Prediabetes Progression and Reversion: Social Factors and Racial/Ethnic Differences.

OBJECTIVE: Racial and ethnic minorities are disproportionately affected by diabetes. Social characteristics, such as family structure, social support, and loneliness, may contribute to these health disparities. In a nationally representative sample of diverse older adults, we evaluated longitudinal rates of both progression from prediabetes to diabetes and reversion from prediabetes to normoglycemia. RESEARCH DESIGN AND METHODS: Using the longitudinal Health and Retirement Study (2006-2014), our sample included 2625 follow-up intervals with a prediabetes baseline (provided by 2229 individuals). We analyzed 4-year progression and reversion rates using HbA1c and reported presence or absence of physician-diagnosed diabetes. We utilized chi-square and logistic regression models to determine how race/ethnicity and social variables influenced progression or reversion controlling for comorbidities and demographics. RESULTS: Overall, progression to diabetes was less common than reversion (17% vs. 36%). Compared to Whites, Hispanic/Latino respondents had higher odds of progression to diabetes from prediabetes while Black respondents had lower odds of reversion, adjusting for physical health and demographics. For social variables, Hispanics/Latinos had the highest reliance on and openness with family and the lowest rates of loneliness. The inclusion of social variables in regression models reduced the odds of progression for Hispanics/Latinos but did not alter Black's lower rate of reversion. CONCLUSIONS: Hispanic/Latinos and Blacks not only had different transition pathways leading to diabetes, but also had different social profiles, affecting Hispanic/Latino progression, but not Black reversion. These differences in the influence of social variables on diabetes risk may inform the design of culturally-specific efforts to reduce disparities in diabetes burden.

Induction therapy in heart transplantation: A systematic review and network meta-analysis for developing evidence-based recommendations.

INTRODUCTION: Induction therapy (IT) utility in heart transplantation (HT) remains contested. Commissioned by a clinical-practice guidelines panel to evaluate the effectiveness and safety of IT in adult HT patients, we conducted this systematic review and network meta-analysis (NMA). METHODS: We searched for studies from January 2000 to October 2022, reporting on the use of any IT agent in adult HT patients. Based on patient-important outcomes, we performed frequentist NMAs separately for RCTs and observational studies with adjusted analyses, and assessed the certainty of evidence using the GRADE framework. RESULTS: From 5156 publications identified, we included 7 RCTs and 12 observational studies, and report on two contemporarily-used IT agents-basiliximab and rATG. The RCTs provide only very low certainty evidence and was uninformative of the effect of the two agents versus no IT or one another. With low certainty in the evidence from observational studies, basiliximab may increase 30-day (OR 1.13; 95% CI 1.06-1.20) and 1-year (OR 1.11; 95% CI 1.02-1.22) mortality compared to no IT. With low certainty from observational studies, rATG may decrease 5-year cardiac allograft vasculopathy (OR .82; 95% CI .74-.90) compared to no IT, as well as 30-day (OR .85; 95% CI .80-.92), 1-year (OR .87; 95% CI .79-.96), and overall (HR .84; 95% CI .76-.93) mortality compared to basiliximab. CONCLUSION: With low and very low certainty in the synthetized evidence, these NMAs suggest possible superiority of rATG compared to basiliximab, but do not provide compelling evidence for the routine use of these agents in HT recipients.

miR-644a is a tumor cell-intrinsic mediator of sex bias in glioblastoma.

Background: Biological sex is an important risk factor for glioblastoma (GBM), with males having a higher incidence and poorer prognosis. The mechanisms for this sex bias are thought to be both tumor intrinsic and tumor extrinsic. MicroRNAs (miRNAs), key post-transcriptional regulators of gene expression, have been previously linked to sex differences in various cell types and diseases, but their role in the sex bias of GBM remains unknown. Methods: We leveraged previously published paired miRNA and mRNA sequencing of 39 GBM patients (22 male, 17 female) to identify sex-biased miRNAs. We further interrogated a separate single-cell RNA sequencing dataset of 110 GBM patients to examine whether differences in miRNA target gene expression were tumor cell intrinsic or tumor cell extrinsic. Results were validated in a panel of patient-derived cell models. Results: We identified 10 sex-biased miRNAs (adjusted < 0.1), of which 3 were more highly expressed in males and 7 more highly expressed in females. Of these, miR-644a was higher in females, and increased expression of miR-644a target genes was significantly associated with decreased overall survival (HR 1.3, p = 0.02). Furthermore, analysis of an independent single-cell RNA sequencing dataset confirmed sex-specific expression of miR-644a target genes in tumor cells (p < 10-15). Among patient derived models, miR-644a was expressed a median of 4.8-fold higher in females compared to males. Conclusions: Our findings implicate miR-644a as a candidate tumor cell-intrinsic regulator of sex-biased gene expression in GBM.

