Publications by Year: 2025

OBJECTIVE: Antiseizure medications are approved based on clinical trials that demonstrate their efficacy as measured by reductions in seizure frequency (SF). When designing these trials, trialists must select inclusion criteria where SF can be reliably measured to maintain statistical power. Statistical power is based on the magnitude and uncertainty of the difference between active treatment and placebo. To inform choices about how minimum, maximum, and individual participant SF impacts the statistical power of trials, we evaluated how the uncertainty in SF was associated with average SF within multiple clinical trials.

METHODS: Using data from 11 double-blind placebo-controlled trials of antiseizure medications for either focal or generalized onset epilepsy, we used log-log multivariable regression to associate the SD of SF in maintenance with the average SF in baseline and maintenance. We also evaluated whether capturing more seizures in people with high average SF offset the increased uncertainty in SF and asked whether these associations persisted when time to event designs were used.

RESULTS: The uncertainty (SD) of maintenance SF was proportional to baseline average SF (daily diaries: slope of log-log association = .575, 95% confidence interval [CI] = .556-.593; fortnightly diaries: .657, 95% CI = .0642-.0671). Increased uncertainty for high SF was offset by counting more seizures. These relationships were maintained with a time to event design.

SIGNIFICANCE: This study validates the foundational L-relationship between average and SD of SF in which the uncertainty of seizure counts increased proportional to the number of seizures counted. When used for efficacy outcomes of trials, the statistical benefit of counting more seizures in participants with high SF was much greater than the increased challenge from higher uncertainty seizure counts. These results provide quantitative insights for SF-based inclusion criteria and statistical power calculations.

Background: Serious illness conversations are an iterative, interprofessional, team-based process that includes recommendations about medical care. Yet, it is not clear how clinicians in different role groups work together in this process. Objectives: We sought to examine how interprofessional clinicians in the medical intensive care unit (MICU) who were trained in the serious illness care program (SICP) document recommendations after serious illness conversations. Design: This is a retrospective chart review and inductive content analysis. Settings/Subjects: We reviewed the charts of patients admitted to the MICU of an academic hospital with a long history of palliative care (PC) in the northeastern United States between January 1 and December 31, 2019, who had at least one documented serious illness conversation. Results: Of the 207 conversations identified, 177 (85.5%) included a recommendation: 44.6% (79/177) were documented by registered nurses, 36.7% (65/177) by physician trainees (internal medicine residents and pulmonology/critical care fellows), and 18.6% (33/177) by PC consultants (physicians, nurse practitioners, and PC fellows). Recommendations were categorized into several domains: (1) code status (2) treatment interventions, (3) psychosocial support, and (4) communication. The recommendations textbox was also used to document general updates and patient education. The most common domains documented were code status and treatment interventions, respectively: Registered nurses (40.5%; 20.3%), physician trainees (52.3%; 36.4%), and PC clinicians (42.4%; 32.3%). Clinicians used the direct/active voice to document recommendations concordant with their scope of practice and the reporter/passive voice to document recommendations given by others. Conclusions: SICP-trained interprofessional MICU clinicians commonly give and document recommendations on a range of domains and flexibly use direct/active and reporter/passive voice to signal their scope of practice.

Background: Patients undergoing nasal reconstruction with the paramedian forehead flap (PMFF) can lead to scalp hair transfer and brow distortion. To minimize this, we have adopted the low median forehead flap (LMFF). Objectives: To compare the hypothetical flap reach of the LMFF with the PMFF and measure flap viability and hair transfer amongst patients undergoing nasal reconstruction. Materials and Methods: A multi-institutional retrospective chart review of patients undergoing the LMFF collected demographics, flap viability, brow distortion, and hair transfer. Photograph measurements compared the hypothetic flap reach between an LMFF or PMFF design. Results: Eighty patients (mean age 65 ± 13 [SD] years, 56.3% female) met inclusion after LMFF for nasal defects, mostly from skin cancer resection (93.8%) involving the tip (67.1%) and ala (73.4%); with ≥3 involved subunits (63.8%). Transferred scalp hair (n = 1, 1.3%), and no flap compromise occurred. In photograph analysis, the LMFF showed an 11.6% increase in flap reach as compared to the PMFF (p < 0.0001). Intra-rater and inter-rater variances were nonsignificant. Conclusions: The LMFF is a viable modification to the PMFF for nasal reconstruction, especially in patients with short hairline and/or distal nasal tip/alar defects where increased flap reach and minimal hair transfer are desired.

