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Sequential adaptive trial designs can help accomplish the goals of personalized medicine, optimizing outcomes and avoiding unnecessary toxicity. Here we describe the results of incorporating a promising antibody-drug conjugate, datopotamab-deruxtecan (Dato-DXd) in combination with programmed cell death-ligand 1 inhibitor, durvalumab, as the first sequence of therapy in the I-SPY2.2 phase 2 neoadjuvant sequential multiple assignment randomization trial for high-risk stage 2/3 breast cancer. The trial includes three blocks of treatment, with initial randomization to different experimental agent(s) (block A), followed by a taxane-based regimen tailored to tumor subtype (block B), followed by doxorubicin-cyclophosphamide (block C). Subtype-specific algorithms based on magnetic resonance imaging volume change and core biopsy guide treatment redirection after each block, including the option of early surgical resection in patients predicted to have a high likelihood of pathologic complete response, which is the primary endpoint assessed when resection occurs. There are two primary efficacy analyses: after block A and across all blocks for six prespecified HER2-negative subtypes (defined by hormone receptor status and/or response-predictive subtypes). In total, 106 patients were treated with Dato-DXd/durvalumab in block A. In the immune-positive subtype, Dato-DXd/durvalumab exceeded the prespecified threshold for success (graduated) after block A; and across all blocks, pathologic complete response rates were equivalent to the rate expected for the standard of care (79%), but 54% achieved that result after Dato-DXd/durvalumab alone (block A) and 92% without doxorubicin-cyclophosphamide (after blocks A + B). The treatment strategy across all blocks graduated in the hormone-negative/immune-negative subtype. No new toxicities were observed. Stomatitis was the most common side effect in block A. No patients receiving block A treatment alone had adrenal insufficiency. Dato-DXd/durvalumab is a promising therapy combination that can eliminate standard chemotherapy in many patients, particularly the immune-positive subtype.ClinicalTrials.gov registration: NCT01042379 .

Purpose of reviewThis study is to highlight the incidence of corneal pseudomicrocysts in FDA-approved antibody-drug conjugates (ADCs), and success of preventive therapies for pseudomicrocysts and related ocular surface adverse events (AEs).Recent findingsADCs are an emerging class of selective cancer therapies that consist of a potent cytotoxin connected to a monoclonal antibody (mAb) that targets antigens expressed on malignant cells. Currently, there are 11 FDA-approved ADCs with over 164 in clinical trials. Various AEs have been attributed to ADCs, including ocular surface AEs (keratitis/keratopathy, dry eye, conjunctivitis, blurred vision, corneal pseudomicrocysts). While the severity and prevalence of ADC-induced ocular surface AEs are well reported, the reporting of corneal pseudomicrocysts is limited, complicating the development of therapies to prevent or treat ADC-related ocular surface toxicity.SummaryThree of 11 FDA-approved ADCs have been implicated with corneal pseudomicrocysts, with incidence ranging from 41 to 100% of patients. Of the six ADCs that reported ocular surface AEs, only three had ocular substudies to investigate the benefit of preventive therapies including topical steroids, vasoconstrictors, and preservative-free lubricants. Current preventive therapies demonstrate limited efficacy at mitigating pseudomicrocysts and other ocular surface AEs.

PURPOSE: This study characterizes attitudes and decision-making around the desire for future children in young women newly diagnosed with early-stage breast cancer and assesses how clinical factors and perceived risk may impact these attitudes. METHODS: This is a prospective study in women

