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MTCH Regulates Mitochondrial Clearance during Development
No full textMitochondria are essential for cell health and survival. Understanding the quality control machinery that mitochondria employ to maintain a healthy network is critical for health and disease. Much of what is known about mitochondrial quality control is thought to involve the PINK1/Parkin mitochondrial autophagy (mitophagy) pathway, but alternate pathways have emerged. Our lab showed that the lipid transfer protein Vps13D plays a critical role in mitophagy in the Drosophila developing midgut. Vps13D has been implicated in human movement disorders, highlighting the importance of understanding how it controls this process. Importantly, we do not know what proteins Vps13D may be interacting with at the mitochondrial surface to facilitate mitophagy.
To investigate mitochondrial interactions with Vps13D at the mitochondrial membrane, I performed an RNAi screen against mitochondrial protein-encoding genes that were shown to physically interact with Vps13D in human cells. I discovered that Mtch, the fly homolog of human MTCH2, phenocopies both mitochondrial and autophagic defects that Vps13D mutants display, including failure to clear mitochondria, autophagic cargoes like p62, and the autophagy protein Atg8a. I generated a null mutant for Mtch, which displays phenotypes similar to what is observed by Mtch knockdown with RNAi and Vps13D mutants. Importantly, Mtch mutant cells exhibit a robust decrease in Vps13D protein puncta. I used this Mtch mutant to: (1) characterize the function of Mtch in mitophagy, (2) determine the relationship between Mtch and Vps13D in mitophagy, and (3) investigate the relationship between Mtch and critical regulators of mitophagy, including PINK1, Parkin, and BNIP3. I discovered that Mtch influences each of these mitophagy regulators, particularly the localization of BNIP3 to the mitochondria which may reflect why Mtch mutant cells inhibit mitochondrial clearance. These studies will advance the field by creating a better understanding of mitophagy and will also provide a novel genetic pathway to study that could lead to targeted therapies to correct mitochondrial disorders.Interdisciplinary Graduate Program1 year2026-08-1
Endovascular Therapy for Late-Window M2-Segment Middle Cerebral Artery Occlusion: Analysis of the CLEAR Study
No full textBackground: There is uncertainty about whether patients with M2 occlusion benefit from endovascular therapy (EVT) in the late (6-24-hour) time window. We evaluated the clinical outcomes of patients with M2 occlusion selected for EVT compared with those who received medical management (MM) in the late window.
Methods: This multinational cohort study was conducted at 66 sites across 10 countries (January 2014 to May 2022). We included consecutive patients with late-window stroke due to M2 occlusion, baseline National Institutes of Health Stroke Scale score of ≥5, and premorbid modified Rankin Scale score of ≤2 who received EVT or MM alone. The primary end point was 90-day ordinal shift in the modified Rankin Scale score. Safety end points were symptomatic intracranial hemorrhage and 90-day mortality. Differences in outcomes were determined using inverse probability of treatment weighting-adjusted logistic regression models.
Results: Among 5098 patients, 496 met inclusion criteria (median [interquartile range] age, 74 years [62-81 years]; baseline National Institutes of Health Stroke Scale score, 12 [8-17]), of whom 394 (79.4%) received EVT and 102 (20.6%) MM. In inverse probability of treatment weighting adjusted analyses, there was no favorable 90-day ordinal modified Rankin Scale shift (odds ratio, 1.39 [95% CI, 0.92-2.12]) and no difference of functional independence rates (modified Rankin Scale score of 0-2; odds ratio, 1.72 [95% CI, 0.93-3.15]) with EVT compared with MM. Moreover, symptomatic intracranial hemorrhage risk (odds ratio, 3.46 [95% CI, 0.50-23.92]) and 90-day mortality (odds ratio, 1.11 [95% CI, 0.66-1.87]) were not statistically different between treatment groups.
Conclusions: In patients with M2 occlusion in the 6- to 24-hour time window, there was no difference in disability outcomes or symptomatic intracranial hemorrhage risk between patients treated with EVT compared with MM. Results of ongoing randomized trials will provide further insight.
Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04096248.No embarg
The association between patient's experience of empathy and self-reported health status in a large multisite primary care trial
No full textObjective: The authors report a secondary analysis from a large, multisite, pragmatic trial focused on increasing the degree of behavioral health and primary care service integration. In this analysis, the authors tested for an association between patients' reports of their clinicians' clinical empathy and the patients' self-reported physical and mental health status.
