Citations

AbstractArtificial intelligence (AI) has been influencing healthcare and medical research for several years and will likely become indispensable in the near future. AI is intended to support healthcare professionals to make the healthcare system more efficient and ultimately improve patient outcomes. Despite the numerous benefits of AI systems, significant concerns remain. Errors in AI systems can pose serious risks to human health, underscoring the critical need for safety, as well as adherence to ethical and moral standards, before these technologies can be integrated into clinical practice. To address these challenges, the development, certification, and deployment of medical AI systems must adhere to strict and transparent regulations. The European Commission has already established a regulatory framework for AI systems by enacting the European Union Artificial Intelligence Act. This review article, part of an AI learning series, discusses key considerations for medical AI systems such as reliability, accuracy, trustworthiness, lawfulness and legal compliance, ethical and moral alignment, sustainability, and regulatory oversight.Level of EvidenceLevel V.

Background Parkinsonism following hypoxic ischemic damage of the basal ganglia is an uncommon phenomenon that has been infrequently reported. However, only a few cases have noted improvement of symptoms with dopaminergic therapy. We report the clinical and imaging features of five patients with post-anoxic parkinsonism responsive to dopamine supplementation. Objective To describe a retrospective case series of five cases of dopamine-responsive post-anoxic parkinsonism. Methods We identified all the cases using the Mayo Clinic Data Management System utilizing advanced data explorer search engine for any patients evaluated for post anoxic parkinsonism and its associated acronyms from 2000–2024. Clinical features, neuroimaging, medication trials, and responses were obtained from chart review of identified patients. Results Five patients met the inclusion criteria. All patients underwent anoxic events followed by development of parkinsonism. Patients exhibited parkinsonism described as combinations of bradykinesia, rigidity, tremor, and postural instability. All patients underwent evaluation by a neurologist, MRI imaging, and treatment by dopaminergic agents. Of the five patients, four received carbidopa/levodopa whereas one received a dopamine agonist. All patients were clinically followed for a median of approximately 4 years and showed improvement in parkinsonism. Conclusions Parkinsonism following a hypoxic ischemic insult is a rare occurrence but response to dopaminergic therapy in those cases is even more scarcely described. Our cases series provides important implications for treatment options for patients with post anoxic parkinsonism.

Abstract Blood-based multicancer early detection (MCED) tests represent a new approach for cancer detection. To gain insights into the utility of various approaches of evaluating a cancer signal detected (CSD) test result, we evaluated diagnostic journeys of a subset of 6,662 participants in PATHFINDER who had a CSD on both an initial and refined version of an MCED test that also provided a prediction of cancer signal origin (CSO). We sought to determine whether CSO prediction–guided diagnostic evaluations led to diagnostic resolution; whether participants with known risk factors for cancer beyond age alone and a negative initial diagnostic evaluation had a cancer diagnosis during study follow-up; the utility of whole-body imaging in reaching diagnostic resolution; and differences in the diagnostic journeys needed to reach diagnostic resolution for both true- and false-positive results. Of the 39 participants in this analysis, 82% (32/39) achieved diagnostic resolution after the initial evaluation, including 78% (25/32) who reached resolution specifically with a CSO prediction–directed workup. Eighteen percent (7/39) required additional evaluation for persistent clinical suspicion of cancer, all of whom achieved resolution (3 with and 4 without cancer). Whole-body imaging contributed to diagnostic resolution in only 49% of CSD cases. Approximately 90% of true- and false-positive cases had imaging tests; more true positives versus false positives (81.0% vs. 38.9%) had nonsurgical and/or surgical procedures. In conclusion, CSO prediction–directed evaluations enabled diagnostic resolution for most participants, although some with negative initial evaluations but persistent suspicion of cancer required additional testing. Prevention Relevance: MCED testing has the potential to increase detection of cancer at earlier stages. As MCED testing is a new technology, there are few data on the diagnostic journeys patients undergo following testing. We observed that for most patients, CSO prediction–directed workups were efficient, leading to diagnostic resolution after initial evaluation.

