight. Little or no evidence was found for the effect of SGLT-2 inhibitors or GLP-1 receptor agonists on limb amputation, blindness, eye disease, neuropathic pain, or health related quality of life. The absolute benefits of these drugs vary substantially across patients from low to very high risk of cardiovascular and renal outcomes (eg, SGLT-2 inhibitors resulted in 3 to 40 fewer deaths in 1000 patients over five years; see interactive decision support tool (https://magicevidence.org/match-it/200820dist/#!/) for all outcomes. CONCLUSIONS: In patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with some differences in benefits and harms. Absolute benefits are determined by individual risk profiles of patients, with clear implications for clinical practice, as reflected in the BMJ Rapid Recommendations directly informed by this systematic review. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019153180.

The small number of hematopoietic stem and progenitor cells in cord blood units limits their widespread use in human transplant protocols. We identified a family of chemically related small molecules that stimulates the expansion ex vivo of human cord blood cells capable of reconstituting human hematopoiesis for at least 6 months in immunocompromised mice. The potent activity of these newly identified compounds, UM171 being the prototype, is independent of suppression of the aryl hydrocarbon receptor, which targets cells with more-limited regenerative potential. The properties of UM171 make it a potential candidate for hematopoietic stem cell transplantation and gene therapy.

Quantitative extraction of high-dimensional mineable data from medical images is a process known as radiomics. Radiomics is foreseen as an essential prognostic tool for cancer risk assessment and the quantification of intratumoural heterogeneity. In this work, 1615 radiomic features (quantifying tumour image intensity, shape, texture) extracted from pre-treatment FDG-PET and CT images of 300 patients from four different cohorts were analyzed for the risk assessment of locoregional recurrences (LR) and distant metastases (DM) in head-and-neck cancer. Prediction models combining radiomic and clinical variables were constructed via random forests and imbalance-adjustment strategies using two of the four cohorts. Independent validation of the prediction and prognostic performance of the models was carried out on the other two cohorts (LR: AUC = 0.69 and CI = 0.67; DM: AUC = 0.86 and CI = 0.88). Furthermore, the results obtained via Kaplan-Meier analysis demonstrated the potential of radiomics for assessing the risk of specific tumour outcomes using multiple stratification groups. This could have important clinical impact, notably by allowing for a better personalization of chemo-radiation treatments for head-and-neck cancer patients from different risk groups.

OBJECTIVE: To evaluate the safety and efficacy of long-term intraarticular (IA) steroid injections for knee pain related to osteoarthritis (OA). METHODS: In a randomized, double-blind trial, 68 patients with OA of the knee received IA injections of triamcinolone acetonide 40 mg (34 patients) or saline (34 patients) into the study knee every 3 months for up to 2 years. The primary outcome variable was radiologic progression of joint space narrowing of the injected knee after 2 years. Measurements of minimum joint space width were performed by an automated computerized method on standardized fluoroscopically guided radiographs taken with the patient standing and with the knee in a semiflexed position. The clinical efficacy measure of primary interest was the pain subscale from the Western Ontario and McMaster Universities OA Index (WOMAC). Efficacy measures of secondary interest were the total score on the WOMAC, physician's global assessment, patient's global assessment, patient's assessment of pain, range of motion (ROM) of the affected knee, and 50-foot walking time. Clinical symptoms were assessed just before each injection. RESULTS: At the 1-year and 2-year followup evaluations, no difference was noted between the two treatment groups with respect to loss of joint space over time. The steroid-injected knees showed a trend toward greater symptom improvement, especially at 1 year, for the WOMAC pain subscale, night pain, and ROM values (P = 0.05) compared with the saline-injected knees. Using area under the curve analyses, knee pain and stiffness were significantly improved throughout the 2-year study by repeated injections of triamcinolone acetonide, but not saline (P < 0.05). CONCLUSION: Our findings support the long-term safety of IA steroid injections for patients with symptomatic knee OA. No deleterious effects of the long-term administration of IA steroids on the anatomical structure of the knee were noted. Moreover, long-term treatment of knee OA with repeated steroid injections appears to be clinically effective for the relief of symptoms of the disease.