Background Residency application patterns by gender and race/ethnicity offer important insights about diversity in residency recruitment. It is unknown how the COVID-19 pandemic and virtual interviewing affected these patterns. Objective We hypothesized that the introduction of virtual interviews caused an increase in applications submitted per applicant and that there may be differences by gender and race/ethnicity. Methods We extracted publicly reported Electronic Residency Application Service application data from 2018 to 2022 for 14 residency specialties with 1000 or more applicants in 2022 by self-reported gender and underrepresented in medicine (UIM) status. We compared patterns before and after virtual interviews were introduced in 2021. Results Among 401 480 residency applicants, the average number of applications submitted per applicant increased for all specialties between 2018 and 2022 across gender and race/ethnicity. Across all years, women applied to more programs than men in 5 specialties (dermatology, neurology, obstetrics/gynecology, pediatrics, and surgery), whereas men applied to more programs than women in 3 (anesthesia, family medicine, and physical medicine and rehabilitation). Across all years, non-UIM applicants applied to more programs than UIM applicants in all 14 specialties. There were no clear changes in application patterns by gender and race/ethnicity during in-person versus virtual interview years. Conclusions The average number of applications submitted per applicant increased over time across gender and race/ethnicity. In some specialties, women applied to more programs than men, and in others vice-versa, whereas non-UIM applicants applied to more programs than UIM applicants in all specialties. Virtual interviews did not change these patterns.

PURPOSE: We hypothesized that eribulin combined with cyclophosphamide (EC) would be an effective combination with tolerable toxicity for the treatment of advanced breast cancer (ABC). METHODS: Patients with histologically confirmed metastatic or unresectable ABC with any number of prior lines of therapy were eligible to enroll. In the dose escalation cohort, dose level 0 was defined as eribulin 1.1 mg/m2 and cyclophosphamide 600 mg/m2, and dose level 1 was defined as eribulin 1.4 mg/m2 and cyclophosphamide 600 mg/m2. Eribulin was given on days 1 and 8 and cyclophosphamide on day 1 of a 21-day cycle. In the dose expansion cohort, enrollment was expanded at dose level 1. The primary objective was clinical benefit rate (CBR), and secondary objectives were response rate (RR), duration of response (DOR), progression-free survival (PFS), and safety. RESULTS: No dose-limiting toxicities were identified in the dose escalation cohort (n = 6). In the dose expansion cohort, an additional 38 patients were enrolled for a total of 44 patients, including 31 patients (70.4%) with hormone receptor-positive (HR +)/HER2- disease, 12 patients (27.3%) with triple-negative breast cancer (TNBC), and 1 patient (2.3%) with HR + /HER2 + disease. Patients had a median age of 56 years (range 33-82 years), 1 prior line of hormone therapy (range 0-6), and 2 prior lines of chemotherapy (range 0-7). CBR was 79.5% (35/44; 7 partial response, 28 stable disease) and the median DOR was 16.4 weeks (range 13.8-21.1 weeks). Median PFS was 16.4 weeks (95% CI: 13.8-21.1 weeks). The most common grade 3/4 adverse event was neutropenia (47.7%, n = 21). Fourteen of 26 patients (53.8%) with circulating tumor cell (CTC) data were CTC-positive ([Formula: see text] 5 CTC/7.5 mL) at baseline. Median PFS was shorter in patients who were CTC-positive vs. negative (13.1 vs 30.6 weeks, p = 0.011). CONCLUSION: In heavily pretreated patients with ABC, treatment with EC resulted in an encouraging CBR of 79.5% and PFS of 16.4 weeks, which compares favorably to single-agent eribulin. Dose reduction and delays were primarily due to neutropenia. The contribution of cyclophosphamide to eribulin remains unclear but warrants further evaluation. NCT01554371.

