Publications by Year: 2025

OBJECTIVES: People with serious illness approaching end of life often end up in emergency and hospital care, frequently against expressed preferences. Consequently, oncology trials record care days as a measure of treatment burden called "time toxicity." However, this measure ignores the diminishing marginal utility of time: that the value of a day is higher when fewer remain. We aimed to incorporate this relationship into time toxicity.

METHODS: We derived a preference-independent time-toxicity metric sensitive to time remaining, end-weighted time toxicity. It has units of toxiles and is based on the fraction of the patient's remaining time taken up by a care visit. We trialed this metric in a cohort of Swedish cancer patients referred to palliative care.

RESULTS: There were 192 patients in the cohort; 146 (76%) eventually enrolled in palliative care. In the cohort, mean (SD, skewness) and median (IQR) end-weighted time toxicities were 0.63 (0.89, 1.77) and 0.23 (0.03-0.81) toxiles. End-weighted time toxicity was significantly less for the group eventually enrolled in palliative care (0.52 [0.75] and 0.22 [0.04-0.63] toxiles) than for the never enrolled group (0.97 [1.18] and 0.27 [0.27-1.76] toxiles) (P = .024). A time-series analysis showed that total toxicity in never- or not-yet-enrolled patients was 120.2 toxiles, whereas total toxicity in already-enrolled patients was 1.0 toxiles.

CONCLUSIONS: A healthcare metric that incorporates diminishing marginal utility of time can highlight the effect of palliative care and could improve resource allocation and patient satisfaction with care near end of life. Further research should explore stakeholder perspectives and practical applications.

Recent evidence highlights the significance of a new type of tumour suppressors, which are not frequently mutated but inhibited by metabolic cues in cancers. Here, we identify BATF2 as a tumour suppressor whose expression is epigenetically silenced by glutamine in Head and Neck Squamous Cell Carcinomas (HNSCC). BATF2 correlates with type-I interferon and Th1 signatures in human HNSCC, with correlation coefficients even stronger than those of the positive control, STING. The phosphorylation of BATF2 at serine 227 promotes the oligomerization of STING. BATF2 deficiency or high glutamine levels result in higher oxygen consumption rates and metabolic profiles unfavorable for type-I interferon production. An isocaloric glutamine-rich diet abolishes STING-mediated effector cell expansion in tumours, weakening STING agonist-induced tumour control. Cancer cell-specific BATF2 expression promotes an Id2-centered T-cell effector signature, reduces T-cell exhaustion, and triggers spontaneous HNSCC rejection in a type-I interferon-dependent fashion. Utilizing syngeneic subcutaneous, orthotopic, and 24-week-long cigarette smoke carcinogen-induced HNSCC models, we demonstrate that host Batf2 deficiency results in increased infiltration of CD206+ myeloid cells and reduced effector CD8+ T-cells, accelerating the initiation of cancers. Overall, we reveal a tumour suppressor BATF2 whose loss is mediated by unique metabolic cues in the TME and drives cancer immune escape.

Although computational models have deepened our understanding of neuroscience, it is still highly challenging to link actual low-level physiological activity (spiking, field potentials) and biochemistry (transmitters and receptors) directly with high-level cognitive abilities (decision-making, working memory) and associated disorders. Here, we introduce a mechanistically accurate multi-scale model directly generating simulated physiology from which extended neural and cognitive phenomena emerge. The model produces spiking, fields, phase synchronies, and synaptic change, directly generating working memory, decisions, and categorization. These were then validated on extensive experimental macaque data from which the model received no prior training of any kind. Moreover, the simulation uncovered a previously unknown neural code ("incongruent neurons") that specifically predicts upcoming erroneous behaviors, also subsequently confirmed in empirical data. The biomimetic model thus directly and predictively links decision and reinforcement signals, of computational interest, with spiking and field codes, of neurobiological importance.

OBJECTIVES: To analyze obstetric ultrasound utilization and expenditures per live birth delivery among the commercially insured from 2016 to 2022 and present updated trends and variation in use by type of ultrasound and across subgroups.

METHODS: In this retrospective United States-based cohort study, obstetric ultrasound utilization and expenditures during pregnancy were measured for a cohort of all deliveries with at least 28-week gestation that resulted in a live birth between January 1, 2017 and December 31, 2022, using the Health Care Cost Institute commercial claims database. We report utilization trends and the clinical and sociodemographic factors correlated with utilization using descriptive statistics and negative binomial regression.

