Alpha-1 Antitrypsin Augmentation Therapy in Chronic Pancreatitis Patients Undergoing Total Pancreatectomy and Islet Autotransplantation: A Randomized, Controlled Study.

Stress-induced islet graft loss during the peri-transplantation period reduces the efficacy of islet transplantation. In this prospective, randomized, double-blind clinical trial, we evaluated the safety and efficacy of 60 mg/kg human alpha-1 antitrypsin (AAT) or placebo infusion weekly for four doses beginning before surgery in chronic pancreatitis (CP) patients undergoing total pancreatectomy and islet autotransplantation (TP-IAT). Subjects were followed for 12 months post-TP-IAT. The dose of AAT was safe, as there was no difference in the types and severity of adverse events in participants from both groups. There were some biochemical signals of treatment effect with a higher oxygen consumption rate in AAT islets before transplantation and a lower serum C-peptide (an indicator of islet death) in the AAT group at 15 min after islet infusion. Findings per the statistical analysis plan using a modified intention to treat analysis showed no difference in the C-peptide area under the curve (AUC) following a mixed meal tolerance test at 12 months post-TP-IAT. There was no difference in the secondary and exploratory outcomes. Although AAT therapy did not show improvement in C-peptide AUC in this study, AAT therapy is safe in CP patients and there are experiences gained on optimal clinical trial design in this challenging disease.

Text And Telephone Screening And Referral Improved Detection And Treatment Of Maternal Mental Health Conditions.

Effective screening and referral practices for perinatal mental health disorders, perinatal substance use disorders (SUDs), and intimate partner violence are greatly needed to reduce maternal morbidity and mortality. We conducted a randomized controlled trial from January 2021 to April 2023 comparing outcomes between Listening to Women and Pregnant and Postpartum People (LTWP), a text- and telephone-based screening and referral program, and usual care in-person screening and referral within the perinatal care setting. Participants assigned to LTWP were three times more likely to be screened compared with those assigned to usual care. Among participants completing a screen, those assigned to LTWP were 3.1 times more likely to screen positive, 4.4 times more likely to be referred to treatment, and 5.7 times more likely to attend treatment compared with those assigned to usual care. This study demonstrates that text- and telephone-based screening and referral systems may improve rates of screening, identification, and attendance to treatment for perinatal mental health disorders and perinatal SUDs compared with traditional in-person screening and referral systems. System-level changes and complementary policies and insurance payments to support adoption of effective text- and telephone-based screening and referral programs are needed.

Establishing New Isosexual Pairs in Adult Male Guinea Pigs (Cavia porcellus) to Facilitate Social Housing.

Guinea pigs (Cavia porcellus) are a commonly used species in biomedical research. As social creatures, compatible guinea pigs should be housed together unless scientific objectives or veterinary care require otherwise. Extensive literature suggests that adult male guinea pigs are highly aggressive in the presence of females, but data are lacking regarding the compatibility of cohoused adult males in the absence of females. Most studies that use adult males do not report housing densities. We used serial wound scoring and observations of behavior to determine whether unfamiliar adult male guinea pigs will develop stable, prosocial isosexual pairs. Wound scoring was performed before and 24 h after pairing. Serial behavioral observations assessed affiliative and agonistic behaviors at 0.5, 2, 24, and 48 h after pairing. Wound scoring and behavioral observations continued weekly for 1 mo and monthly thereafter. Wound scores were significantly higher at 24 h after pairing as compared with baseline and all other time points. Wounding was rare after week 2, indicating reduced aggression. Furthermore, affiliative behaviors significantly increased over time while agonistic behaviors were rare. Together, these data suggest that unfamiliar adult male guinea pigs establish stable prosocial pairs after an acclimation period. As was done in the present study, providing ample space, separate shelters for each animal, and the absence of female guinea pigs will likely facilitate successful pairing. We recommend consideration of a social housing program for adult male guinea pigs to provide companionship and enrich their housing environment.

Barriers and facilitators to the implementation of family cancer history collection tools in oncology clinical practices.

