Faculty Bibliography

INTRODUCTION/BACKGROUND:Approximately 50 % of resected stage II-IV melanoma patients develop recurrent disease by 5 years despite adjuvant anti-PD-1 therapy. Data to define best management of recurrences is lacking. METHODS:This was a multicentre, international, retrospective cohort study. Patients with resected stage II-IV melanoma who commenced adjuvant anti-PD-1-based therapy before January 2022 and later recurred were identified. Data on demographics, disease characteristics, recurrence patterns, management and outcomes were collected. RESULTS:711 patients from 17 sites were included. Median age was 60 [range 16-92], 64 % were male, 2 % stage II, 91 % were stage III, 7 % stage IV. Median time to recurrence was 6.2 months (0-68.5) and median follow up time from recurrence was 19.8 months (range 0.2-73.1). 63 % recurred on anti-PD-1 therapy, 36 % off therapy [3 % < 6 months, 33 % > 6 months]. Initial recurrences were locoregional (LR) alone in 44 %, distant alone (DR) in 43 %, and 11 % in both sites. LR recurrences were managed with local therapy, alone (62 %) or with "second adjuvant" anti-PD-1 (14 %) or BRAF/MEK therapy (23 %); 12 m RFS2 was 25 %, 29 % and 69 % respectively (p = 0.0045). Definitive systemic therapy at first recurrence was given in 16 % LR and 86 % DR, with best outcomes for anti-CTLA4 + anti-PD-1 and trial combinations (24 m PFS 63 % and 69 %, respectively). The 24 m OS for the entire cohort was 65 %. CONCLUSION/CONCLUSIONS:Most recurrences following adjuvant anti-PD-1 based therapy occur early and while still on drug. Outcomes are poor, regardless of site, timing of recurrence, and subsequent treatment.

In this Perspective, our 2024 Pathway to Independence Fellows provide their thoughts on the future of their field. Covering topics as diverse as plant development, tissue engineering and adaptation to climate change, and using a wide range of experimental organisms, these talented postdocs showcase some of the major open questions and key challenges across the spectrum of developmental biology research.

BACKGROUND:Generative artificial intelligence (AI) and large language models, such as OpenAI's ChatGPT, have shown promising potential in supporting medical education and clinical decision-making, given their vast knowledge base and natural language processing capabilities. As a general purpose AI system, ChatGPT can complete a wide range of tasks, including differential diagnosis without additional training. However, the specific application of ChatGPT in learning and applying a series of specialized, context-specific tasks mimicking the workflow of a human assessor, such as administering a standardized assessment questionnaire, followed by inputting assessment results in a standardized form, and interpretating assessment results strictly following credible, published scoring criteria, have not been thoroughly studied. OBJECTIVE:This exploratory study aims to evaluate and optimize ChatGPT's capabilities in administering and interpreting the Sour Seven Questionnaire, an informant-based delirium assessment tool. Specifically, the objectives were to train ChatGPT-3.5 and ChatGPT-4 to understand and correctly apply the Sour Seven Questionnaire to clinical vignettes using prompt engineering, assess the performance of these AI models in identifying and scoring delirium symptoms against scores from human experts, and refine and enhance the models' interpretation and reporting accuracy through iterative prompt optimization. METHODS:We used prompt engineering to train ChatGPT-3.5 and ChatGPT-4 models on the Sour Seven Questionnaire, a tool for assessing delirium through caregiver input. Prompt engineering is a methodology used to enhance the AI's processing of inputs by meticulously structuring the prompts to improve accuracy and consistency in outputs. In this study, prompt engineering involved creating specific, structured commands that guided the AI models in understanding and applying the assessment tool's criteria accurately to clinical vignettes. This approach also included designing prompts to explicitly instruct the AI on how to format its responses, ensuring they were consistent with clinical documentation standards. RESULTS:Both ChatGPT models demonstrated promising proficiency in applying the Sour Seven Questionnaire to the vignettes, despite initial inconsistencies and errors. Performance notably improved through iterative prompt engineering, enhancing the models' capacity to detect delirium symptoms and assign scores. Prompt optimizations included adjusting the scoring methodology to accept only definitive "Yes" or "No" responses, revising the evaluation prompt to mandate responses in a tabular format, and guiding the models to adhere to the 2 recommended actions specified in the Sour Seven Questionnaire. CONCLUSIONS:Our findings provide preliminary evidence supporting the potential utility of AI models such as ChatGPT in administering standardized clinical assessment tools. The results highlight the significance of context-specific training and prompt engineering in harnessing the full potential of these AI models for health care applications. Despite the encouraging results, broader generalizability and further validation in real-world settings warrant additional research.

Individuals living with CKD are disproportionately burdened by a multitude of adverse clinical and person-centered outcomes. When patients transition from advanced kidney disease to kidney failure, the psychosocial effects as well as social determinants of health challenges are magnified, making this a particularly difficult time for patients beginning kidney replacement therapy. The key social determinants of health challenges often include food and housing insecurity, poverty, unreliable transportation, low level education and/or health literacy, lack of language interpreters and culturally concordant educational materials, lack of health care insurance coverage, and mistrust of the health care system. Psychosocial and physical stressors, such as depression, anxiety, sexual dysfunction, sleep difficulty, fatigue, and pain, are often part of the illness burden among individuals living with CKD and can interact synergistically with the social challenges making the transition to kidney replacement therapy particularly challenging. To better support patients during this time, it is critical that social and structural determinants of health as well as mental health be assessed and if needs are identified, that services be provided.