Study Design Systematic Review. Objective To assess the current literature regarding the accuracy of different imaging modalities and criteria used to assess lumbar fusion, and their correlation with surgical direct observation as the current Gold Standard. Methods Following PRISMA guidelines, we conducted a comprehensive search of PubMed, Embase, Google Scholar, and Cochrane Library, studies were included if they focused on patients with a prior history of lumbar interbody fusion and at least 1 year of radiographic follow-up. The review assessed the sensitivity, specificity, and accuracy of different imaging techniques, and their correlation with surgical findings. Results Thirteen studies (1989-2019) were reviewed, including 715 patients, common imaging modalities included plain radiographs (53.8%), Computed Tomography (CT) (69.2%), and dynamic radiographs (30.7%). CT appeared as the most utilized modality post-2006. There was substantial variability in diagnostic accuracy, with CT showing high variability in sensitivity and specificity. Descriptive criteria for fusion were widely used, but interobserver agreement was generally low. Conclusion The review highlights a lack of standardized criteria for assessing lumbar fusion. Despite advancements in imaging techniques, the variability in diagnostic parameters suggests a need for consensus and multicentric studies to stablish reliable, universal criteria for evaluating fusion success.

Abstract Background In 2021, the American Academy of Physical Medicine and Rehabilitation established the Multi‐Disciplinary Post‐Acute Sequelae of SARS‐CoV‐2 Infection Collaborative to provide guidance from established Long COVID clinics for the evaluation and management of Long COVID. The collaborative previously published eight Long COVID consensus guidance statements using a primarily symptom‐based approach. However, Long COVID symptoms most often do not occur in isolation. Aims This compendium aims to equip clinicians with an efficient, up‐to‐date clinical resource for evaluating and managing adults experiencing Long COVID symptoms. The primary intended audience includes physiatrists, primary care physicians, and other clinicians who provide first‐line assessment and management of Long COVID symptoms, especially in settings where subspecialty care is not readily available. This compendium provides a holistic framework for assessment and management, symptom‐specific considerations, and updates on prevalence, health equity, disability considerations, pathophysiology, and emerging evidence regarding treatments under investigation. Because Long COVID closely resembles other infection‐associated chronic conditions (IACCs) such as myalgic encephalomyelitis/chronic fatigue syndrome, the guidance in this compendium may also be helpful for clinicians managing these related conditions. Methods Guidance in this compendium was developed by the collaborative's established modified Delphi approach. The collaborative is a multidisciplinary group whose members include physiatrists, primary care physicians, pulmonologists, cardiologists, psychiatrists, neuropsychologists, neurologists, occupational therapists, physical therapists, speech and language pathologists, patients, and government representatives. Over 40 Long COVID centers are represented in the collaborative. Results Long COVID is defined by the National Academies of Sciences, Engineering, and Medicine as “an IACC that occurs after SARS‐CoV‐2 infection and is present for at least 3 months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems.” The current global prevalence of Long COVID is estimated to be 6%. Higher prevalence has been identified among female gender, certain racial and ethnic groups, and individuals who live in nonurban areas. However, anyone can develop Long COVID after being infected with the SARS‐CoV‐2 virus. Long COVID can present as a wide variety of symptom clusters. The most common symptoms include exaggerated fatigue and diminished energy windows, postexertional malaise (PEM)/postexertional symptom exacerbation (PESE), cognitive impairment (brain fog), dysautonomia, pain/myalgias, and smell and taste alterations. Holistic assessment should include a traditional history, physical examination, and additional diagnostic testing, as indicated. A positive COVID‐19 test during acute SARS‐CoV‐2 infection is not required to diagnose Long COVID, and currently, there is no single laboratory finding that is definitively diagnostic for confirming or ruling out the diagnosis of Long COVID. A basic laboratory assessment is recommended for all patients with possible Long COVID, and consideration for additional labs and diagnostic procedures is guided by the patient's specific symptoms. Current management strategies focus on symptom‐based supportive care. Critical considerations include energy conservation strategies and addressing comorbidities and modifiable risk factors. Additionally, (1) it is essential to validate the patient's experience and provide reassurance that their symptoms are being taken seriously because many patients have had their symptoms dismissed by loved ones and clinicians; (2) physical activity recommendations must be carefully tailored to the patient's current activity tolerance because overly intense activity can trigger PEM/PESE and worsened muscle damage; and (3) treatment recommendations should be delivered with humility because there are many persistent unknowns related to Long COVID. To date, there are limited data to guide medication management specifically in the context of Long COVID. As such, medication use generally follows standard practice regarding indications and dosing, with extra attention to prioritize (1) patient preference via shared decision‐making and (2) cautious use of medications that may improve some symptoms (eg, cognitive/attention impairment) but may worsen other symptoms (eg, PEM/PESE). Numerous clinical trials are investigating additional treatments. The return‐to‐work process for individuals with Long COVID can be challenging because symptoms can fluctuate, vary in nature, affect multiple functional areas (eg, physical and cognitive), and often manifest as an “invisible disability” that may not be readily acknowledged by employers or coworkers. Clinicians can help patients return to work by identifying suitable workplace accommodations and resources, providing necessary documentation, and recommending occupational or vocational therapy when needed. If these efforts are unsuccessful and work significantly worsens Long COVID symptoms or impedes recovery, applying for disability may be warranted. Long COVID is recognized as a potential disability under the Americans with Disabilities Act. Conclusion To contribute to the overall health and well‐being for all patients, Long COVID care should be delivered in a holistic manner that acknowledges challenges faced by the patient and uncertainties in the field. For more detailed information on assessment and management of specific Long COVID symptoms, readers can reference the collaborative's symptom‐specific consensus guidance statements.