INTRODUCTION: This study aimed to identify barriers and facilitators to the implementation of family cancer history (FCH) collection tools in clinical practices and community settings by assessing clinicians' perceptions of implementing a chatbot interface to collect FCH information and provide personalized results to patients and providers. OBJECTIVES: By identifying design and implementation features that facilitate tool adoption and integration into clinical workflows, this study can inform future FCH tool development and adoption in healthcare settings. MATERIALS AND METHODS: Quantitative data were collected using survey to evaluate the implementation outcomes of acceptability, adoption, appropriateness, feasibility, and sustainability of the chatbot tool for collecting FCH. Semistructured interviews were conducted to gather qualitative data on respondents' experiences using the tool and recommendations for enhancements. RESULTS: We completed data collection with 19 providers (n = 9, 47%), clinical staff (n = 5, 26%), administrators (n = 4, 21%), and other staff (n = 1, 5%) affiliated with the NCI Community Oncology Research Program. FCH was systematically collected using a wide range of tools at sites, with information being inserted into the patient's medical record. Participants found the chatbot tool to be highly acceptable, with the tool aligning with existing workflows, and were open to adopting the tool into their practice. DISCUSSION AND CONCLUSIONS: We further the evidence base about the appropriateness of scripted chatbots to support FCH collection. Although the tool had strong support, the varying clinical workflows across clinic sites necessitate that future FCH tool development accommodates customizable implementation strategies. Implementation support is necessary to overcome technical and logistical barriers to enhance the uptake of FCH tools in clinical practices and community settings.

Impact of Reducing Fluoroscopy Pulse Rate on Adult Modified Barium Swallow Studies.

Modified Barium Swallow Studies (MBSS) are a critical part of the evaluation, treatment planning, and outcome assessment for persons with swallowing disorders. Since MBSSs use ionizing radiation with associated cancer risks, many clinicians have reduced radiation exposure by reducing the fluoroscopic pulse rate. However, by reducing pulse rate, we also decrease the temporal resolution of MBSSs which has been shown in pilot studies to significantly reduce diagnostic accuracy. Two hundred MBSSs from patients routinely undergoing MBSS as standard of care conducted at 30 pulses per second (pps) using the Modified Barium Swallow Study Impairment Profile (MBSImP™) standardized administration protocol were selected. A stratified sampling method ensured that a full range of swallowing impairments (etiology, type, and severity) was represented. Recordings were down sampled from 30 pps to 15, 7.5, and 4 pps. MBSSs were rated using the MBSImP components and Penetration-Aspiration Scale (PAS) score for each swallow. Percent agreement was calculated across raters for MBSImP and PAS scores by bolus type and volume. The Least-Squares Method was used for hypothesis testing. Statistically significant and clinically meaningful changes in scores of swallowing physiology and penetration/aspiration occurred when reducing pulse rate below 30pps. These changes were evident across bolus types and volumes. Given the impact on diagnostic accuracy and the low radiation risks to adults undergoing MBSSs, reducing pulse rate to 15pps or below is not aligned with the As Low As Reasonably Achievable (ALARA) principle and should not be used as a viable method to reduce radiation exposure from MBSSs.

Comparison of three magnetic resonance imaging measures of brain iron in healthy and cocaine use disorder participants.