OBJECTIVE:Uncooperative behavior in pediatric dentistry is one of the most common manifestations of dental anxiety. Managing anxious patients can be attained by moderate sedation. This study aimed to compare the effect of sedation by dexmedetomidine-ketamine combination (DEX-KET) versus dexmedetomidine (DEX) on behavior of uncooperative pediatric dental patients. METHODOLOGY/METHODS:In total, 56 uncooperative healthy children (3-5 years old) requiring dental treatment were divided randomly into two groups: Group I (study group), which received buccal dexmedetomidine (2 μg/kg) and ketamine (2 mg/kg), and Group II (control group), which received only buccal dexmedetomidine (4 μg/kg). Drugs effects were assessed in terms of hemodynamic parameters, patient's drug acceptance, child behavior, postoperative effect of sedation, amnesic effect, incidence of adverse events, as well as procedural induced stress measured by salivary secretory immunoglobulin A (s-IgA). RESULTS:Hemodynamic results did not reveal a statistically significant difference between the two study groups (P>0.05). There was a significant difference in patient's acceptance to sedative drug between both groups, favoring DEX (p=0.005). Children who received DEX-KET showed significantly better behavior than those who received DEX for local anesthesia (p=0.017) and during operative procedure (p=0.037). Adverse events, post-operative and amnesic effects of drugs were comparable in both groups (p>0.05). Moreover, the mean difference in the salivary s-IgA levels between initial and final value was not statistically significant between both groups (p=0.556). CONCLUSION/CONCLUSIONS:Both DEX-KET combination and DEX alone are effective in providing hemodynamic stability. DEX-KET combination significantly improved the behavior of sedated children compared to DEX alone but the drug acceptance was decreased in the DEX-KET group. Both regimens did not have a negative effect on postoperative behavior of children and had comparable amnesic effect with no significant adverse events. Salivary s-IgA is not considered a potential stress biomarker in sedated children.

Although St-Jules et al have presented the case for postprandial hyperkalemia with food, including plant foods, there (still) is little to no direct evidence supporting the occurrence of postprandial hyperkalemia, mostly due to a lack of studies performed exclusively using food. Food is different than salts or supplements, and it is likely that a banana behaves differently than potassium salts. A growing body of evidence supports the use of plant foods without causing hyperkalemia in patients with kidney disease. Currently, only 1 study has reported on the postprandial effects of hyperkalemia. In this study, there was a substantial reduction in the instances of postprandial hyperkalemia in participants consuming a diet that included more plant foods and more fiber. At the time of this writing, there is no evidence to support risk or safety of certain foods with regard to postprandial hyperkalemia, and additional research is warranted.

INTRODUCTION/UNASSIGNED:HIV-1 envelope (Env) is the key target for antibodies (Abs) against the virus and thus an important HIV-1 vaccine component. Env is synthesized from a gp160 precursor with a signal peptide (SP) at its N-terminus. This study investigated the influence of the SP on Env antigenicity and immunogenicity. METHODS/UNASSIGNED:Env proteins from two HIV-1 isolates, AA05 and AC02, were analyzed as gp120 and gp160 in their native wild-type (WT) forms and as chimeras with swapped SPs (AA05-02 and AC02-05). The WT and chimeric Env were assessed for antigenicity and glycosylation using monoclonal antibodies (mAbs) and glycan probes. Immunogenicity was tested in mice using three vaccine types: gp120 protein, gp120 DNA+gp120 protein, and gp120 DNA+gp160 DNA. RESULTS/UNASSIGNED:The recombinant AC02 gp120 protein was antigenically superior to AA05 as indicated by higher reactivity with most mAbs tested. When SPs were swapped, the antigenicity of the chimeric gp120s (AA05-02 and AC02-05) resembled that of the gp120s from which the SPs were derived; AA05-02 was similar to AC02 and vice versa. Glycan probe reactivity followed a similar pattern: AA05-02 and AC02 showed similar affinity to high-mannose specific mAbs and lectins. Interestingly, the antigenicity of gp160s showed an opposite pattern; membrane-bound gp160 expressed with the AA05 SP (AA05 and AC02-05) showed greater mAb binding than gp160 with the AC02 SP (AC02 and AA05-02). Mice immunized with gp120 protein showed that AA05-02 induced stronger cross-reactive binding Ab responses than AA05 WT, and AC02 elicited stronger responses than AC02-05, indicating AC02 SP enhanced gp120 immunogenicity. However, when DNA vaccines were included (gp120 DNA+gp120 protein and gp120 DNA+gp160 DNA), the use of heterologous SPs diminished the immunogenicity of the WT immunogens. Among the three vaccine regimens tested, only gp120 DNA+gp160 DNA immunization elicited low-level Tier 2 neutralizing Abs, with AA05 WT inducing Abs with greater neutralization capabilities than AA05-02. CONCLUSION/UNASSIGNED:These data demonstrate that the SP can significantly impact the antigenicity and immunogenicity of HIV-1 Env proteins. Hence, while SP swapping is a common practice in constructing Env immunogens, this study highlights the importance of careful consideration of the effects of replacing native SPs on the immunogenicity of Env vaccines.