Androgen loss weakens anti-tumor immunity and accelerates brain tumor growth.

Many cancers, including glioblastoma (GBM), have a male-biased sex difference in incidence and outcome. The underlying reasons for this sex bias are unclear but likely involve differences in tumor cell state and immune response. This effect is further amplified by sex hormones, including androgens, which have been shown to inhibit anti-tumor T cell immunity. Here, we show that androgens drive anti-tumor immunity in brain tumors, in contrast to its effect in other tumor types. Upon castration, tumor growth was accelerated with attenuated T cell function in GBM and brain tumor models, but the opposite was observed when tumors were located outside the brain. Activity of the hypothalamus-pituitary-adrenal gland (HPA) axis was increased in castrated mice, particularly in those with brain tumors. Blockade of glucocorticoid receptors reversed the accelerated tumor growth in castrated mice, indicating that the effect of castration was mediated by elevated glucocorticoid signaling. Furthermore, this mechanism was not GBM specific, but brain specific, as hyperactivation of the HPA axis was observed with intracranial implantation of non-GBM tumors in the brain. Together, our findings establish that brain tumors drive distinct endocrine-mediated mechanisms in the androgen-deprived setting and highlight the importance of organ-specific effects on anti-tumor immunity.

Routinely collected burn clinical data in Canada: Determining the knowledge gap.

Unlike other developed countries that hold national burn registries to monitor burn injury and care, Canada relies on single-centre secondary datasets and administrative databases as surveillance mechanisms. The objective of this study was to determine the knowledge gap faced in Canada for not having a dedicated burn registry. A comprehensive scoping review was conducted to identify the burn literature that has arisen from secondary datasets in Canada. Literature of all study designs was included with the exception of case reports and cases series. Once data extraction was concluded, a thematic framework was constructed based on the information that arose from nations that hold national burn registries. Eighty-eight studies were included. Twelve studies arose from national datasets, and 18 from provincial databases, most of which were from Ontario and British Columbia. Only seven studies were conducted using a combination of Canadian units' single-centre datasets. The majority of included studies (58%) resulted from non-collaborative use of single-centre secondary datasets. Research efforts were predominantly conducted by burn units in Ontario, British Columbia, Manitoba and Alberta. A significant number of the included studies were outdated and several provinces/territories had no published burn data whatsoever. Efforts should be made towards the development of systems to surveil burn injury and care in Canada. This study supports the development of a nation-wide burn registry to bridge this knowledge gap.

Müllerian-type carcinosarcoma arising in gastric endometriosis: Case report and review of the literature.

Although endometriosis is a common condition, both extrapelvic endometriosis and endometriosis associated malignancy (EAM) are rare. We describe the first reported case of a patient with Müllerian-type carcinosarcoma arising in gastric endometriosis.

Biased effects of pre-diagnostic physical activity on breast cancer survival: Systematic review and meta-analysis.

BACKGROUND: Pre-diagnostic physical activity is reported to improve survival for women with breast cancer. However, studies of pre-diagnostic exposures and cancer survival are susceptible to bias, made clear when applying a target trial framework. We investigated the impact of selection bias, immortal time bias, confounding and bias due to inappropriate adjustment for post-exposure variables in a systematic review and meta-analysis of pre-diagnostic physical activity and survival after breast cancer. METHODS: Medline, Embase and Emcare were searched from inception to November 2021 for studies examining pre-diagnostic physical activity and overall or breast cancer-specific survival for women with breast cancer. Random-effects meta-analysis was used to estimate pooled hazard ratios (HRs) and 95% confidence intervals (CIs) comparing highest versus lowest pre-diagnostic physical activity. Subgroup meta-analyses were used to compare HRs of studies with and without different biases. ROBINS-E was used to assess risk of bias. RESULTS: We included 22 studies. Women with highest versus lowest pre-diagnostic physical activity had higher overall and breast cancer-specific survival across most analyses. The overall risk of bias was high. We observed marked differences in estimated HRs between studies that did and did not adjust for post-exposure variables or have immortal time bias. All studies were at risk of selection bias due to participants becoming eligible for study when they have survived to post-exposure events (e.g., breast cancer diagnosis). Insufficient studies were available to investigate confounding. CONCLUSION: Biases can substantially change effect estimates. Due to misalignment of treatment assignment (before diagnosis), eligibility (survival to post-exposure events) and start of follow-up, bias is difficult to avoid. It is difficult to lend a causal interpretation to effect estimates from studies of pre-diagnostic physical activity and survival after cancer. Biased effect estimates that are difficult to interpret may be less useful for clinical or public health policy applications.