Several magnetic resonance imaging (MRI) measures for quantifying endogenous nonheme brain iron have been proposed. These correspond to distinct physical properties with varying sensitivities and specificities to iron. Moreover, they may depend not only on tissue iron concentration, but also on the intravoxel spatial pattern of iron deposition, which is complex in many brain regions. Here, the three MRI brain iron measures of R 2 * , magnetic field correlation (MFC), and magnetic susceptibility are compared in several deep gray matter regions for both healthy participants (HPs) and individuals with cocaine use disorder (CUD). Their concordance is assessed from their correlations with each other and their relative dependencies on age. In addition, associations between the iron measures and microstructure in adjacent white matter regions are investigated by calculating their correlations with diffusion MRI measures from the internal capsule, and associations with cognition are determined by using results from a battery of standardized tests relevant to CUD. It is found that all three iron measures are strongly correlated with each other for the considered gray matter regions, but with correlation coefficients substantially less than one indicating important differences. The age dependencies of all three measures are qualitatively similar in most regions, except for the red nucleus, where the susceptibility has a significantly stronger correlation with age than R 2 * . Weak to moderate correlations are seen for the iron measures with several of the diffusion and cognitive measures, with the strongest correlations being obtained for R 2 * . The iron measures differ little between the HP and CUD groups, although susceptibility is significantly lower in the red nucleus for the CUD group. For the comparisons made, the iron measures behave similarly in most respects, but with notable quantitative differences. It is suggested that these differences may be, in part, attributable to a higher sensitivity to the spatial pattern of iron deposition for R 2 * and MFC than for susceptibility. This is supported most strongly by a sharp contrast between the values of the iron measures in the globus pallidus relative to those in the red nucleus. The observed correlations of the iron measures with diffusion and cognitive scores point to possible connections between gray matter iron, white matter microstructure, and cognition.

A study of collagen refractility in dermatofibroma and dermatofibrosarcoma protuberans using diffractive microscopy.

BACKGROUND: Diffractive microscopy creates contrast within samples that are otherwise uniform under bright light. This technique can highlight subtle differences in refractive indices within birefringent samples containing varying amounts of mature collagen. Dermatofibroma (DF) and dermatofibrosarcoma protuberans (DFSP) possess differences in their mature collagen content and, therefore, may be distinguishable using diffractive microscopy. METHODS: Two hundred forty-two DF and 85 DFSP hematoxylin-eosin (H&E)-stained specimens were analyzed using diffractive microscopy. Data regarding the distribution pattern and strength of refractility was recorded. RESULTS: DFSP was more frequently found to be focally, weakly, or non-refractile (82.9%; n = 68) under diffractive microscopy, while DF more often showed diffusely bright refractility (52.9%; n = 128). DFSP samples with diffuse refractility in portions of the lesion (17.1%; n = 14) also exhibited a unique checkerboard pattern distinct from that which was seen in DF samples. CONCLUSIONS: The absence of diffuse refractility was more closely associated with DFSP, as was the presence of a unique checkerboard diffraction pattern. Despite high sensitivity (Sn = 82.9%), absent refractility was not a specific test (Sp = 52.9%), with 47.1% (n = 114) of DF samples sharing this feature. The distinction between DF and DFSP is often diagnosed using H&E alone. In difficult cases, examination of collagen under diffractive microscopy may be useful in distinguishing DFSP from DF and provide an alternative cost-effective tool to immunohistochemical staining.

Cytologic atypia of benign inflammatory versus neoplastic cutaneous squamous lesions.

BACKGROUND: Cytologic atypia encompasses several features of abnormal cellular morphology. We sought to quantify these features in benign and premalignant/malignant squamous cell lesions to better characterize criteria for malignancy. METHODS: We conducted a rater-blinded observational study in which histopathology slides were evaluated under light microscopy, and the presence and relative quantity of 24 distinct cytological features were recorded, along with respective diagnoses. Each slide was evaluated, and the ratings were recorded and analyzed. RESULTS: The most helpful findings, whose presence in high numbers indicates an increased likelihood that the tissue sample is premalignant/malignant, were: (1) pleomorphic parakeratosis; (2) pleomorphic nuclei in the epithelium; (3) irregular nuclei; (4) thick refractile nuclear envelope; (5) presence of nuclear hyperchromasia (dark gray); (6) peripheral nucleoli; and (7) nucleolar stems. Higher values of round or oval nuclear shape and vesicular nuclei increase the likelihood that the tissue sample is benign. CONCLUSIONS: Certain nuclear features have a higher association with premalignancy/malignancy and may guide histologic evaluation of a given lesion. These findings can be used in combination with architectural features and clinical history to add to a complete diagnostic picture.

Dermatofibroma Versus Dermatofibrosarcoma Protuberans: A Nuclear Morphology Study.