RESULTS: In our sample of 1,731,823 pregnancies, there were an average of 5.3 (SD ± 3.9) claims for obstetric ultrasounds per live birth delivery. After adjusting for covariates, the number of ultrasounds per live birth increased by 8.3% and inflation-adjusted spending for these ultrasounds increased 5.6% over the 7-year study period (p < .001); though utilization decreased during the COVID-19 pandemic in 2020. Follow-up ultrasound (CPT 76816) was the fastest growing procedure.

CONCLUSION: Obstetric ultrasound utilization and expenditures increased from 2016 to 2022. Information on the variation in patterns and trends related to obstetric ultrasound use may assist policy makers in their assessment of resource utilization and approach to reimbursement design, such as obstetric bundled payments.

INTRODUCTION: Increasing the diversity of medical students is a challenge and priority in many countries. In France, systems-level changes have been introduced to attract candidates from diverse backgrounds, specifically the traditional pathway to medical studies, the PASS (Parcours Accès Spécifique Santé/Specific Access to Health Training, biomedical sciences-focused) has been supplemented with a second pathway, the LAS (Licence Accès Santé/Bachelor's Degree with Access to Health Studies) combining a broader major with a health-access module. This study is the first to assess the effectiveness of the LAS in increasing the social, geographic, and sex diversity of candidates admitted to Medical or Dental Schools in France.

METHODS: This prospective cohort included candidates to health studies. Socioeconomic origin was determined according to parents' profession. Primary outcome was admission to Medical or Dental School. Mediation analysis assessed the role of prior academic performance (assessed by the French Baccalaureate grade) between socioeconomic origin and admission.

RESULTS: Among 2,059 candidates (women: 70%), 230/1,534 PASS (15% of admission, women: 55%, upper socioeconomic origin: 68%) and 43/525 LAS (8% of admission, women: 74%, upper socioeconomic origin: 49%) were admitted to Medical or Dental School. In multivariable logistic regression, sex (OR = 0.37 for women, 95%CI [0.26-0.53], p<.001), upper socioeconomic origin (OR = 1.78, 95%CI [1.20-2.64], p<.01), and prior academic performance predicted admission in PASS (OR = 5.57, 95%CI [2.90-10.7], p<.001). In LAS, only prior academic performance was independently associated with admission (OR = 8.93, 95%CI [3.99-20.0], p<.001). Prior academic performance partially mediated the effect of socioeconomic origin on admission in PASS, and fully mediated the effect in LAS.

DISCUSSION: Introducing the LAS pathway measurably improved diversity among admitted students and reduced socioeconomic and sex-related disparities. In contrast, the historical PASS system continues to reinforce these inequities. By widening the academic lens used for selection, LAS shows that reforms can meaningfully counteract social reproduction while maintaining academic rigor.

DESCRIPTION: Babesiosis is a tick-borne disease that is endemic in the United States (US). The major species, Babesia microti, is readily transmissible via blood transfusion. Since 2019, blood donors in 14 US states and Washington DC have been routinely screened for Babesia infection using highly sensitive and specific nucleic acid testing (NAT). Currently, there are no recommendations regarding the management of asymptomatic blood donors who test positive for Babesia.

METHODS: A multidisciplinary expert panel was convened to develop guidance for the management of asymptomatic Babesia-infected blood donors. A survey was distributed through the Infectious Diseases Society of America (IDSA) Emerging Infections Network (EIN) to evaluate how a geographically diverse group of infectious diseases specialists would approach this problem.

RESULTS: The expert panel recommends that all Babesia NAT positive blood donors should be referred for clinical evaluation and retested using peripheral blood smear (PBS) and B. microti PCR within two months of blood donation screening. The panel also recommends observation rather than treatment for a reactive molecular test alone. Antimicrobial therapy should be considered for PBS positive cases. Donors should be counseled regarding the typically self-limiting nature of this infection and instructed to seek medical care if symptoms develop. The EIN survey results are consistent with these recommendations.

CONCLUSIONS: Several factors support these management recommendations. Blood donors typically comprise healthy, immunocompetent adults in whom most Babesia infections are self-limited based on studies showing that molecular evidence of infection clears in almost all asymptomatic blood donors without intervention.

BACKGROUND AND AIMS: Liver stiffness measurement (LSM) by vibration-controlled transient elastography correlates well with liver-related events (LREs), but previous head-to-head comparisons with liver histology were limited by small sample size. This study aimed to compare the prognostic performance of LSM and histology for predicting LREs in patients with metabolic dysfunction-associated steatotic liver disease (MASLD).