Homeostatic iron regulatory protein drives glioblastoma growth via tumor cell-intrinsic and sex-specific responses.

Background: Glioblastoma (GBM) displays alterations in iron that drive proliferation and tumor growth. Iron regulation is complex and involves many regulatory mechanisms, including the homeostatic iron regulator (HFE) gene, which encodes the homeostatic iron regulatory protein. While HFE is upregulated in GBM and correlates with poor survival outcomes, the function of HFE in GBM remains unclear. Methods: We interrogated the impact of cell-intrinsic Hfe expression on proliferation and survival of intracranially implanted animals through genetic gain- and loss-of-function approaches in syngeneic mouse glioma models, along with in vivo immune assessments. We also determined the expression of iron-associated genes and their relationship to survival in GBM using public data sets and used transcriptional profiling to identify differentially expressed pathways in control compared to Hfe-knockdown cells. Results: Overexpression of Hfe accelerated GBM proliferation and reduced animal survival, whereas suppression of Hfe induced apoptotic cell death and extended survival, which was more pronounced in females and associated with attenuation of natural killer cells and CD8+ T cell activity. Analysis of iron gene signatures in Hfe-knockdown cells revealed alterations in the expression of several iron-associated genes, suggesting global disruption of intracellular iron homeostasis. Further analysis of differentially expressed pathways revealed oxidative stress as the top pathway upregulated following Hfe loss. Hfe knockdown indeed resulted in enhanced 55Fe uptake and generation of reactive oxygen species. Conclusions: These findings reveal an essential function for HFE in GBM cell growth and survival, as well as a sex-specific interaction with the immune response.

Two zebrafish cacna1s loss-of-function variants provide models of mild and severe CACNA1S-related myopathy.

CACNA1S-related myopathy, due to pathogenic variants in the CACNA1S gene, is a recently described congenital muscle disease. Disease associated variants result in loss of gene expression and/or reduction of Cav1.1 protein stability. There is an incomplete understanding of the underlying disease pathomechanisms and no effective therapies are currently available. A barrier to the study of this myopathy is the lack of a suitable animal model that phenocopies key aspects of the disease. To address this barrier, we generated knockouts of the two zebrafish CACNA1S paralogs, cacna1sa and cacna1sb. Double knockout fish exhibit severe weakness and early death, and are characterized by the absence of Cav1.1 α1 subunit expression, abnormal triad structure, and impaired excitation-contraction coupling, thus mirroring the severe form of human CACNA1S-related myopathy. A double mutant (cacna1sa homozygous, cacna1sb heterozygote) exhibits normal development, but displays reduced body size, abnormal facial structure, and cores on muscle pathologic examination, thus phenocopying the mild form of human CACNA1S-related myopathy. In summary, we generated and characterized the first cacna1s zebrafish loss-of-function mutants, and show them to be faithful models of severe and mild forms of human CACNA1S-related myopathy suitable for future mechanistic studies and therapy development.

Educational Podcasts in Plastic Surgery: A Cross-Sectional Analysis of Content, Metrics, and Target Audiences.

BACKGROUND: Podcasts provide an efficient means for asynchronous learning. However, no study to date has thoroughly assessed the landscape of educational podcasts in plastic surgery. Thus, this study aims to evaluate and characterize current educational plastic surgery podcasts to ultimately inform future efforts. METHODS: Three platforms were queried for educational plastic surgery podcasts: Apple Podcasts, Spotify, and Google Podcasts. Podcast descriptions and episodes were then independently reviewed to determine primary target audiences, performance metrics, and content categories. RESULTS: There were a total of 163 plastic surgery podcasts. 145 of these 163 podcasts were targeted toward a nonmedical audience. The remaining 18 podcasts met inclusion criteria as educational plastic surgery podcasts. Of all educational podcast episodes, 8.8% targeted a medical student audience, 33.8% targeted trainees (residents/fellows), and 57.4% targeted practicing surgeons or emphasized recent research in the field. Episode content categories included breast (14.2%), cosmetic (11.8%), experimental (0.5%), hand/peripheral nerve (8.6%), pediatric/craniofacial (8.2%), reconstructive (15.6%), practice management (14.8%), residency (6.6%), and others (19.6%). CONCLUSIONS: Despite the large number of plastic surgery podcasts available, few podcasts focus on educating a medical audience. Within this small subset, there is a paucity of content targeted towards medical students interested in plastic surgery. While there is a wide breadth of content available, there is significant room for growth and refinement in the podcast sector for plastic surgery education.

Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.