ABSTRACT: The locally invasive soft-tissue sarcoma, dermatofibrosarcoma protuberans (DFSPs), shares certain histologic features of the much more common and benign dermatofibroma (DF). While immunohistochemical stains, specifically cluster of differentiation 34 and Factor XIIIa, can be used to distinguish the 2 entities using microscopy, these markers are not entirely sensitive nor specific. Three-dimensionally, DFSP nuclei resemble a "puck" or "coin"-like shape. As hematoxylin/eosin-stained slides are prepared, these "puck" nuclei are fixed in an infinite number of orientations depending on their current position in rotation about their axes within the tumor cells. Under histological examination, this random nuclear positioning produces the appearance of 2 predominate morphologies: an ovoid "disk" shape (en face) and a narrow spindled shape (side view), which distribute in a roughly 50:50 ratio throughout the tumor sample slide. Nuclear morphology was analyzed in 324 DFSP and DF samples at high magnification (×400) to determine the presence or absence of a predominant morphology in which nuclei appear to alternate between an ovoid (en face) and spindled (side view) throughout most of the tumor sample. An alternating ovoid-spindled nuclear morphology was the predominant cytology in 98% of DFSP and was not predominant in 100% of DF samples (P < 0.001). This morphology was found to be highly specific (Sp = 1) and sensitive (Sn = 0.98) for DFSP. This unique nuclear morphology may be a more sensitive and specific diagnostic tool in identifying DFSP from DF in comparison with costly immunohistochemical stains.

Identifying barriers to obstructive sleep-disordered breathing care: Parental perspectives.

OBJECTIVE: Despite established clinical practice guidelines for pediatric obstructive sleep-disordered breathing (SDB), disparities persist for this common condition. Few studies have investigated parental experiences about challenges faced in obtaining SDB evaluation and tonsillectomy for their children. To better understand parent-perceived barriers to treatment of childhood SDB, we administered a survey to assess parental knowledge of this condition. MATERIALS & METHODS: A cross-sectional survey was designed to be completed by parents of children diagnosed with SDB. Two validated surveys were administered: 1) Barriers to Care Questionnaire and 2) Obstructive Sleep-Disordered Breathing and Adenotonsillectomy Knowledge Scale for Parents. Logistic regression modeling was performed to assess for predictors of parental barriers to SDB care and knowledge. RESULTS: Eighty parents completed the survey. Mean patient age was 7.4 ± 4.6 years, and 48 (60%) patients were male. The survey response rate was 51%. Patient racial/ethnic categories included 48 (60.0%) non-Hispanic White, 18 (22.5%) non-Hispanic Black, and 14 (17.5%) Other. Parents reported challenges in the 'Pragmatic' domain, including appointment availability and cost of healthcare, as the most frequently described barrier to care. Adjusting for age, sex, race, and education, parents in the middle-income bracket ($26,500 - $79,500) had higher odds of reporting greater barriers to care than parents in the highest (>$79,500) income tier (OR 5.536, 95% CI 1.312-23.359, P = 0.020) and lowest income tier (<$26,500) (OR 3.920, 95% CI 1.096-14.020). Parents whose children had tonsillectomy (n = 40) answered only a mean 55.7% ± 13.3% of questions correctly on the knowledge scale. CONCLUSION: Pragmatic challenges were the most encountered barrier that parents reported in accessing SDB care. Families in the middle-income tier experienced the greatest barriers to SDB care compared to lower and higher income families. In general, parental knowledge of SDB and tonsillectomy was relatively low. These findings represent potential areas of improvement to target interventions to promote equitable care for SDB.

Hyperbilirubinemia in hospitalized patients: Etiology and outcomes.