Abstract Background With life expectancy on the rise, there has been an increase in patients with concomitant degenerative hip and spine pathology, defined as hip-spine syndrome (HSS). Patients affected by HSS may require both total hip arthroplasty (THA) and lumbar spinal fusion (LSF), although there is a paucity of data regarding how the sequential timing of these procedures may influence clinical outcomes. This study aims to compare complications and spinopelvic parameters in patients with HSS who underwent either LSF first or THA first. Methods A systematic search of PubMed and Scopus was conducted for randomized and nonrandomized studies investigating complications and spinopelvic parameters in patients with HSS who had undergone THA and LSF. The Methodological Index for Non-Randomized Studies (MINORS) tool was utilized to assess the risk of bias in included studies. Relevant outcomes were pooled for meta-analysis. Results Eleven articles were included in this study. There was a significantly higher THA dislocation rate in patients who had undergone LSF first compared to those who had THA first (OR: 3.17, 95% CI 1.23–8.15, P = 0.02). No significant difference was found in terms of THA aseptic loosening (OR: 0.86; 95% CI 0.32–2.32, p = 0.77) and revision rate (OR: 1.18, 95% CI: 0.53–2.62) between these two groups. Individuals who received THA only showed a significantly lower risk of hip dislocation (OR: 0.14, 95% CI: 0.08–0.25, P

While adjuvant treatment with the selective-estrogen receptor modulator (SERM) tamoxifen has been the standard of care for pre-menopausal patients with hormone receptor (HR) positive breast cancer, recent trials showed a benefit of aromatase inhibitors (AI) and ovarian function suppression (OFS) for some patients. The approach to endocrine therapy has not been well studied in pre-menopausal patients with invasive lobular carcinoma (ILC). We identified 202 pre-menopausal patients with HR positive stage I-III ILC in an institutional database. We investigated factors associated with endocrine therapy type and determined changes in systemic therapy from 1990-2021. We evaluated associations between endocrine therapy type and disease-free survival (DFS) with a multivariate Cox proportional hazards model. Of 202 patients, most (69.3%) were prescribed a SERM (99.3% tamoxifen). Those who received an AI had significantly higher stage disease. Over time, use of OFS and AI increased significantly in stage II or III cases (from 0% in 1990 to 56% after 2015 for stage II; from 0% to 80% after 2015 for stage III). Concurrently, adjuvant chemotherapy use significantly decreased in stage II cases (from 67% to 19%). In an exploratory multivariable model, longer duration of AI compared to tamoxifen was associated with significantly improved DFS (HR 0.31; 95% CI 0.11-0.86; p = 0.025). While most pre-menopausal patients received adjuvant tamoxifen, the use of OFS and AIs increased significantly over time. The association between AI use and improved DFS may be consistent with prior randomized trials and warrants further investigation into predictive factors to guide treatment selection.

Abstract Objective Many patients with melanoma treated with immune checkpoint inhibitors (ICIs) do not derive response. Preclinical and retrospective studies identified that inhibition of the cyclooxygenase (COX) pathway may improve response to ICI treatment. Methods This prospective single site phase II trial accrued patients with advanced/metastatic melanoma. Participants underwent high-dose aspirin daily combined with pembrolizumab and ipilimumab every 3 weeks for 4 cycles followed by high-dose aspirin and pembrolizumab monotherapy. The primary endpoint was objective response rate (ORR). Longitudinal sampling of blood was performed to assess peripheral immune correlates. Results Twenty-seven subjects were enrolled with median follow-up of 32 months. An ORR of 62.9% was reached prior to discontinuation due to low likelihood of achieving the pre-specified ORR of 80%. 17 patients (63%) experienced a treatment-related adverse event (TRAEs) grade 3 or higher. A per-protocol analysis showed that patients able to continue aspirin alongside ICI through the induction period experienced significant survival benefit. Ten cytokines and increased regulatory T cells in the periphery correlated with beneficial response. Conclusions The addition of high-dose aspirin to combination ICI within this study results in response comparable to ICI alone. Future clinical studies of COX inhibition will need to focus on mitigation of AEs to establish the clinical utility of this combination.