BACKGROUND: The immunostimulatory monoclonal antibody elotuzumab plus lenalidomide and dexamethasone has been shown to be effective in patients with relapsed or refractory multiple myeloma. The immunomodulatory agent pomalidomide plus dexamethasone has been shown to be effective in patients with multiple myeloma that is refractory to lenalidomide and a proteasome inhibitor. METHODS: Patients with multiple myeloma that was refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor were randomly assigned to receive elotuzumab plus pomalidomide and dexamethasone (elotuzumab group) or pomalidomide and dexamethasone alone (control group). The primary end point was investigator-assessed progression-free survival. RESULTS: A total of 117 patients were randomly assigned to the elotuzumab group (60 patients) or the control group (57 patients). After a minimum follow-up period of 9.1 months, the median progression-free survival was 10.3 months in the elotuzumab group and 4.7 months in the control group. The hazard ratio for disease progression or death in the elotuzumab group as compared with the control group was 0.54 (95% confidence interval [CI], 0.34 to 0.86; P=0.008). The overall response rate was 53% in the elotuzumab group as compared with 26% in the control group (odds ratio, 3.25; 95% CI, 1.49 to 7.11). The most common grade 3 or 4 adverse events were neutropenia (13% in the elotuzumab group vs. 27% in the control group), anemia (10% vs. 20%), and hyperglycemia (8% vs. 7%). A total of 65% of the patients in each group had infections. Infusion reactions occurred in 3 patients (5%) in the elotuzumab group. CONCLUSIONS: Among patients with multiple myeloma in whom treatment with lenalidomide and a proteasome inhibitor had failed, the risk of progression or death was significantly lower among those who received elotuzumab plus pomalidomide and dexamethasone than among those who received pomalidomide plus dexamethasone alone. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-3 ClinicalTrials.gov number, NCT02654132 .).

The term monoclonal gammopathy of renal significance (MGRS) was introduced by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. The IKMG met in April 2017 to refine the definition of MGRS and to update the diagnostic criteria for MGRS-related diseases. Accordingly, in this Expert Consensus Document, the IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy. The diagnosis of MGRS-related disease is established by kidney biopsy and immunofluorescence studies to identify the monotypic immunoglobulin deposits (although these deposits are minimal in patients with either C3 glomerulopathy or thrombotic microangiopathy). Accordingly, the IKMG recommends a kidney biopsy in patients suspected of having MGRS to maximize the chance of correct diagnosis. Serum and urine protein electrophoresis and immunofixation, as well as analyses of serum free light chains, should also be performed to identify the monoclonal immunoglobulin, which helps to establish the diagnosis of MGRS and might also be useful for assessing responses to treatment. Finally, bone marrow aspiration and biopsy should be conducted to identify the lymphoproliferative clone. Flow cytometry can be helpful in identifying small clones. Additional genetic tests and fluorescent in situ hybridization studies are helpful for clonal identification and for generating treatment recommendations. Treatment of MGRS was not addressed at the 2017 IKMG meeting; consequently, this Expert Consensus Document does not include any recommendations for the treatment of patients with MGRS.

OBJECTIVE: To compare the efficacy and safety of scheduled quetiapine to placebo for the treatment of delirium in critically ill patients requiring as-needed haloperidol. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: Three academic medical centers. PATIENTS: Thirty-six adult intensive care unit patients with delirium (Intensive Care Delirium Screening Checklist score > or = 4), tolerating enteral nutrition, and without a complicating neurologic condition. INTERVENTIONS: Patients were randomized to receive quetiapine 50 mg every 12 hrs or placebo. Quetiapine was increased every 24 hrs (50 to 100 to 150 to 200 mg every 12 hrs) if more than one dose of haloperidol was given in the previous 24 hrs. Study drug was continued until the intensive care unit team discontinued it because of delirium resolution, therapy > or = 10 days, or intensive care unit discharge. MEASUREMENTS AND MAIN RESULTS: Baseline characteristics were similar between the quetiapine (n = 18) and placebo (n = 18) groups. Quetiapine was associated with a shorter time to first resolution of delirium [1.0 (interquartile range [IQR], 0.5-3.0) vs. 4.5 days (IQR, 2.0-7.0; p =.001)], a reduced duration of delirium [36 (IQR, 12-87) vs. 120 hrs (IQR, 60-195; p =.006)], and less agitation (Sedation-Agitation Scale score > or = 5) [6 (IQR, 0-38) vs. 36 hrs (IQR, 11-66; p =.02)]. Whereas mortality (11% quetiapine vs. 17%) and intensive care unit length of stay (16 quetiapine vs. 16 days) were similar, subjects treated with quetiapine were more likely to be discharged home or to rehabilitation (89% quetiapine vs. 56%; p =.06). Subjects treated with quetiapine required fewer days of as-needed haloperidol [3 [(IQR, 2-4)] vs. 4 days (IQR, 3-8; p = .05)]. Whereas the incidence of QTc prolongation and extrapyramidal symptoms was similar between groups, more somnolence was observed with quetiapine (22% vs. 11%; p = .66). CONCLUSIONS: Quetiapine added to as-needed haloperidol results in faster delirium resolution, less agitation, and a greater rate of transfer to home or rehabilitation. Future studies should evaluate the effect of quetiapine on mortality, resource utilization, post-intensive care unit cognition, and dependency after discharge in a broader group of patients.