There is little information on the differential diagnosis and prognosis of hospitalized patients with hyperbilirubinemia. Here, we hypothesized that hyperbilirubinemia in hospitalized patients is associated with specific diseases and outcomes. This retrospective cohort analysis included patients admitted to the Medical University of South Carolina with a total bilirubin >3 mg/dL from January 9, 2015 to August 25, 2017. Collected clinical data included demographics, primary diagnosis, Charlson Comorbidity Index (CCI), laboratory data, and clinical outcomes. We separated and analyzed the cohort into seven primary diagnostic groups. We identified 1693 patients with a bilirubin level >3 mg/dL. The cohort was 42% female, had an average age of 54, average CCI of 4.8, and average length of stay of 13 days. The causes of hyperbilirubinemia included the following: primary liver disease (868/1693; 51%) with cirrhosis being most common (385/1693; 23%), benign biliary obstruction (252/1693; 15%), hemolytic anemia (149/1693; 9%), malignant biliary obstruction (121/1693; 7%), unknown etiology (108/1693; 6%), primary liver cancer (74/1693; 4%), and metastatic cancer to the liver (57/1693; 3%). Overall, the mortality/discharge to hospice rate in patients with a bilirubin >3 mg/dL was 30%, and was proportional to the severity of hyperbilirubinemia, including when controlling for the underlying severity of illness. Mortality was highest in patients with primary liver disease and malignancy and was lowest in patients with non-cancerous obstruction or hemolytic jaundice. Hyperbilirubinemia in hospitalized patients is most often due to primary liver disease, and identifies patients with a poor prognosis, particularly when caused by primary liver disease or cancer.

Anticipating adaptation: tracking the impact of planned and unplanned adaptations during the implementation of a complex population-based genomic screening program.

In 2021, the Medical University of South Carolina (MUSC) launched In Our DNA SC. This large-scale initiative will screen 100,000 individuals in South Carolina for three preventable hereditary conditions that impact approximately two million people in the USA but often go undetected. In anticipation of inevitable changes to the delivery of this complex initiative, we developed an approach to track and assess the impact of evaluate adaptations made during the pilot phase of program implementation. We used a modified version of the Framework for Reporting Adaptations and Modification-Enhanced (FRAME) and Adaptations to code adaptations made during the 3-month pilot phase of In Our DNA SC. Adaptations were documented in real-time using a REDCap database. We used segmented linear regression models to independently test three hypotheses about the impact of adaptations on program reach (rate of enrollment in the program, rate of messages viewed) and implementation (rate of samples collected) 7 days pre- and post-adaptation. Effectiveness was assessed using qualitative observations. Ten adaptations occurred during the pilot phase of program implementation. Most adaptations (60%) were designed to increase the number and type of patient contacted (reach). Adaptations were primarily made based on knowledge and experience (40%) or from quality improvement data (30%). Of the three adaptations designed to increase reach, shortening the recruitment message potential patients received significantly increased the average rate of invitations viewed by 7.3% (p = 0.0106). There was no effect of adaptations on implementation (number of DNA samples collected). Qualitative findings support improvement in effectiveness of the intervention after shortening the consent form and short-term positive impact on uptake of the intervention as measured by team member's participation. Our approach to tracking adaptations of In Our DNA SC allowed our team to quantify the utility of modifications, make decisions about pursuing the adaptation, and understand consequences of the change. Streamlining tools for tracking and responding to adaptations can help monitor the incremental impact of interventions to support continued learning and problem solving for complex interventions being delivered in health systems based on real-time data.

We tracked adaptations to a large-scale population genetic screening program at the Medical University of South Carolina (MUSC) using the Framework for Reporting Adaptations and Modifications-Enhanced (FRAME). We found adaptations during program roll-out that impacted implementation outcomes. Our approach to tracking adaptations for the program allowed us to quantify the utility of modifications, make decision about pursuing changes, and understand consequences of adaptations.

Sociodemographic Factors Affecting Loss to Follow-Up After Newborn Hearing Screening: A Systematic Review and Meta-Analysis.

