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UMCCTS Newsletter, January 2025
Get PDFThis is the January 2025 issue of the UMass Center for Clinical and Translational Science Newsletter containing news and events of interest.Supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grants UL1 TR001453, TL1 TR001454 and KL2 TR001455.No embarg
Interventional Management of Pain with Cryoneurolysis: Expert Consensus Recommendations for Standardizing Patient Selection and Techniques Based on Delphi Process
No full textPURPOSE: To develop expert consensus recommendations for patient selection and procedural techniques in cryoneurolysis for chronic pain management using a Delphi process.
MATERIALS AND METHODS: A panel of 22 international interventionists participated in a two-round Delphi process. Participants rated 42 statements on a 10-point Likert scale (1 = strongly disagree, 10 = strongly agree). Consensus was predefined as ≥ 75% of ratings ≥ 7. Descriptive statistics (n, mean ± SD, % ≥ 7) were calculated.
RESULTS: High agreement supported cryoneurolysis for localized chronic pain refractory to conservative therapies (mean 8.55 ± 0.60; 100% ≥ 7) and cases with identifiable peripheral nerve targets (8.45 ± 0.74; 100% ≥ 7). Imaging guidance was deemed essential for nerve identification and probe placement (8.91 ± 0.29; 100% ≥ 7). The panel endorsed individualized freeze-thaw cycles to achieve Sunderland II injury (8.27 ± 0.83; 91% ≥ 7) and emphasized thorough patient education (9.0 ± 0.0; 100% ≥ 7). Experts recommended repeat cryoneurolysis within weeks if initial response was incomplete (8.64 ± 0.65; 100% ≥ 7) and alternative therapies after two unsuccessful sessions (8.36 ± 0.73; 95% ≥ 7). No consensus was reached on restricting treatment to a single anatomical region (5.82 ± 2.91; 50% ≥ 7) or routine prophylactic antibiotics (6.27 ± 2.57; 54% ≥ 7).
CONCLUSION: This Delphi study establishes expert-derived consensus standards for cryoneurolysis, highlighting careful patient selection, mandatory imaging guidance, and flexible freeze protocols while identifying areas requiring further research.No embarg
Early life adversity increases risk for chronic post-traumatic pain, data from humans and rodents
No full textTraumatic stress exposures (TSEs) are common in life. Although most individuals recover after a TSE, a substantial subset develop adverse post-traumatic neuropsychiatric sequelae such as chronic post-traumatic musculoskeletal pain (CPMP). Vulnerability factors for CPMP are poorly understood, which hinders identification of high-risk individuals for targeted interventions. One known vulnerability factor for many pain types is exposure to early life adversity (ELA), but few studies have assessed whether ELA increases risk for CPMP. This study used data from the Advancing Understanding of RecOvery afteR traumA study, a prospective human cohort study of TSE survivors, to test the hypothesis that ELA increases risk for CPMP. In addition, in secondary analyses, we assessed which subtypes of ELA (including childhood bullying) were most predictive of CPMP and whether a rat ELA model consisting of neonatal limited bedding, combined with single prolonged stress (SPS) in adulthood, would accurately model human findings. In Advancing Understanding of RecOvery afteR traumA study participants (n = 2480), using multinomial logistic regression modeling of 4 identified latent pain classes, we found that ELA increased vulnerability to the high unremitting pain class (odds ratio [OR] = 1.047, P < 0.001), the moderate pain class (OR = 1.031, P < 0.001), and the moderate recovery pain class (OR = 1.018, P = 0.004), with physical abuse, emotional abuse, and bullying being the strongest predictors of high pain class assignment. Similarly, in male and female Sprague Dawley rats, in comparison with SPS alone, neonatal limited bedding combined with SPS caused increased baseline sensitivity and prolonged mechanical hypersensitivity (F(11,197) = 3.22, P < 0.001). Further studies in animals and humans are needed to understand mechanisms by which ELA confers vulnerability to CPMP.No embarg
Joint Decomposition of Hi-C Maps Reveals Nuclear Compartmentalization Across Tissues and Model Systems
Get PDFThe three-dimensional organization of chromatin within the cell nucleus establishes a critical structure-function relationship, significantly influencing gene regulation, cell identity, and organ development. Although contact frequency maps from chromosome conformation capture-based technologies (e.g. Hi-C, Micro-C) are now available for many samples, integrative analysis of the variability, stability, and differences in genome architecture across tissues and cell types remains limited due to methodological challenges. For the study of genome compartmentalization and long-range interactions within and between chromosomes, the traditional analytical framework involves matrix decomposition of suitably pre-processed Hi-C maps. The first component of this approach produces the widely recognized “A/B” compartment score. However, conventional methods, when applied separately to multiple samples, result in low-dimensional embeddings situated in distinct vector spaces that are not directly comparable. Existing normalization approaches are insufficient to overcome this limitation, especially for higher-order components, which capture more complex features of compartmentalization and more subtle patterns of interaction.