IntroductionEGFR mutations drive a subset of NSCLC. Patients harboring the common EGFR mutations, deletion of exon 19 and L858R, respond well to osimertinib, a third-generation tyrosine kinase inhibitor. Nevertheless, the effect of osimertinib on NSCLC with atypical EGFR mutations is not well described. This multicenter retrospective study evaluates the efficacy of osimertinib among patients with NSCLC harboring atypical EGFR mutations.MethodsPatients with metastatic NSCLC treated with osimertinib, harboring at least one atypical EGFR mutation, excluding concurrent deletion of exon 19, L858R, or T790M mutations, from six U.S. academic cancer centers were included. Baseline clinical characteristics were collected. The primary end point was the time to treatment discontinuation (TTD) of osimertinib. Objective response rate by the Response Evaluation Criteria in Solid Tumors version 1.1 was also assessed.ResultsA total of 50 patients with NSCLC with uncommon EGFR mutations were identified. The most frequent EGFR mutations were L861Q (40%, n = 18), G719X (28%, n = 14), and exon 20 insertion (14%, n = 7). The median TTD of osimertinib was 9.7 months (95% confidence interval [CI]: 6.5-12.9 mo) overall and 10.7 months (95% CI: 3.2-18.1 mo) in the first-line setting (n = 20). The objective response rate was 31.7% (95% CI: 18.1%-48.1%) overall and 41.2% (95% CI: 18.4%-67.1%) in the first-line setting. The median TTD varied among patients with L861Q (17.2 mo), G719X (7.8 mo), and exon 20 insertion (1.5 mo) mutations.ConclusionsOsimertinib has activity in patients with NSCLC harboring atypical EGFR mutations. Osimertinib activity differs by the type of atypical EGFR-activating mutation.

Abstract Background Despite publications assuring no increased risk for acute cardiovascular events (excluding myocarditis) and sudden death following administration of COVID19 vaccines, these issues still stir much public ado. We assessed the risk for acute cardiovascular events that require hospitalization (excluding myocarditis) and for mortality in the short-term following administration of the second dose of the Pfizer COVID19 vaccine in Israel. Methods Using a self-controlled case series (SCCS) study design and national databases, all second-dose vaccinees, who had not been diagnosed with COVID19 and who had an acute cardiovascular event (acute myocardial infarction/acute stroke/acute thromboembolic event) that required hospitalization in the 60 days following vaccine administration between Jan 11th, 2021 and Oct 31st 2021, were included. A similar analysis was carried out for mortality. The first 30 days following vaccination were defined as risk period while the next 30 days were defined as control period. The probability for an event between these periods was compared using a conditional logistic regression model, accounting for sex, age group, background morbidity and seasonal risk. Results Out of 5,700,112 second dose vaccinees, 4,163 had an acute cardiovascular event in the 60 days following vaccine administration. Following exclusion of 106 due to technical considerations, 1,979 events occurred during the risk period and 2,078 during the control period: Odds ratio, OR = 0.95, 95% confidence interval, CI 0.90–1.01, p = 0.12. Adjusted OR was similar (OR = 0.88, 95%CI 0.72–1.08). Stratifying by age showed no increased risk in any age group. Mortality assessment indicated low number of events in both periods. These results were consistent in sensitivity analyses. Conclusions There was no increased risk for acute cardiovascular events (excluding myocarditis) in the risk period compared to the control period following administration of the second dose of Pfizer COVID19 vaccine. Mortality data raised no concerns either, but may have been biased.

Leptomeningeal disease (LMD) is a devastating complication of metastatic breast cancer (MBC). In this non-therapeutic study, we enrolled 12 patients with MBC and known or suspected LMD who were undergoing a lumbar puncture as part of clinical care and collected extra cerebrospinal fluid (CSF) and a paired blood sample from each patient at a single time point. Of the 12 patients, 7 patients are confirmed to have LMD based on positive cytology and/or convincing MRI imaging (LMDpos), and 5 patients are deemed not to have LMD based on similar criteria (LMDneg). Using high-dimensional, multiplexed flow cytometry, we profile and compare the CSF and peripheral blood mononuclear cell (PBMCs) immune populations between patients with LMD and those without. Patients with LMD observe a lower overall frequency of CD45+ cells (29.51% vs. 51.12%, p