Methods: At two time points across 24 months, 3929 adult patients with chronic medical and behavioral conditions completed the Consultation and Relational Empathy (CARE) measure and the Patient-Reported Outcomes Measurement Information System (PROMIS-29) survey. The CARE was divided into 4 empathy ranges from lowest (median 31) to highest (median 50). While controlling for 49 practice and patient characteristics, the authors tested for an association between empathy range and self-reported physical and mental health (PROMIS).
Results: In adjusted analyses, moving from the lowest to the highest empathy range increased PROMIS (range 20-66) mental health by 2.4-3.0 points and physical health by 1.9-3.2 points. All the models were highly significant. These associations were not explained by any of the 49 measured confounders.
Conclusion: The self-reported health status of primary care patients with multiple chronic conditions is positively correlated with the patient's experience of their clinician's empathy. It is unclear if empathic care is responsible for better outcomes, if better health engenders higher reports of empathy, or if both are caused by a third, unmeasured factor. This finding adds to the evidence that empathic care is associated with improved patient-centered health outcomes.
Practice implications: Providing primary care services that patients experience as high in empathy is a promising strategy for improving physical and mental health.No embarg
Revisiting the Role of Structural Connectivity-Based Parcellation in Thalamic Nuclei Segmentation: comparison with recent state-of-the-art methods [preprint]
No full textThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.Accurate thalamic nuclei segmentation is critical for neuroscience research and clinical interventions such as deep brain stimulation and magnetic resonance guided focused ultrasound. Connectivity based parcellation has been widely used for two decades, yet its anatomical validity remains uncertain compared with newer imaging approaches.
Methods: We analyzed high resolution diffusion magnetic resonance imaging (MRI) and T1 weighted data from 67 healthy young adults in the Human Connectome Project. Connectivity based parcellation was performed using probabilistic tractography with cortical targets derived from the HCP MMP1 atlas, generating 8, 11, and 23 region parcellations. Results were compared against three state of the art methods: orientation distribution function (ODF) clustering, track density imaging (TDI), and the structural MRI based segmentation. Group level analyses were conducted in Montreal Neurological Institute and Hospital (MNI) space, and Dice overlap coefficients were calculated against the histology based Morel atlas.
Results: Connectivity based parcellation demonstrated limited anatomical precision, with increasing cortical target counts introducing greater variability and noise without improving nuclear boundary definition. ODF clustering and TDI recovered subdivisions consistent with cytoarchitectonic patterns, particularly in the pulvinar and mediodorsal nuclei. Structural MRI based segmentation achieved the highest overall Dice coefficients, closely approximating Morel defined boundaries, while Connectivity based parcellation consistently underperformed across nuclei.
Conclusion: Despite methodological advances, Connectivity based parcellation remains constrained in its ability to delineate thalamic nuclei with histological accuracy. By contrast, structural and diffusion microstructural (ODF, TDI) approaches provide superior nuclear localization. These findings highlight the need for hybrid workflows that integrate structural and diffusion based information to enable more reliable thalamic segmentation for research and clinical targeting applications.No embarg
Longitudinal Associations Between Peritraumatic Oestradiol and Fear Responding in Women and Men
No full textPTSD is more prevalent in women than men and associated with autonomic dysfunction. Higher oestradiol levels have been associated with decreased PTSD severity, however, the impact of oestradiol on autonomic function is not well characterised. We examined associations among peritraumatic oestradiol levels and autonomic function in the multi-site AURORA study. Participants (n = 283, 69.6% female) were recruited from the emergency department (ED) following trauma exposure. Skin conductance (SC) was measured during trauma recall at the ED. Oestradiol was assayed from blood collected at ED, 2-week and 6-month. Fear conditioning, including fear potentiated startle (FPS), was completed at 2-week and 6-month. In women, ED oestradiol was significantly positively associated with ED SC and FPS at 6-month. In men, significant negative correlations between ED oestradiol and SC were found. Among women in the study, peritraumatic oestradiol was positively associated with fear responding 6-month. Findings suggest that the protective effects of oestradiol on PTSD may depend on other factors, such as time since trauma. Additional research is needed to elucidate how peritraumatic oestradiol and autonomic function may interact to confer risk for PTSD.No embarg
Digital Assessment of Cognitive Health in Outpatient Primary Care: Usability Study
Get PDFBackground: Screening for cognitive impairment in primary care is important, yet primary care physicians (PCPs) report conducting routine cognitive assessments for less than half of patients older than 60 years of age. Linus Health's Core Cognitive Evaluation (CCE), a tablet-based digital cognitive assessment, has been used for the detection of cognitive impairment, but its application in primary care is not yet studied.