APPROACH AND RESULTS: We analyzed data from 3532 metabolic dysfunction-associated steatotic liver disease patients (mean age 51.9 y, 57.3% male) in the multicenter vibration-controlled transient elastography-prognosis cohort, all having undergone both LSM and liver biopsy. The primary outcome was LREs, defined as hepatic decompensation, liver transplantation, or liver-related death. Secondary outcomes included HCC and decompensation analyzed separately. Median baseline LSM was 8.8 kPa; 33.5% had F3-F4 fibrosis. Over a median follow-up of 56.6 months, 126 patients (3.6%) developed LREs (123 decompensation). LSM and histology demonstrated similar prognostic performance for LREs, with comparable 5-year AUROC values (0.870 vs. 0.869), integrated AUROCs (0.878 vs. 0.852), and integrated precision-recall curves (0.137 vs. 0.0.68). The 5-year integrated Brier scores were also similar (1.389% vs. 1.391%), and the integrated discrimination improvement index showed no significant difference. Similar results were found across all the outcomes, time points, and sensitivity analyses.

CONCLUSIONS: In this large metabolic dysfunction-associated steatotic liver disease cohort, LSM by vibration-controlled transient elastography showed comparable prognostic accuracy to histology. As a noninvasive tool, LSM may serve as an alternative surrogate endpoint in clinical trials.

INTRODUCTION: Past studies of hepatitis B vaccines in persons with HIV (PWH) have shown mixed results about improving responses with increases in dose or dose frequency, leading to inconsistent guidelines and practice. We examined vaccine series completion and revaccinations in PWH lacking a seroprotective response.

METHODS: Hepatitis B vaccination histories were evaluated as a retrospective study in 561 participants of A5379 trial (NCT04193189). Individuals in 41 sites in Africa, Asia, South America, and USA qualified for the trial with antibody titers below the seroprotective level (<10 mIU/mL) despite past hepatitis B vaccinations. The primary measure of interest was the number of vaccines in the past vaccination records.

RESULTS: Of the 1098 trial candidates, 561 (51%) did not have seroprotective titers at the time of screening and enrolled in A5379. Median age at the time of screening was 46 years (18 to 70 years), which varied across the regions: the lowest in Africa and the highest in USA. The number of past hepatitis B vaccines varied widely across and within geographic regions. Twenty-four percent of the participants received ≥4 doses, up to 12, yet did not have seroprotective antibody titers.

CONCLUSIONS: Regardless of past vaccine records, antibody titers should be checked in PWH for revaccination needs. The recently approved long-acting (LA) and injectable antiretroviral treatment (ART) lacks protective effect against HBV, unlike tenofovir-based ART. As the LA ART becomes more widely used, we recommend reassessing serologies and offering the recommended CpG-adjuvanted vaccine series with promising response durability to individuals without seroprotection.

PURPOSE: Older and frail adults were under-represented in clinical trials evaluating ICIs, leading to a knowledge gap on their risk of acute care use and immune-related adverse events (irAEs). We performed a population-level study evaluating the impact of age and frailty among older adults receiving ICIs on acute care use and irAE-related hospitalizations.

METHODS: Patients with cancer, age ≥ 65 initiating ICIs between June 2012-October 2018 (Ontario, Canada) were identified using systemic therapy administration data. The cohort was linked to other databases to obtain covariates and outcomes. Multivariable Cox proportional models evaluated the impact of age and frailty on acute care use and irAE-related hospitalizations.

RESULTS: Among 2,737 patients, median age was 73 and 26% were pre-frail and 4% frail; 72% required acute care use, while 8% had an irAE-related hospitalization. Increasing frailty was associated with increased risk of acute care use (pre-frail vs robust, aHR = 1.20,95% CI[1.07-1.36], p = .003; frail vs robust, aHR = 1.45[1.12-1.86], p = .004), while age was not associated with acute care use. Increasing age was associated with reduced risk of irAE-related hospitalization (aHR = 0.97 per year[0.95-0.99], p = .01); patients age ≥ 80 compared to 65-69 had reduced risk of irAE-related hospitalization (aHR = 0.63[0.39-1.01], p = .05). Frailty was not associated with irAE-related hospitalizations. Associations remained consistent when evaluating age and frailty in the same models.

CONCLUSIONS: Age was associated with reduced risk of an irAE-related hospitalization but not acute care use, while increasing frailty was associated acute care use, but not irAE-related hospitalization. Age and frailty may need to be considered independently when evaluating their impact on toxicity among older adults receiving ICIs.