BACKGROUND: People with HIV (PWH) may have a higher risk of heart failure (HF) due to traditional and HIV-related factors. Incidence and risk prediction of HF in PWH are not well characterized. We aimed to quantify the risk of HF events in a global population of PWH with low-to-moderate estimated atherosclerotic cardiovascular disease risk.

METHODS: HF incidence (events/1000 person years) was described overall and by demographic, HIV-specific, and HF factors, including estimated Predicting Risk of Cardiovascular Disease Events 10-year risk of HF. Confirmed HF events included adjudicated HF hospitalization and adverse events identified via a standardized Medical Dictionary for Regulatory Archives HF query.

RESULTS: We analyzed 7769 REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) participants from 5 global regions (median, 50 years; 31% female). Over a median follow-up of 5.6 years (interquartile range, 4.3-5.9), HF incidence was higher in women, among Black participants in high-income regions, participants in sub-Saharan Africa, and among those with preexisting hypertension and obesity compared with the absence of these factors. Current and nadir CD4+T-cell count, and HIV-1 RNA level were not related to the incidence of HF events. Median (Q1-Q3) Predicting Risk of Cardiovascular Disease Events HF score was 1.66% (1.01-2.62). HF incidence was 1.65/1000 person-years (95% CI, 1.30-2.09). Expected number of HF events by Predicting Risk of Cardiovascular Disease Events HF (n=73) was consistent with observed (n=67).

CONCLUSIONS: Select demographics, clinical factors, and global regions contribute to a higher incidence of HF events among PWH. In PWH, the observed overall number of HF events aligned with the estimated Predicting Risk of Cardiovascular Disease Events HF risk rates.

INTRODUCTION: Growing demand for liver transplantation (LTx) has increased the use of elderly donors. In Argentina, however, data on the clinical impact of donor age on post-transplant outcomes remain limited.

OBJECTIVE: To evaluate the effect of donor age on clinical, functional, and molecular outcomes after LTx at Hospital Universitario Fundación Favaloro Buenos Aires, Argentina.

METHODS: We performed a retrospective cohort study of 494 LTx conducted between 2009 and 2020. Patients were stratified into two age groups: 18-59 years (Younger) and ≥60 years (Elderly). Overall and graft survival (OS and GS) were assessed using Kaplan-Meier and Cox regression analyses adjusted for recipient age, donor age, recipient gender, donor gender, transplant year, MELD score, disease etiology, donor BMI, DRI, CIT, WIT, Total Bilirubin (TBIL) and INR. Early postoperative complications including early allograft dysfunction (EAD) and early renal replacement therapy (RRT) were evaluated. Post-transplant liver function was assessed by routine biochemical tests. Gene expression of pro-inflammatory and senescence markers was quantified by qRT-PCR, and lipofuscin deposition was measured using ImageJ.

RESULTS: After applying exclusion criteria, 267 LTx were included (Younger donors: n = 222; Elderly donors: n = 45). Recipients of elderly donor grafts showed significantly lower OS and GS (p < 0.05). In the multivariable analysis, donor age and TBIL remained independent predictors of GS, whereas donor age, recipient age, and TBIL were associated with OS. In contrast, neither the incidence of EAD nor early RRT differed between recipients of elderly versus young donor grafts. Early postoperative biochemical profiles were also similar between groups, with no significant differences in ALT, AST, ALP, or TBIL levels. Molecular analyses demonstrated that elderly donor livers exhibited significantly higher expressions of IL-1β, IL-6, TNF-α, p21 and CCND1, Elderly donor livers displayed higher baseline lipofuscin accumulation (p < 0.05), consistent with age-associated cellular senescence, and trends toward higher rejection rates.

CONCLUSION: Donor liver aging, characterized by increased inflammatory and senescence signatures, is associated with reduced patient and graft survival. These findings underscore the clinical relevance of considering donor biological age, beyond chronological age, in organ allocation and selection strategies.

Individuals with Alice in Wonderland syndrome can present with a wide variety of visual symptoms. Most commonly, visual disturbances in size perception such as micropsia or macropsia are observed. However, rarer disturbances such as the visual perception of multiple images, termed polyopia, as well as kinetopsia, a visual illusion in which stationary objects are perceived as moving, have also been described. Previous neuroimaging of different individuals with Alice in Wonderland syndrome has shown the involvement of topographically separate brain regions. Here, we describe an individual who sequentially developed both micropsia and concurrent polyopia with kinetopsia following multi-focal infarction from underlying endocarditis. We show and describe his neuroimaging findings, as well as contextualize this with recent work showing how Alice in Wonderland syndrome may be subserved by a common distributed brain network.