OBJECTIVE: Universal newborn hearing screening (NBHS) has been widely implemented as a part of early hearing detection and intervention (EHDI) programs worldwide. Even with excellent provider knowledge and screening rates, many infants do not receive definitive hearing testing or intervention after initial screening. The objective of this study was to identify sociodemographic factors contributing to loss of follow-up. DATA SOURCES: PubMed, Scopus, and CINAHL. REVIEW METHODS: Per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the databases were searched from the date of inception through December 28, 2021. Studies containing sociodemographic information on patients who were referred to NBHS were included. Meta-analysis of odds ratios (ORs) was performed comparing rates of sociodemographic variables between patients adherent and nonadherent to follow-up. RESULTS: A total of 169,238 infants from 19 studies were included. Low birth weight (OR 1.6 [95% confidence interval, CI 1.2-2.2, p < .001), racial minority (OR 1.4 [95% CI 1.2-1.6], p < .001), rural residence (OR 1.5 [95% CI 1.1-1.9], p = .005), lack of insurance (OR 1 [95% CI 1.4-2.5], p < .001), and public or state insurance (OR 1.7 [95% CI 1.2-4.2], p = .008) were associated with missed follow-up after referred NBHS. Associated maternal factors included low maternal education (OR 1.8 [95% CI 1.6-2.0], p < .001), young maternal age (OR 1.5 [95% CI 1.5-1.6], p < .001), unmarried maternal status (OR 1.5 [95% CI 1.1-1.9], p = .003), and current or former maternal smoking status (OR 1.8 [95% CI 1.4-2.2], p < .001). CONCLUSION: Both infant and maternal sociodemographic factors influence follow-up compliance after referred NBHS. Focused efforts should be made by medical providers and policymakers to address these factors to ensure appropriate newborn hearing care and interventions are achieved.

COPE and oxytocin for the treatment of co-occurring PTSD and alcohol use disorder: Design and methodology of a randomized controlled trial in U.S. military veterans.

BACKGROUND: A significant proportion of individuals with alcohol use disorder (AUD) also meet criteria for posttraumatic stress disorder (PTSD). Military veterans are at increased risk for developing co-occurring AUD/PTSD, with prevalence rates 2-4 times higher than the general population. Research is needed to develop more effective treatments for this common comorbidity. The current investigation addresses this need by examining the synergistic effects of a novel pharmacotherapy combined with psychotherapy for co-occurring AUD/PTSD among veterans. Accumulating evidence suggests that the neuropeptide oxytocin (OT) is a promising pharmacotherapy to augment psychotherapy for AUD/PTSD. OT targets neurobiological and behavioral dysregulation common to both AUD and PTSD, in particular, corticolimbic connectivity. Human and animal studies show OT reduces alcohol self-administration, tolerance, and withdrawal; enhances fear extinction; and promotes prosocial behaviors. The current study builds on previous work by examining OT among veterans with AUD/PTSD receiving Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure (COPE), an evidence-based integrated treatment. METHODS: This paper describes the rationale, design, and methodology of a Stage II, 12-week, double-blind, randomized clinical trial of intranasal OT (40 IU) versus placebo combined with COPE among veterans (N = 180) with current AUD/PTSD. In addition, the effects of treatment on corticolimbic connectivity will be examined using functional magnetic resonance imaging (fMRI) at pre- and post-treatment. CONCLUSIONS: The proposed study will provide new knowledge and mechanistic insights to accelerate research in this understudied area and may lead to improved treatment outcomes for co-occurring AUD/PTSD. CLINICALTRIALS: gov: NCT04523922.

Guided Bronchoscopy for the Evaluation of Pulmonary Lesions: An Updated Meta-analysis.