Objective: This study aimed to explore the integration of CCE implementation in a primary care setting.
Methods: A cohort of participants was recruited from the upcoming schedules of participating PCPs at UMass Memorial Medical Center. Eligibility criteria included individuals aged ≥65 years; ability to read, write, and speak in English or Spanish; no previous diagnosis of cognitive impairment; and no known untreated hearing or vision impairment. Research coordinators collected consent from participants and facilitated the screening process. PCPs reviewed reports in real time, immediately before the scheduled visits, and shared results at their discretion. A report was uploaded to each participant's REDCap (Research Electronic Data Capture; Vanderbilt University) record and linked to the encounter in the electronic health record. Feedback from patients and their caregivers (if applicable) was collected by a tablet-based survey in the clinic before and after screening. Participating PCPs were interviewed following the completion of the study.
Results: The screened cohort included 150 patients with a mean age of 74 (SD 7) years, of whom 65% (97/150) were female. The CCE identified 40 patients as borderline and 7 as positive for cognitive impairment. A total of 84 orders were placed for select laboratory tests or referrals to neurology and neuropsychology within 20 days of CCE administration. Before the assessment, 95% (143/150) of patients and all 15 caregivers expressed a desire to know if their or their loved one's brain health was declining. All except one patient also completed the postassessment survey. Among them, 96% (143/149) of patients reported finding the CCE easy to complete, and 70% (105/149) felt that the experience was beneficial. In addition, 87% (130/149) of patients agreed or strongly agreed that they wanted to know their CCE results. Among the 7 participating PCPs, 6 stated that the CCE results influenced their patient care management, and all 7 indicated they would continue using the CCE if it were made available after the study.
Conclusions: We explored the integration of the CCE into primary care visits, which showed minimal disruption to the practice workflow. Future studies will be warranted to further validate the implementation of digital cognitive impairment screening tools within primary care settings in the real world.No embarg
Applications of spectral CT in emergency department imaging, with a focus on neuroimaging
No full textMulti-energy detector spectral CT is a specialized form of dual-energy CT, an imaging technique that takes full advantage of the entire X-ray spectrum applied during CT scans, enabling superior differentiation of materials that may be indistinguishable on traditional CT. Contrary to source-based dual-energy CT, the benefits of detector-based spectral CT are always available with every scan, without needing to preemptively manually select dual source technique at the time of scanning. In cases of questionable findings on conventional CT images that require enhanced material differentiation, "spectral" data collected alongside CT images scanned utilizing this technique can be instantly analyzed to improve diagnostic confidence, without needing to re-scan the patient. While applicable to various patient populations and clinical scenarios, spectral CT is particularly useful for neuroradiology in the often fast-paced emergency department. The authors' facility uses the Philips Healthcare IQon Spectral CT in its own emergency department. This paper strives to briefly introduce some ways that spectral CT can be utilized to improve patient care in this setting.No embarg
Mechanistic Insights into Drug Resistance, Substrate Recognition, and Allostery in SARS-CoV-2 Main Protease
No full textSARS-CoV-2 main protease (Mpro) is essential for viral replication and a leading target for antiviral development against COVID-19. The direct-acting antiviral (DAA) in Paxlovid, nirmatrelvir, inhibits Mpro effectively, but design efforts thus far have not prioritized the avoidance of drug resistance. Emerging drug resistance to Paxlovid could result in massive public health implications, since no other DAAs against Mpro are approved for use at this time.
This dissertation investigates how SARS-CoV-2 Mpro develops resistance, how to design inhibitors that prevent resistance, and what features are essential for broad-spectrum Mpro inhibition across other coronaviruses of pandemic potential. To identify inhibitor interactions most vulnerable to resistance, I calculated the substrate envelope of SARS-CoV-2 Mpro as the consensus shape of its substrates in the active site, and used the envelope to predict possible drug resistance mutations from current therapeutics. Using the substrate envelope, I predicted that E166 would be a hotspot of resistance arising from nirmatrelvir treatment. Thus, I characterized resistant variants E166A and E166V and discovered that L50F is not only hyperactive as a standalone variant but is also a compensatory mutation that restores some catalytic efficiency in combination with highly resistant E166 mutations. These findings offer actionable strategies for designing SARS-CoV-2 DAAs that mimic natural substrates, avoid resistance-prone interactions, and retain potency against resistant variants. To support the development of pan-coronaviral inhibitors, I investigated the evolutionary and structural diversity of coronavirus Mpros. This included solving crystal structures of Mpros from SW1 and HKU15, which revealed both conserved features that may be exploited for broad-spectrum design and divergent elements that may pose challenges for inhibitor generalizability. Finally, I investigated how Mpro coordinates cleavage between its two distal active sites, which exhibit positive cooperativity despite being ~40 Å apart. I designed novel heterodimeric cleavage assays and performed targeted mutagenesis to reveal a conserved network of residues that mediates communication between sites. This work yielded new insights and new questions about Mpro’s cleavage cycle—the sequence of events in dimerization, substrate binding, catalysis, and product release.