Abstract Climate contrasts across drainage divides, such as orographic precipitation, are ubiquitous in mountain ranges, and as a result, mountain topography is often asymmetric. During glacial periods, these climate gradients can generate asymmetric glaciation, which may modify topographic asymmetry and drive divide migration during glacial‐interglacial cycles. Here we quantify topographic asymmetry caused by asymmetric glaciation and its sensitivity to different climate scenarios. Using an analytical model of a steady‐state glacial profile, we find that the degree of topographic asymmetry is primarily controlled by differences in the equilibrium line altitude across the divide. Our results show that glacial erosion can respond to the same climate asymmetry differently than fluvial erosion. When there are precipitation differences across the divide, glacial erosion produces greater topographic asymmetry than fluvial erosion, all else equal. These findings suggest that glaciations may promote drainage reorganization and landscape transience in intermittently glaciated mountain ranges.

This historical review on the semantic evolution of human senses and sensors revealed that Aristotle’s list of the five senses sight, hearing, touch, taste, and smell is still in use among non-scientific lay persons. It is no surprise that his classification in the work “De Anima” (On the Soul) from 350 BC confuses the sensor “touch” with the now more comprehensively defined somatosensory system and that senses are missing such as the later discovered vestibular system and the musculotendinous proprioception of the position of parts of the body in space. However, it is surprising that in the three most influential ancient cultures, Egypt, Greece, and China—which shaped the history of civilization—the concept prevailed that the heart rather than the brain processes perception, cognition, and emotions. This “cardiocentric view” can be traced back to the “Doctrine of Aristotle,” the “Book of the Dead” in ancient Egypt, and the traditional Chinese medicine of correspondence documented in the book “Huang di Neijing.” In Greek antiquity the philosophers Empedocles, Democritus and Aristotle were proponents of the allocation of the spirit and the soul to the heart connected to the body via the blood vessels. Opponents were the pre-Socratic mathematician Pythagoras, the philosopher Plato, and especially the Greek physician Hippocrates who regarded the brain as the most powerful organ in humans in his work “De Morbo Sacro.” The Greek physician Galen of Pergamon further elaborated on the concept of the brain (“cephalocentric hypothesis”) connected to the body by a network of nerves. The fundamental concepts for understanding functions and disorders of the vestibular system, the perception of self-motion, verticality and balance control were laid by a remarkable group of 19th century scientists including Purkynӗ, Mach, Breuer, Helmholtz, and Crum-Brown. It was also in the 19th century that Bell described a new sense of a reciprocal sensorimotor loop between the brain and the muscles which he called “muscular sense,” later termed “kinaesthesia” by Bastian and defined in 1906 as “proprioception” by Sherrington as “the perception of joint and body movements as well as position of the body or body segments, in space.” Both, the vestibular system and proprioception could be acknowledged as senses six or seven. However, we hesitate to recommend “pain”—which is variously assigned to the somatosensory system or extero-, intero-, visceroception—as a separate sensory system. Pain sensors are often not specific but have multisensory functions. Because of this inconsistent, partly contradictory classification even by experts in the current literature on senses and sensors we consider it justified to recommend a comprehensive reorganization of classification features according to the present state of knowledge with an expansion of the number of senses. Such a project has also to include the frequent task-dependent multisensory interactions for perceptual and sensorimotor achievements, and higher functions or disorders of the visual and vestibular systems as soon as cognition or emotions come into play. This requires a cooperation of sensory physiologists, neuroscientists and experienced physicians involved in the management of patients with sensory and multisensory disorders.

Recent breakthroughs in artificial intelligence (AI) language models have elevated the vision of using conversational AI support for mental health, with a growing body of literature indicating varying degrees of efficacy. In this paper, we ask when, in therapy, it will be easier to replace humans and, conversely, in what instances, human connection will still be more valued. We suggest that empathy lies at the heart of the answer to this question. First, we define different aspects of empathy and outline the potential empathic capabilities of humans versus AI. Next, we consider what determines when these aspects are needed most in therapy, both from the perspective of therapeutic methodology and from the perspective of patient objectives. Ultimately, our goal is to prompt further investigation and dialogue, urging both practitioners and scholars engaged in AI-mediated therapy to keep these questions and considerations in mind when investigating AI implementation in mental health.