To address this gap, I developed jointly-hic, a novel analytical framework and software package to jointly decompose interchromosomal Hi-C contact maps into a shared vector space. The package handles large-scale datasets with fixed memory usage and linear compute time scaling with the number of samples. Comparisons between jointly-hic and traditional methods demonstrate that jointly-hic produces robust and coherent embeddings of multiple datasets. Applying jointly-hic to an integrative analysis encompassing 89 high-quality Hi-C datasets and more than 1,500 complementary epigenomic assays, including ChIP-seq, ATAC-seq, and RNA-seq revealed sets of genomic loci sharing distinct long-range interaction patterns within and across cell types. Further investigation provided evidence for distinct nuclear architectures associated with ex vivo tissues, peripheral immune cells, and in vitro cell cultures characterized by differences in heterochromatin composition. Additionally, we explored the interplay between genome architecture, gene expression, and regulatory changes using an in vitro cardiomyocyte developmental model, demonstrating that the inclusion of higher-order components provides a substantial improvement in explanatory power for changes in gene regulation and expression. Finally, we applied jointly-hic to an in vitro hepatocyte developmental model, revealing an increase in compartmentalization, interaction stability, and chromosome territoriality following the lineage commitment transition during cellular differentiation.
Collectively, this dissertation introduces a new analytical framework for long-range 3D genomic studies, enabling integrative analysis across diverse tissues, conditions, and developmental contexts. These findings provide valuable insights into genome compartmentalization across human tissues and cell types and how these patterns change during differentiation.MD/PhDBioinformatics and Computational BiologyNo embarg
High-density Lipoprotein Over Midlife and Future Cognition in Women: The SWAN HDL Ancillary Study
No full textContext: Limited data provides evidence-based insights on the association between the comprehensive metrics of high-density lipoproteins (HDL) and cognitive performance, especially in midlife women for whom the benefit might be the greatest.
Objective: To assess the associations of serum HDL metrics including HDL lipid content [HDL cholesterol, phospholipid (HDL-PL), triglyceride], proteins/subclasses [apolipoprotein A-1 (apoA-1); small, medium, large, total HDL particle (HDL-P); and HDL size], and cholesterol efflux capacity with cognitive performance in midlife women.
Methods: This prospective cohort study was conducted among 503 midlife women (1234 observations) from the Study of Women's Health Across the Nation HDL ancillary study. Joint models were applied to examine associations of HDL metrics assessed at midlife (50.2 ± 2.9 years, baseline of the current study) and their changes over midlife (6.1 ± 3.9 years of duration) with subsequent cognitive performance [working memory (Digit Span Backward Test), processing speed (Symbol Digit Modalities Test), and episodic memory immediate and delayed recall (East Boston Memory Test)] assessed repeatedly (maximum 5 times) 1.5 ± 1 years later over 7.72 ± 4.10 years of follow-up.
Results: Higher total HDL-P and smaller HDL size at midlife were associated with a better subsequent immediate recall, delayed recall, and/or processing speed. Greater increase in HDL-PL, apoA-1, medium HDL-P, and total HDL-P and less increase in HDL size over midlife were associated with a better subsequent immediate and/or delayed recall.
Conclusion: Enhancing specific serum HDL metrics during midlife could be promising in cognitive restoration, particularly memory, the initial and predominant symptom of Alzheimer's disease.No embarg
Biological rhythms: In the sea, two clocks are better than one
No full textHow marine species cope with both diurnal and tidal cycles is unclear. A new study in crustaceans identifies distinct brain cells that exhibit either 24- or 12.4-hour rhythms of gene expression, thus providing a mechanism for tracking multiple environmental cycles.No embarg
The Role of Grhl3 in the Mouse Thymus
No full textThe thymus plays a key role in central tolerance through maturation and selection of thymocytes into functional and non-self-reactive T cells. Within the thymus, the primary functional cells are the thymic epithelial cells (TECs), which are further divided between the cortex, responsible for positive selection of functional thymocytes, and the medulla, responsible for negative selection of self-reactive T cells. While there is increasing knowledge of the heterogeneity within TECs, and in particular TECs within the medulla (mTECs), the precise mechanisms underlying the regulatory control leading to this heterogeneity remains largely unknown. Recent studies have identified members of the Grainyhead-like (Grhl) transcription factor family, specifically Grhl1 and Grhl3, to be associated with multiple facets of thymus development. Here, we focus on Grhl3, identifying it as more specific to early mTEC development than other members of the family and utilize a conditional knockout to reveal two opposing effects within the adult thymus. Furthermore, we identify perturbed development in the embryonic thymus, providing some evidence of a possible origin for the perturbations in the adult. In summary, this dissertation provides insight into the role of the Grainyhead-like family within the thymus and the regulatory control that it exerts.Bioinformatics and Computational Biology2 years8/19/202
POCUS Standoff: Comparing Ultrasound Interfaces for Soft Tissue Foreign Body Imaging
No full textBackground: Point-of-care ultrasound can be used to identify foreign bodies (FBs) in soft tissue. Imaging interfaces such as standoff pads and water baths can improve image resolution for superficial soft tissue structures. Our objective was to determine the optimal interface for FB detection. We hypothesized that water baths would be associated with the greatest FB detection accuracy and image quality.