BACKGROUND: Peritoneal carcinomatosis (PC) from nonovarian malignancies long has been regarded as a terminal disease. Over the past decade, new locoregional therapeutic approaches combining cytoreductive surgery with perioperative intraperitoneal chemotherapy (PIC) have evolved that have demonstrated improved survival. METHODS: A retrospective, multicenter cohort study was performed in French-speaking institutions to evaluate toxicity and principal prognostic factors after cytoreductive surgery and PIC (hyperthermic intraperitoneal chemotherapy [HIPEC] and/or early postoperative intraperitoneal chemotherapy [EPIC]) for PC from nongynecologic malignancies. RESULTS: The study included 1290 patients from 25 institutions who underwent 1344 procedures between February 1989 and December 2007. HIPEC was performed in 1154 procedures. The principal origins of PC were colorectal adenocarcinoma (N = 523), pseudomyxoma peritonei (N = 301), gastric adenocarcinoma (N = 159), peritoneal mesothelioma (N = 88), and appendiceal adenocarcinoma (N = 50). The overall morbidity and mortality rates were 33.6% and 4.1%, respectively. In multivariate analysis, patient age, the extent of PC, and institutional experience had a significant influence on toxicity. The overall median survival was 34 months; and the median survival was 30 months for patients with colorectal PC, not reached for patients with pseudomyxoma peritonei, 9 months for patients with gastric PC, 41 months for patients with peritoneal mesothelioma, and 77 months for patients with PC from appendiceal adenocarcinoma. Independent prognostic indicators in multivariate analysis were institution, origin of PC, completeness of cytoreductive surgery, extent of carcinomatosis, and lymph node involvement. CONCLUSIONS: A therapeutic approach that combined cytoreductive surgery with PIC was able to achieve long-term survival in a selected group of patients who had PC of nonovarian origin and had acceptable morbidity and mortality. The current results indicated that this treatment should be centralized to institutions with expertise in the management of PC.

PurposeFoundation models are a novel type of artificial intelligence algorithms, in which models are pretrained at scale on unannotated data and fine-tuned for a myriad of downstream tasks, such as generating text. This study assessed the accuracy of ChatGPT, a large language model (LLM), in the ophthalmology question-answering space.DesignEvaluation of diagnostic test or technology.ParticipantsChatGPT is a publicly available LLM.MethodsWe tested 2 versions of ChatGPT (January 9 “legacy” and ChatGPT Plus) on 2 popular multiple choice question banks commonly used to prepare for the high-stakes Ophthalmic Knowledge Assessment Program (OKAP) examination. We generated two 260-question simulated exams from the Basic and Clinical Science Course (BCSC) Self-Assessment Program and the OphthoQuestions online question bank. We carried out logistic regression to determine the effect of the examination section, cognitive level, and difficulty index on answer accuracy. We also performed a post hoc analysis using Tukey’s test to decide if there were meaningful differences between the tested subspecialties.Main Outcome MeasuresWe reported the accuracy of ChatGPT for each examination section in percentage correct by comparing ChatGPT’s outputs with the answer key provided by the question banks. We presented logistic regression results with a likelihood ratio (LR) chi-square. We considered differences between examination sections statistically significant at a P value of < 0.05.ResultsThe legacy model achieved 55.8% accuracy on the BCSC set and 42.7% on the OphthoQuestions set. With ChatGPT Plus, accuracy increased to 59.4% ± 0.6% and 49.2% ± 1.0%, respectively. Accuracy improved with easier questions when controlling for the examination section and cognitive level. Logistic regression analysis of the legacy model showed that the examination section (LR, 27.57; P = 0.006) followed by question difficulty (LR, 24.05; P < 0.001) were most predictive of ChatGPT’s answer accuracy. Although the legacy model performed best in general medicine and worst in neuro-ophthalmology (P < 0.001) and ocular pathology (P = 0.029), similar post hoc findings were not seen with ChatGPT Plus, suggesting more consistent results across examination sections.ConclusionChatGPT has encouraging performance on a simulated OKAP examination. Specializing LLMs through domain-specific pretraining may be necessary to improve their performance in ophthalmic subspecialties.Financial Disclosure(s)Proprietary or commercial disclosure may be found after the references. Foundation models are a novel type of artificial intelligence algorithms, in which models are pretrained at scale on unannotated data and fine-tuned for a myriad of downstream tasks, such as generating text. This study assessed the accuracy of ChatGPT, a large language model (LLM), in the ophthalmology question-answering space. Evaluation of diagnostic test or technology. ChatGPT is a publicly available LLM. We tested 2 versions of ChatGPT (January 9 “legacy” and ChatGPT Plus) on 2 popular multiple choice question banks commonly used to prepare for the high-stakes Ophthalmic Knowledge Assessment Program (OKAP) examination. We generated two 260-question simulated exams from the Basic and Clinical Science Course (BCSC) Self-Assessment Program and the OphthoQuestions online question bank. We carried out logistic regression to determine the effect of the examination section, cognitive level, and difficulty index on answer accuracy. We also performed a post hoc analysis using Tukey’s test to decide if there were meaningful differences between the tested subspecialties. We reported the accuracy of ChatGPT for each examination section in percentage correct by comparing ChatGPT’s outputs with the answer key provided by the question banks. We presented logistic regression results with a likelihood ratio (LR) chi-square. We considered differences between examination sections statistically significant at a P value of < 0.05. The legacy model achieved 55.8% accuracy on the BCSC set and 42.7% on the OphthoQuestions set. With ChatGPT Plus, accuracy increased to 59.4% ± 0.6% and 49.2% ± 1.0%, respectively. Accuracy improved with easier questions when controlling for the examination section and cognitive level. Logistic regression analysis of the legacy model showed that the examination section (LR, 27.57; P = 0.006) followed by question difficulty (LR, 24.05; P < 0.001) were most predictive of ChatGPT’s answer accuracy. Although the legacy model performed best in general medicine and worst in neuro-ophthalmology (P < 0.001) and ocular pathology (P = 0.029), similar post hoc findings were not seen with ChatGPT Plus, suggesting more consistent results across examination sections. ChatGPT has encouraging performance on a simulated OKAP examination. Specializing LLMs through domain-specific pretraining may be necessary to improve their performance in ophthalmic subspecialties.