Together, these findings improve our understanding of which features of Mpro are most vulnerable to resistance, and how to design inhibitors that avoid those liabilities while preserving potency. By calculating the substrate envelope, identifying compensatory and resistance-conferring mutations, solving divergent coronavirus Mpro crystal structures, and mapping the communication network between active sites, this work lays a foundation for designing resilient antivirals against both SARS-CoV-2 and future coronaviruses with pandemic potential. Plus, it highlights inhibitor design strategies which may be broadly applicable to many drug target enzymes.Biochemistry and Molecular Biotechnology2 years7/31/202
A Summary of the HCC-CARE Symposium: Collaborative Approaches to Reaching Equity in Hepatocellular Carcinoma in Boston by 2030
Get PDFHepatocellular carcinoma (HCC) is a leading cause of cancer mortality in the United States. Disparities in HCC incidence and mortality are amplified in Boston, Massachusetts, which has 42% higher HCC mortality than the nation. HCC-CARE was a one-day symposium that aimed to identify goals and strategies necessary to eliminate HCC disparities in the Greater Boston area by 2030. Sixty-six local and state stakeholders attended the symposium, including HCC clinical experts (eg, medical oncologists) and primary care clinicians representing all seven of Boston's major cancer centers, ancillary staff members (eg, social workers) and state and local government agencies. The symposium included introductory sessions on HCC disparities, conceptual approaches to addressing disparities, and perspectives of local stakeholders on HCC disparities, followed by two interactive workshops where nine groups brainstormed and voted on goals, then developed preliminary action plans. Symposium participants identified four priority goals and developed associated action plans to eliminate HCC disparities by 2030: 1) improving HCC screening rates to enable early detection, 2) employing community engagement and outreach to communities at high risk of HCC, 3) developing a multi-institutional HCC registry to inform care delivery improvements, and 4) connecting patients with HCC to support services to address common barriers to care. A fifth priority around addressing disparities in HCC treatment emerged from post-symposium feedback. HCC-CARE established a knowledge base and raised the saliency of HCC disparities among participants, created a multi-institutional consortium of individuals committed to addressing HCC disparities, and leveraged the wide-ranging expertise of the participants to identify key goals and strategies for achieving equity in HCC outcomes by 2030. These strategies require further development and implementation through multi-institutional committees established after the symposium for each priority area. The Symposium represented a key first step in launching coordinated efforts to reduce HCC disparities that other cities may emulate.No embarg
Storytelling for Health Promotion: A Scoping Review
No full textObjective
To examine storytelling interventions as health promotion tools in underserved populations across disease states, including hypertension, diabetes, overall chronic disease, obstetric care, and preventative health to assess intervention design and cultural tailoring and analyze reported quantitative and qualitative health outcomes.
Data Source
A comprehensive literature search was performed in PUBMED.
Study Inclusion and Exclusion Criteria
Studies were included if they implemented a storytelling intervention to promote health knowledge, behavior change, or health-related outcomes. Excluded studies lacked an evaluated intervention or reported outcomes. Reviews, commentaries, editorials, protocols without outcome data, and duplicate publications without novel findings were excluded. Only English-language studies were included due to reviewer fluency.
Data Extraction
Twenty-five studies were included and categorized based on disease focus.
Data Synthesis
A narrative synthesis and inductive content analysis was performed. Studies were grouped by disease state and analyzed for population demographics, intervention development and delivery, cultural tailoring, storytelling theory, and measured outcomes.
Results
Storytelling, in digital and oral formats, improved health knowledge, self-efficacy, and preventive behaviors. Several methods were employed to culturally tailor interventions. Interventions were based on multiple behavioral theories.
Conclusions
When culturally tailored and rooted in theory, regardless of delivery format, storytelling can foster behavior change across diverse health conditions.No embarg