Abstract The range of Babesia microti (Franca, 1910)-infected ticks is expanding, resulting in locally acquired human babesiosis cases occurring in new areas: Maryland (2009), the District of Columbia (2013), Virginia (2016), and West Virginia (2017). We collected host-seeking ticks from old fields, ecotones, forested habitats and animal hosts in Delaware, Maryland, and Virginia, 2010 to 2024. Ixodes scapularis Say, the tick vector of babesiosis, was captured in all 3 states. PCR revealed B. microti in 2.7% (36/1310) of I. scapularis, with site prevalence ranging from <1% to 12.5% infected. The first B. microti-positive I. scapularis was collected in Northampton County, Virginia, 2012. Of the B. microti-infected ticks, 50% (18/36) were coinfected with Borrelia burgdorferi and one was triple-infected with B. microti, B. burgdorferi, and Anaplasma phagocytophilum. We collected Ixodes keiransi Beati, Nava, Venzal, and Guglielmone ticks from Delaware and Virginia. We found B. microti and B. burgdorferi in those from Virginia, and B. burgdorferi in ticks from a shrew in Delaware. To our knowledge, this is the first report of B. microti and B. burgdorferi-positive I. keiransi from Virginia, and the first report of B. burgdorferi-positive I. keiransi from Delaware. Ixodes keiransi ticks rarely bite humans but are involved in the maintenance and spread of pathogens when sympatric with I. scapularis. We tested a subset of both tick species for Babesia duncani; none were positive. Jurisdictions in the southern mid-Atlantic region should expect babesiosis cases, and Lyme disease and anaplasmosis coinfections, and healthcare providers should consider these tick-borne infections as part of the differential diagnosis.

Abstract Breast cancer affects 1 in 8 women and often results from mutations caused by oxidative DNA damage from reactive oxygen species. Two key lesions, 8-hydroxy-adenine (8-OH-Ade) and 4, 6-diamino-5-formamidopyrimidine (FAPY-Ade), exhibit two distinct patterns: FAPY-Ade lesions are predominant in normal tissues, while 8-OH-Ade lesions are abundant in cancerous tissues. These shifts reflect tissue redox status, which may provide a pathway to assess future breast cancer risk. Quantitation of these lesions by chemical detection methods is precise but time-intensive and impractical for high-throughput clinical applications. To address this, monoclonal antibodies have been developed and offer a rapid, scalable, and clinically practical alternative for efficiently detecting and quantifying these biomarkers. This innovation can potentially support personalized breast cancer screening strategies. BALB/c mice were immunized with 8-OH-Ade or FAPY-Ade haptens coupled to Keyhole Limpet Hemocyanin (KLH). After three monthly immunizations, the serums of IgG and IgM titers were evaluated. The mice having the highest IgG titer for each antigen were given an intravenous boost, and the spleens were removed three days later for fusions according to standard methods. Using hapten-conjugated BSA-coated 96-well Pro-Bind plates, the ELISA results demonstrated 30-40 positive wells for each antigen. Up to ten positive wells for each antigen were selected and cloned to yield monoclonal antibody-producing hybridomas. The ELISA of the anti-FAPY-Ade antibody, FA5, showed concentration-dependent reduced binding to immobilized BSA-FAPY-Ade hapten conjugate in increasing FAPY-Ade, confirming its FAPY-Ade binding specificity. Immunohistochemistry using normal and cancerous breast tissue revealed significant staining of normal breast tissue compared to cancerous breast tissue using the FA5 antibody. Conversely, the anti-8-OH-Ade antibody, 8A6, displayed weak staining of normal breast tissue with higher staining of cancerous breast tissues. The results demonstrate that monoclonal antibodies specific for 8-OH-Ade and a novel antibody specific for the ring-opening reactive oxygen product, FAPY-Ade, are practical and rapid alternatives to chemical detection methods for their analysis. Immunohistochemistry mirrored past results using chemical detection methods for these oxidized bases, with high FAPY-Ade compared to 8-OH-Ade in normal tissues and the opposite result in cancer-derived tissues. The potential for high-throughput analysis of 8-OH-Ade and FAPY-Ade levels in the DNA of breast tissues may provide information on future breast cancer risk. Further research is underway to evaluate this hypothesis. Citation Format: Zenzeale A. Hudson, Sarah McLaughlin, Alfredo A. Paredes, Gary K. Ostrander, Eric H. Holmes. Monoclonal antibody evaluation of oxidative DNA base damage in normal and neoplastic breast tissues: development of antibodies specific for 8-OH-adenine and 4, 6-diamino-5-formamidopyrimidine (FAPY-adenine) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7063.