BACKGROUND: Guided bronchoscopy is increasingly used to diagnose peripheral pulmonary lesions (PPLs). A meta-analysis published in 2012 demonstrated a pooled diagnostic yield of 70%; however, recent publications have documented yields as low as 40% and as high as 90%. RESEARCH QUESTION: Has the diagnostic yield of guided bronchoscopy in patients with PPLs improved over the past decade? STUDY DESIGN AND METHODS: A comprehensive search was performed of studies evaluating the diagnostic yield of differing bronchoscopic technologies used to reach PPLs. Study quality was assessed using the Quality assessment of diagnostic accuracy of studies (QUADAS-2) assessment tool. Number of lesions, type of technology used, overall diagnostic yield, and yield by size were extracted. Adverse events were recorded. Meta-analytic techniques were used to summarize findings across all studies. RESULTS: A total of 16,389 lesions from 126 studies were included. There was no significant difference in diagnostic yield prior to 2012 (39 studies; 3,052 lesions; yield 70.5%) vs after 2012 (87 studies; 13,535 lesions; yield 69.2%) (P > .05). Additionally, there was no significant difference in yield when comparing different technologies. Studies with low risk of overall bias had a lower diagnostic yield than those with high risk of bias (66% vs 71%, respectively; P = .018). Lesion size > 2 cm, presence of bronchus sign, and reports with a high prevalence of malignancy in the study population were associated with significantly higher diagnostic yield. Significant (P < .0001) between-study heterogeneity was also noted. INTERPRETATION: Despite the reported advances in bronchoscopic technology to diagnose PPLs, the diagnostic yield of guided bronchoscopy has not improved.

Utilizing multimodal mass spectrometry imaging for profiling immune cell composition and N-glycosylation across colorectal carcinoma disease progression.

Colorectal cancer (CRC) stands as a leading cause of death worldwide, often arising from specific genetic mutations, progressing from pre-cancerous adenomas to adenocarcinomas. Early detection through regular screening can result in a 90% 5-year survival rate for patients. However, unfortunately, only a fraction of CRC cases are identified at pre-invasive stages, allowing progression to occur silently over 10-15 years. The intricate interplay between the immune system and tumor cells within the tumor microenvironment plays a pivotal role in the progression of CRC. Immune cell clusters can either inhibit or facilitate tumor initiation, growth, and metastasis. To gain a better understanding of this relationship, we conducted N-glycomic profiling using matrix-assisted laser desorption-ionization mass spectrometry imaging (MALDI-MSI). We detected nearly 100 N-glycan species across all samples, revealing a shift in N-glycome profiles from normal to cancerous tissues, marked by a decrease in high mannose N-glycans. Further analysis of precancerous to invasive carcinomas showed an increase in pauci-mannose biantennary, and tetraantennary N-glycans with disease progression. Moreover, a distinct stratification in the N-glycome profile was observed between non-mucinous and mucinous CRC tissues, driven by pauci-mannose, high mannose, and bisecting N-glycans. Notably, we identified immune clusters of CD20+ B cells and CD3/CD44+ T cells distinctive and predictive with signature profiles of bisecting and branched N-glycans. These spatial N-glycan profiles offer potential biomarkers and therapeutic targets throughout the progression of CRC.

Fiber Ball White Matter Modeling Reveals Microstructural Alterations in Healthy Brain Aging.

Age-related white matter degeneration is characterized by myelin breakdown and neuronal fiber loss that preferentially occur in regions that myelinate later in development. Conventional diffusion MRI (dMRI) has demonstrated age-related increases in diffusivity but provide limited information regarding the tissue-specific changes driving these effects. A recently developed dMRI biophysical modeling technique, Fiber Ball White Matter (FBWM) modeling, offers enhanced biological interpretability by estimating microstructural properties specific to the intra-axonal and extra-axonal spaces. We used FBWM to illustrate the biological mechanisms underlying changes throughout white matter in healthy aging using data from 63 cognitively unimpaired adults ages 45-85 with no radiological evidence of neurodegeneration or incipient Alzheimer's disease. Conventional dMRI and FBWM metrics were computed for two late-myelinating (genu of the corpus callosum and association tracts) and two early-myelinating regions (splenium of the corpus callosum and projection tracts). We examined the associations between age and these metrics in each region and tested whether age was differentially associated with these metrics in late- vs. early-myelinating regions. We found that conventional metrics replicated patterns of age-related increases in diffusivity in late-myelinating regions. FBWM additionally revealed specific intra- and extra-axonal changes suggestive of myelin breakdown and preferential loss of smaller-diameter axons, yielding in vivo corroboration of findings from histopathological studies of aged brains. These results demonstrate that advanced biophysical modeling approaches, such as FBWM, offer novel information about the microstructure-specific alterations contributing to white matter changes in healthy aging. These tools hold promise as sensitive indicators of early pathological changes related to neurodegenerative disease.