Methods: Prospective analysis of ultrasound imaging interfaces to detect FBs. 18 emergency physicians in training were enrolled: 8 interns, 8 senior residents, and 2 fellows. Four imaging interfaces were compared: gel, saline bag standoff, water bath, and a novel proposed interface: water-filled patient belongings bag (PBB). Standardized FBs (wood, plastic, and metal) were inserted into porcine models, which were imaged by participants using the interfaces. The primary outcome was the accuracy of FB detection for the interfaces. Secondary outcomes included time to FB detection, image quality, and impact of training level. Ultrasounds were reviewed by 2 blinded ultrasound fellowship-trained emergency physicians to determine FB visibility and image quality. Data analysis was performed using the χ2 test and Kruskal-Wallis test with GraphPad Prism Software.
Results: Eighteen participants completed 16 stations. Two hundred eighty-eight ultrasounds total. Interface types demonstrated a trend of greatest accuracy for PBB, followed by water bath, gel, and saline bag. Gel was significantly more accurate than saline bag (P=0.0120). Gel did not have a significant difference from PBB (P=0.1425) or water bath (P=0.125). As training level increased, time to FB detection significantly decreased (P=0.02), and accuracy increased. Accuracy for fellows was significantly greater than for senior residents (P=0.0473) and interns (P=0.0027). There was a trend of greater accuracy in senior residents from interns.However, there was no significant difference (P=0.0729).
Conclusions: PBBs may be a viable alternative interface for soft tissue FB detection. PBBs, water baths, and gel should be considered prior to saline standoffs.No embarg
Exploring Racial Microaggressions in Baccalaureate Nursing Education: A Qualitative Descriptive Study
No full textAim: The purpose of this study was to examine how baccalaureate nursing students who identify as persons of color perceive the impact of racial microaggressions on academic integration, sense of belonging, and persistence to graduation.
Background: In the United States, baccalaureate students with historically marginalized racial or ethnic identities experience higher attrition than White students. Racial microaggressions convey discriminatory messages and promote exclusion.
Method: Undergirded by Tinto's institutional departure model, a qualitative descriptive study was conducted using semistructured interviews. Data were analyzed using Braun and Clarke's thematic analysis.
Results: All participants (n = 15) experienced and/or witnessed racial microaggressions as nursing students, most commonly in the clinical setting by patients. Three themes emerged: microaggressions are common, burden of microaggressions, and desired solutions.
Conclusion: Experiencing racial microaggressions leaves students feeling unsafe, unheard, and ruminative. Nurse educators should validate students' experienced reality and lead efforts for intervention.No embarg
Gut microbiome phytoestrogen production and its protective role in Alzheimer’s disease
Get PDFBackground: In Alzheimer’s disease (AD), changes in intestinal microbiota and
systemic inflammation are concomitant with neuroinflammation and cognitive decline.
This has led to the theory of microbial communities or infections as being causative
in the development of neuroinflammation and immunosenescence seen in AD.
Our research has demonstrated a decreased taxonomic diversity and an increased
abundance of pathobionts in the gut of AD patients (Haran, mBio 2019), which is
sufficient to promote amyloid and tau deposition in a mouse model (Chen, Gut 2023).
It is unclear, however, if effects from the AD microbiome on the central nervous
system can be mitigated. Here, we propose a protective mechanism where bacterial
metabolites influence cognition via estrogen signaling.
Method: We have performed gut microbiome profiling on a cohort of 178 nursing
home residents and used in vitro models to quantify the effects of AD-associated
bacteria and bacterial products on inflammation.
Result: We have identified a commensal bacterium, Adlercreutzia equolifaciens, to
be depleted in our cohort of older adults with AD and further depleted in adults
with progressive versus stable AD. A. equolifaciens metabolizes dietary isoflavones
to produce (s)-equol, a bacterial metabolite which binds to estrogen receptors. We
treated cells expressing estrogen receptor beta, which is predominately expressed
along the intestinal epithelium, with (s)-equol and demonstrated (s)-equol induces
transcription of host genomic estrogen response genes (Vehicle normalized luciferase
= 0.007, estradiol = 1.04, (s)-equol = 1.23, p<0.0001). We have further demonstrated
that treatment of intestinal epithelial cells with 17β-estradiol induced the transcription
of regulators of the innate immune response in an ERβ dependent manner (Vehicle RQ
= 0.88, estradiol = 1.84, p<0.05). Finally, we have discovered that colonization with A.
equolifaciens in the gut of older adults is associated with lower rates of colonization by
the intestinal pathobiont Escherichia (Estimation of regression β-coefficient = -1.422,
p<0.05). Conclusion: Adlercreutzia equolifaciens and similar phytoestrogen-metabolizing
bacteria may protect the intestinal epithelium against bacterial invasion and
subsequent systemic inflammation, thereby preventing cognitive decline. Our
continuing work aims to further establish the connection between AD related
neurocognitive decline, the microbiome, and immune system. A. equolifaciens is
therefore a strong candidate as a microbiome-based therapeutic acting along the
gut-brain axis in AD.No embarg