Despite improvements in cardiopulmonary resuscitation (CPR), survival and neurologic recovery after cardiac arrest remain poor due to ischemia and subsequent reperfusion injury. As the likelihood of survival and favorable neurologic outcome decreases with increasing severity of ischemia during CPR, developing methods to measure the magnitude of ischemia during resuscitation is critical for improving overall outcomes. Cerebral oximetry, which measures regional cerebral oxygen saturation (rSO2) by near‐infrared spectroscopy, has emerged as a potentially beneficial marker of cerebral ischemia during CPR. In numerous preclinical and clinical studies, higher rSO2 during CPR has been associated with improved cardiac arrest survival and neurologic outcome. There is also emerging evidence that this can be integrated with electroencephalogram (EEG) monitoring to provide a bimodal system of brain monitoring during CPR. In this method’s review, we discuss the feasibility, application, and implications of this integrated monitoring approach, highlighting its significance for improving clinical outcomes in cardiac arrest management and guiding future research directions.

There are still many limitations related to the understanding of the natural history of differing forms of coccidioidomycosis (CM), including characterizing the spectrum of pulmonary disease. The historical Veterans Administration-Armed Forces database, recorded primarily before the advent of antifungal therapy, presents an opportunity to characterize the natural history of pulmonary CM. We performed a retrospective cohort study of 342 armed forces service members who were diagnosed with pulmonary CM at VA facilities between 1955 to 1958, followed through 1966, who did not receive antifungal therapy. Patients were grouped by predominant pulmonary finding on chest radiographs. The all-cause mortality was low for all patients (4.6%). Cavities had a median size of 3-3.9 cm (IQR: 2-2.9-4-4.9 cm), with heterogeneous wall thickness and no fluid level, while nodules had a median size of 1-1.19 cm (Interquartile range [IQR] 1-1.9-2-2.9 cm) and sharp borders. The majority of cavities were chronic (85.6%), and just under half were found incidentally. Median complement fixation titers in both the nodular and cavitary groups were negative, with higher titers in the cavitary group overall. This retrospective cohort study of non-disseminated coccidioidomycosis, the largest to date, sheds light on the natural history, serologic markers, and radiologic characteristics of this understudied disease. These findings have implications for the evaluation and management of CM.

Abstract During the Covid-19 pandemic, accurate PCR tests were augmented by the cheap, rapid, and logistically convenient, yet less sensitive antigen tests. In Israel, a testing policy shift was implemented due to limited availability of PCR tests during the Omicron surge. Thus, both PCR and antigen tests were used, as this was the only alternative for mass testing and surveillance at the time. Yet, evidence-based surveillance requires a robust understanding of the expected consequences of changing the testing policy. Using 41,065 paired tests performed by trained staff between January and April 2022 in Israel, we estimate how the sensitivity of antigen tests changes as a function of Ct value and other key covariates. The results reveal a logarithmic relationship between antigen detection probability and viral load, as quantified by Ct-values of the PCR tests. Further analysis shows a statistically significant association with an odds ratio of approximately 0.76 with each unit of Ct-value. The analysis suggests that in spite of their compromised sensitivity, antigen tests are a natural solution for routine use, while PCR tests should be considered in situations where a false negative result could have serious consequences. These findings are the foundations of policies that will utilize the strengths of the different tests, and achieve enhanced hybrid surveillance.