Brain microstructure abnormalities in the 3xTg-AD mouse - A diffusion MRI and morphology correlation study.

The widely studied triple transgenic (3xTg-AD) mouse provides a robust model of Alzheimer's disease (AD) with region dependent patterns of progressive amyloid-ß (Aß) and tau pathology. Using diffusion MRI (dMRI), we investigated the sensitivity of dMRI measures in capturing AD pathology associated microstructure alterations in older 3xTg-AD mice, and the degree to which dMRI changes correlate with measurements of Aß and tau pathology. 3xTg-AD and normal control (NC) mice, 15 to 21 months of age, were used in this study. In vivo dMRI data were acquired for the generation of diffusion tensor (DT) and diffusional kurtosis (DK) measures within the hippocampus and fimbria (Fi). For these same brain regions, Aß and tau pathology were quantified by morphological analysis of Aß1-42 and AT8 immunoreactivity. Two-tailed, two-sample t-tests were performed to assess group differences in each brain region of interest (ROI), with the Benjamini-Hochberg false discovery rate (FDR) method being applied to adjust for multiple comparisons. Spearman correlation coefficients were calculated to investigate associations between diffusion and morphological measures. Our results revealed, depending on the brain region, DT and DK measures were able to detect group differences. In the dorsal hippocampus (HD), fractional anisotropy (FA) was significantly higher in the 3xTg-AD mice compared with NC mice. In the subiculum (SUB), FA, axial diffusivity (D||) and radial kurtosis (K┴) were significantly higher in 3xTg-AD mice compared with NC mice. Morphological quantification of Aß1-42 and AT8 immunoreactivity showed elevated Aß and tau in the Fi, ventral hippocampus (HV) and SUB of 3xTg-AD mice. The presence of Aß and tau was significantly correlated with several DT and DK measures, particularly in the SUB, where an increase in tau correlated with an increase in mean kurtosis (MK) and K┴. This work demonstrates significant dMRI differences between older 3xTg-AD and NC mice in the hippocampus and Fi. Significant correlations were found between dMRI and morphological measures of Aß and tau pathology. These results support the potential of dMRI-derived parameters as biomarkers of AD pathology. Since the imaging methods employed here are easily translatable to clinical MRI, our results are also relevant for human AD patients.

Repetitive Transcranial Magnetic Stimulation for Tobacco Treatment in Cancer Patients: A Preliminary Report of a One-Week Treatment.

Background: Smoking cessation represents a significant opportunity to improve cancer survival rates, reduces the risk of cancer treatment complications, and improves quality of life. However, about half of cancer patients who smoke continue to smoke despite the availability of several treatments. Previous studies demonstrate that repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) decreases cue craving, reduces cigarette consumption, and increases the quit rate in tobacco use disorder. We investigated whether 5 sessions of rTMS can be safely and efficaciously used for smoking cessation in cancer patients. Methods: We enrolled 11 treatment-seeking smokers with cancer (>5 cigarettes per day) in a randomized, double-blind, sham-controlled proof-of-concept study. Participants received 5 daily sessions of active 10 Hz rTMS of the left DLPFC (3000 pulses per session) or sham rTMS and were followed up for 1 month via phone assessments. Main outcomes included reductions in the number of smoked-cigarettes per day (primary) and craving (secondary). Adverse effects were reported daily by participants. Results: Seven of 11 participants completed 5 sessions of rTMS over one week. Compared to sham treatment (n = 4), the active rTMS (n = 3) exhibited modest effects overtime on smoking (Cohen's f 2 effect size of 0.16) and large effects on cue craving (Cohen's f 2 = 0.40). No serious side effects related to rTMS were reported in the treatment. Conclusions: Five sessions of daily rTMS over the left DLPFC might benefit cancer patients who smoke cigarettes. However, further evidence is needed to determine with more certainty its therapeutic effect and adverse effects for cancer patients who smoke cigarettes.