BACKGROUND: BRAF alterations are common in pediatric low-grade gliomas (LGG) and a subset of high-grade gliomas (HGG) in adults and children. BRAF-targeted therapy can be effective at preventing tumor growth, though resistance commonly emerges in HGG. Recently, tovorafenib was FDA approved for recurrent or refractory LGG with BRAFV600 alterations or BRAF rearrangements. While the trial showed it is effective for children with LGG previously treated with BRAF or MEK inhibitors, the safety in adults and efficacy in HGG is unknown.

METHODS: A cohort of appropriate patients was identified through routine clinical care. This research was conducted in accordance with IRB regulations with a waiver of written consent.

RESULTS: Seven adults (5 HGG, 2 LGG) who received tovorafenib were identified. All patients had received prior BRAF-targeted therapy, and all patients with HGG had received prior radiation and temozolomide as well. Three individuals (2 HGG, 1 LGG) experienced stable disease or better for 4 or more months. Median duration of treatment was 8 weeks (range 3 weeks to 10 months). Two individuals experienced CTCAE grade 4 intratumoral hemorrhage (1 HGG, 1 LGG). Two patients remain on therapy at 4 and 10 months of treatment (1 HGG, 1 LGG).

CONCLUSION: Our experience with tovorafenib indicates some limited efficacy in HGG in combination with other standard treatments. These observations demonstrate the need for further clinical trials in patients with HGG to understand potential clinical utility, either earlier in the disease course or in combination with other therapies.

BACKGROUND: Reproductive health considerations are critical to patients with IDH-mutant (IDHm) glioma as they are mainly diagnosed during their reproductive years. Given the recent introduction of IDH inhibitors (IDHi) for the treatment of IDHm glioma, we sought to review the current understanding of reproductive implications of IDHi therapy, and report how frequently documented reproductive health conversations take place in the clinic when considering IDHi initiation.

METHODS: We searched the literature for studies evaluating the effects of IDHi therapy on reproductive health. We additionally retrospectively collected clinical data from reproductive-age patients with IDHm glioma treated at the Dana-Farber Cancer Institute and Mass General Brigham who received or were considered for IDHi therapy between 2018 and 2024. Medical records were reviewed for documentation of fertility and contraception discussions at the time of IDHi consideration.

RESULTS: Other than limited preclinical studies described on Food and Drug Administration labels, no other data on the effects of IDHi on reproductive health were found. Of 119 patients considered for IDHi therapy, 54 (45%) had no documented fertility conversation in relation to IDHi, and 92 (77%) had no documented contraception conversation. On univariable analysis, factors significantly associated with not having fertility conversations were older age (OR: 0.94, CI: 0.88-1.0), male sex (OR: 0.50, CI: 0.23-1.07), and prior fertility conversation (OR: 0.41, CI: 0.18-0.88).

CONCLUSIONS: According to our institutional data, conversations regarding IDHi reproductive risks are not generally documented, contrary to guideline recommendations. Future studies are required to better understand the impact of IDHi therapy on fertility and fetal development.

Purpose: To highlight the clinical utility of ultra-widefield swept-source optical coherence tomography angiography (SS-OCTA) in evaluating diabetic retinopathy (DR), particularly focusing on its ability to detect peripheral ischemia and neovascularization. Methods: Eyes of 5 participants with varying severity of DR were imaged with expanded-field 12 × 12-mm SS-OCTA scans and ultra-widefield SS-OCTA montages. Montages were created by stitching five 21 × 26-mm scans, offering up to a 200° field of view. Cases were assessed for areas of nonperfusion, intraretinal microvascular abnormalities, and neovascularization extending beyond the posterior pole. Results: Ultra-widefield SS-OCTA imaging demonstrated progressive mid-peripheral and peripheral nonperfusion, intraretinal microvascular abnormalities, and neovascularization in association with increasing DR severity. Peripheral nonperfusion and neovascular changes were detected beyond the scope of standard 12 × 12-mm scan areas. Conclusions: Ultra-widefield SS-OCTA is effective in noninvasively detecting peripheral retinal lesions such as ischemia and neovascularization. This technology offers potential to refine DR staging, improve risk stratification, and guide earlier clinical interventions.

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.