Abstract The utility of X-inactivation based clonality assays for evaluation of human neoplasia is well-documented. However, excessive Lyonization is a potential limitation of these assays, because it mimics clonal derivation of cells. The incidence of excessive Lyonization in healthy females is controversial, with reported incidence varying from 4% to 33%. Several explanations have been offered for the observed variation, including different criteria for excessive Lyonization, diversity of X- linked clonality assays, small population sizes and more recently, tissue specificity of X-inactivation patterns. However, it is also possible that stem cell depletion, clonal hematopoiesis, or selection pressures on blood cells results in an increased incidence of excessive skewing. If any of the latter is true, then the incidence of excessive skewing should increase with age in blood cells. To test this hypothesis, we determined X-inactivation ratios at the human androgen receptor locus of 295 normal females from three age groups: (1) neonates, (2) females 28 to 32 years old and, (3) females aged &gt; or = 60 years. The incidence of skewing (allele ratios &gt; or = 3:1) was 8.6% (14 of 162) in neonates (P = .104 v 28 to 32); 16.4% (11/67) in 28 to 32 y.o. (P = .0064 v &gt; or = 60), and 37.9% (25 of 66) in women &gt; or = 60 y.o. (P &lt; .0001 v neonates). When a more stringent criterion for skewing was used (allele ratios &gt; or = 10:1), the incidence was 1.9% (3 of 162) in neonates (P = .362 v 28 to 32), 4.5% (3 of 67) in 28 to 32 y.o. (P = .0022 v &gt; or = 60), and 22.7% (15 of 66) in &gt; or = 60 y.o. group (P &lt; .0001 v neonates). Results have been confirmed at the phosphoglycerate kinase locus for 48 heterozygous females. The incidence of excessive skewing increases with age. In neonates, the incidence is low and may correspond to true excessive Lyonization. Acquired skewing occurs with aging in normal females and is present in 38% of females over the age of 60. Further studies are needed to determine whether acquired skewing is a consequence of stem cell depletion, true clonal hematopoiesis, growth advantage conferred by parental-specific X-chromosomes, or other causes. These data provide an explanation for variation in reported incidence of excessive skewing in normal females. Furthermore, these findings suggest that any study of clonality using X-inactivation based assays should incorporate age- matched controls for Lyonization.