Abstract Introduction: We previously developed a urine liquid biopsy assay to measure urine tumor DNA (utDNA) levels in bladder cancer (BC) patients. Here, we extended this approach significantly by layering in cell-free DNA fragmentomic and cell-free RNA analysis, and extending the method to the full spectrum of genitourinary (GU) cancers, to enable both GU cancer detection and tumor tissue of origin prediction. Methods: A total of 155 GU cancer patients and 34 healthy adults were enrolled in this prospective study. Preoperative urine was collected from 94 bladder cancer (BC) patients, including 65 with muscle-invasive disease, all undergoing cystectomy. Additionally, urine samples were collected from 18 renal cell carcinoma (RCC) patients undergoing nephrectomy and 42 metastatic prostate cancer (mPC) patients. Urine cfDNA and cfRNA were isolated and sequenced, with cfRNA sequenced to 100 million reads per sample on an Illumina NovaSeq X and cfDNA sequenced at 5x genome-wide coverage on a Novoseq S4 flow cell. To identify malignant tissue of origin, we analyzed somatic copy number alterations (CNAs), genome-wide fragment length ratios, and 4-mer end motifs. Tumor fraction (TFx) was estimated using ichorCNA, while DELFI was employed for fragment length ratios in 5 megabase bins across the genome and chromosome arm-level z-scores. Individual logistic regression models were developed based on each fragmentomic feature, and validated using a training and held-out testing approach. Outputs from these models were combined into a single comprehensive model, also trained and held-out tested using the same approach. Urine cfRNA transcript isoform abundance was quantified using Salmon and normalized to Transcripts Per Million (TPM) to account for sequencing depth variations. Results: Bladder cancer (BC) showed the highest mean tumor fraction (TFx, 10.5%), followed by RCC (3.8%) and mPC (3.4%). Among 94 BC patients, 42% achieved a pCR, while 58% had residual disease and did not. Patients without pCR had significantly higher urine TFx compared to those with pCR (14.7% vs. 4.7%, p=0.0008). A machine learning model based on genome-wide fragment length ratios achieved an ROC AUC of 0.74, while models using genome-wide CNAs and end motifs achieved AUCs of 0.81 and 0.88, respectively. Combining all features into a single model yielded an AUC of 0.92, with classification accuracies of 89% for bladder cancer, 80% for RCC, and 60% for prostate cancer. Additionally, urine cfRNA analysis using the top 1, 000 coding transcripts achieved an AUC of 0.95, with classification accuracies of 100% for mPC, 87% for BC, and 78% for RCC. Conclusion: Fragmentomic features from urine cfDNA and transcriptomic features from urine cfRNA demonstrate strong potential for predicting tumor tissue-of-origin in GU cancers, underscoring the promise of non-invasive diagnosis across the spectrum of GU malignancies through urine liquid biopsy. Citation Format: Pradeep Singh Chauhan, Irfan Alahi, Jessica Linford, Arpit Panda, Nathan Colon, Ryan Mueller, Faridi Qaium, Peter K. Harris, John Sheng, Eric H. Kim, Melissa A. Reimers, Zachary L. Smith, Woodson W. Smelser, Aadel A. Chaudhuri. Predicting genitourinary cancer tissue-of-origin using urine cell-free DNA fragmentomics and cell-free RNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3258.