Significance: Resting-state functional connectivity (RSFC) analyses of functional near-infrared spectroscopy (fNIRS) data reveal cortical connections and networks across the brain. Motion artifacts and systemic physiology in evoked fNIRS signals present unique analytical challenges, and methods that control for systemic physiological noise have been explored. Whether these same methods require modification when applied to resting-state fNIRS (RS-fNIRS) data remains unclear. Aim: We systematically examined the sensitivity and specificity of several RSFC analysis pipelines to identify the best methods for correcting global systemic physiological signals in RS-fNIRS data. Approach: Using numerically simulated RS-fNIRS data, we compared the rates of true and false positives for several connectivity analysis pipelines. Their performance was scored using receiver operating characteristic analysis. Pipelines included partial correlation and multivariate Granger causality, with and without short-separation measurements, and a modified multivariate causality model that included a non-traditional zeroth-lag cross term. We also examined the effects of pre-whitening and robust statistical estimators on performance. Results: Consistent with previous work on bivariate correlation models, our results demonstrate that robust statistics and pre-whitening are effective methods to correct for motion artifacts and autocorrelation in the fNIRS time series. Moreover, we found that pre-filtering using principal components extracted from short-separation fNIRS channels as part of a partial correlation model was most effective in reducing spurious correlations due to shared systemic physiology when the two signals of interest fluctuated synchronously. However, when there was a temporal lag between the signals, a multivariate Granger causality test incorporating the short-separation channels was better. Since it is unknown if such a lag exists in experimental data, we propose a modified version of Granger causality that includes the non-traditional zeroth-lag term as a compromising solution. Conclusions: A combination of pre-whitening, robust statistical methods, and partial correlation in the processing pipeline to reduce autocorrelation, motion artifacts, and global physiology are suggested for obtaining statistically valid connectivity metrics with RS-fNIRS. Further studies should validate the effectiveness of these methods using human data.

Patients with metastatic breast cancer are at high risk for developing vertebral compression fractures due to underlying bone metastases and bone density loss. Vertebral augmentation techniques including percutaneous vertebroplasty and percutaneous balloon kyphoplasty are techniques used to stabilize compression fractures and improve pain. However, rare complications from these interventions have been observed, including spinal cord compression, nerve root compression, venous cement embolism, and pulmonary cement embolism. These complications pose unique potential challenges for patients with cancer who may already have decreased lung function and potential for venous thromboembolism. In this review, we first describe the role of percutaneous vertebral augmentations in patients with metastatic cancer, with a particular focus on patients with breast cancer. Then, we describe complications of vertebral augmentation in two patients with metastatic breast cancer including long-term symptomatic and radiographic follow-up.

Purpose: Declining energy and increasing fatigue, common in older age, predict neurodegenerative conditions, but their neural substrates are not known. We examined brain resting state connectivity in relation to declining self-reported energy levels (SEL) and occurrence of fatigue over time. Methods: We examined resting-state functional MRI in 272 community dwelling older adults participating in the Health Aging and Body Composition Study (mean age 83 years; 57.4 % female; 40.8 % Black) with measures of fatigue and SEL collected at regular intervals over the prior ten years. Functional connectivity (FC) between cortex and striatum was examined separately for sensorimotor, executive, and limbic functional subregions. Logistic regression tested the association of FC in each network with prior fatigue state (reporting fatigue at least once or never reporting fatigue), and with SEL decline (divided into stable or declining SEL groups) and adjusted for demographic, physical function, mood, cognition, and comorbidities. Results: Higher cortico-striatal FC in the right limbic network was associated with lower odds of reporting fatigue (better) at least once during the study period (adjusted odds ratio [95 % confidence interval], p-value: (0.747 [0.582, 0.955], 0.020), independent of SEL. Higher cortico-striatal FC in the right executive network was associated with higher odds of declining SEL (worse) during the study period (adjusted odds ratio [95 % confidence interval], p-value: (1.31 [1.01, 1.69], 0.041), independent of fatigue. Associations with other networks were not significant. Conclusions: In this cohort of older adults, the cortico-striatal functional connectivity of declining SEL appears distinct from that underlying fatigue. Studies to further assess the neural correlates of energy and fatigue, and their independent contribution to neurodegenerative conditions are warranted.