The immune system is a complex set of physiological mechanisms whose general aim is to defend the organism against non-self-bodies, such as pathogens (bacteria, viruses, parasites), as well as cancer cells. Circadian rhythms are endogenous 24-h variations found in virtually all physiological processes. These circadian rhythms are generated by circadian clocks, located in most cell types, including cells of the immune system. This review presents an overview of the clocks in the immune system and of the circadian regulation of the function of immune cells. Most immune cells express circadian clock genes and present a wide array of genes expressed with a 24-h rhythm. This has profound impacts on cellular functions, including a daily rhythm in the synthesis and release of cytokines, chemokines and cytolytic factors, the daily gating of the response occurring through pattern recognition receptors, circadian rhythms of cellular functions such as phagocytosis, migration to inflamed or infected tissue, cytolytic activity, and proliferative response to antigens. Consequently, alterations of circadian rhythms (e.g., clock gene mutation in mice or environmental disruption similar to shift work) lead to disturbed immune responses. We discuss the implications of these data for human health and the areas that future research should aim to address.

BACKGROUND: Reported sensitivity of the galactomannan enzyme immunoassay as an early diagnostic test for invasive aspergillosis (IA) has been widely variable, ranging from 29% to 100% in earlier clinical studies. METHODS: Studies performed to date have analyzed performance using per-patient calculations, limiting their ability to measure the impact of clinical variables that change over time, such as receipt of preventive antifungal therapy. In our study, performance of the test was calculated in per-patient and per-test analyses in a large cohort of patients at high risk for IA from 2 North American centers. A total of 272 serum samples obtained from 46 patients with IA and 3005 serum samples obtained from 269 control patients were analyzed using multiple index cutoff values to define positivity. RESULTS: Per-patient calculations yielded sensitivities of 43% and 70% using index cutoff values of 1.5 and 0.5, respectively; specificity decreased from 93% with use of the 1.5 index cutoff to 70% with use of the 0.5 index cutoff. Per-test calculations yielded sensitivities of 31% and 59% and specificities of 99% and 92% using index cutoff values of 1.5 and 0.5, respectively. Receipt of mold-active antifungal drugs on the day of testing decreased sensitivity; samples obtained from patients not receiving prophylactic or empirical antifungal drugs yielded a sensitivity of 89% and a specificity of 92% (with use of an index cutoff value of 0.5). CONCLUSIONS: These findings have direct implications for preventive strategies, because the diagnostic utility of the antigen assay is compromised during receipt of prophylactic or empirical antifungal therapies.

The utility of X-inactivation based clonality assays for evaluation of human neoplasia is well-documented. However, excessive Lyonization is a potential limitation of these assays, because it mimics clonal derivation of cells. The incidence of excessive Lyonization in healthy females is controversial, with reported incidence varying from 4% to 33%. Several explanations have been offered for the observed variation, including different criteria for excessive Lyonization, diversity of X-linked clonality assays, small population sizes and more recently, tissue specificity of X-inactivation patterns. However, it is also possible that stem cell depletion, clonal hematopoiesis, or selection pressures on blood cells results in an increased incidence of excessive skewing. If any of the latter is true, then the incidence of excessive skewing should increase with age in blood cells. To test this hypothesis, we determined X-inactivation ratios at the human androgen receptor locus of 295 normal females from three age groups: (1) neonates, (2) females 28 to 32 years old and, (3) females aged > or = 60 years. The incidence of skewing (allele ratios > or = 3:1) was 8.6% (14 of 162) in neonates (P = .104 v 28 to 32); 16.4% (11/67) in 28 to 32 y.o. (P = .0064 v > or = 60), and 37.9% (25 of 66) in women > or = 60 y.o. (P < .0001 v neonates). When a more stringent criterion for skewing was used (allele ratios > or = 10:1), the incidence was 1.9% (3 of 162) in neonates (P = .362 v 28 to 32), 4.5% (3 of 67) in 28 to 32 y.o. (P = .0022 v > or = 60), and 22.7% (15 of 66) in > or = 60 y.o. group (P < .0001 v neonates). Results have been confirmed at the phosphoglycerate kinase locus for 48 heterozygous females. The incidence of excessive skewing increases with age. In neonates, the incidence is low and may correspond to true excessive Lyonization. Acquired skewing occurs with aging in normal females and is present in 38% of females over the age of 60. Further studies are needed to determine whether acquired skewing is a consequence of stem cell depletion, true clonal hematopoiesis, growth advantage conferred by parental-specific X-chromosomes, or other causes. These data provide an explanation for variation in reported incidence of excessive skewing in normal females. Furthermore, these findings suggest that any study of clonality using X-inactivation based assays should incorporate age-matched controls for Lyonization.