The glioblastoma microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine is elevated in the glioblastoma tumor microenvironment. Exogenous administration of spermidine drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and phenotype. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+T cell number and function.

Development and Integration of Machine Learning Algorithm to Identify Peripheral Arterial Disease: Multistakeholder Qualitative Study.

BACKGROUND: Machine learning (ML)-driven clinical decision support (CDS) continues to draw wide interest and investment as a means of improving care quality and value, despite mixed real-world implementation outcomes. OBJECTIVE: This study aimed to explore the factors that influence the integration of a peripheral arterial disease (PAD) identification algorithm to implement timely guideline-based care. METHODS: A total of 12 semistructured interviews were conducted with individuals from 3 stakeholder groups during the first 4 weeks of integration of an ML-driven CDS. The stakeholder groups included technical, administrative, and clinical members of the team interacting with the ML-driven CDS. The ML-driven CDS identified patients with a high probability of having PAD, and these patients were then reviewed by an interdisciplinary team that developed a recommended action plan and sent recommendations to the patient's primary care provider. Pseudonymized transcripts were coded, and thematic analysis was conducted by a multidisciplinary research team. RESULTS: Three themes were identified: positive factors translating in silico performance to real-world efficacy, organizational factors and data structure factors affecting clinical impact, and potential challenges to advancing equity. Our study found that the factors that led to successful translation of in silico algorithm performance to real-world impact were largely nontechnical, given adequate efficacy in retrospective validation, including strong clinical leadership, trustworthy workflows, early consideration of end-user needs, and ensuring that the CDS addresses an actionable problem. Negative factors of integration included failure to incorporate the on-the-ground context, the lack of feedback loops, and data silos limiting the ML-driven CDS. The success criteria for each stakeholder group were also characterized to better understand how teams work together to integrate ML-driven CDS and to understand the varying needs across stakeholder groups. CONCLUSIONS: Longitudinal and multidisciplinary stakeholder engagement in the development and integration of ML-driven CDS underpins its effective translation into real-world care. Although previous studies have focused on the technical elements of ML-driven CDS, our study demonstrates the importance of including administrative and operational leaders as well as an early consideration of clinicians' needs. Seeing how different stakeholder groups have this more holistic perspective also permits more effective detection of context-driven health care inequities, which are uncovered or exacerbated via ML-driven CDS integration through structural and organizational challenges. Many of the solutions to these inequities lie outside the scope of ML and require coordinated systematic solutions for mitigation to help reduce disparities in the care of patients with PAD.

Benefits and harms of breast cancer screening: Cohort study of breast cancer mortality and overdiagnosis.

BACKGROUND: Quantifying the benefits and harms of breast cancer screening accurately is important for planning and evaluating screening programs and for enabling women to make informed decisions about participation. However, few cohort studies have attempted to estimate benefit and harm simultaneously. AIMS: We aimed to quantify the impact of mammographic screening on breast cancer mortality and overdiagnosis using a cohort of women invited to attend Australia's national screening program, BreastScreen. METHODS: In a cohort of 41,330 women without prior breast cancer diagnosis, screening, or diagnostic procedures invited to attend BreastScreen Western Australia in 1994-1995, we estimated the cumulative risk of breast cancer mortality and breast cancer incidence (invasive and ductal carcinoma in situ) from age 50 to 85 years for attenders and non-attenders. Data were obtained by linking population-based state and national health registries. Breast cancer mortality risks were estimated from a survival analysis that accounted for competing risk of death from other causes. Breast cancer risk for unscreened women was estimated by survival analysis, while accounting for competing causes of death. For screened women, breast cancer risk was the sum of risk of being diagnosed at first screen, estimated using logistic regression, and risk of diagnosis following a negative first screen estimated from a survival analysis. RESULTS: For every 1,000 women 50 years old at first invitation to attend BreastScreen, there were 20 (95% CI 12-30) fewer breast cancer deaths and 25 (95% CI 15-35) more breast cancers diagnosed for women who attended than for non-attendees by age 85. Of the breast cancers diagnosed in screened women, 21% (95% CI 13%-27%) could be attributed to screening. DISCUSSION: The estimated ratio of benefit to harm was consistent with, but slightly less favourable to screening than most other estimates from cohort studies. CONCLUSION: Women who participate in organised screening for breast cancer in Australia have substantially lower breast cancer mortality, while some screen-detected cancers may be overdiagnosed.

Sex-Biased T-cell Exhaustion Drives Differential Immune Responses in Glioblastoma.

Sex differences in glioblastoma (GBM) incidence and outcome are well recognized, and emerging evidence suggests that these extend to genetic/epigenetic and cellular differences, including immune responses. However, the mechanisms driving immunologic sex differences are not fully understood. Here, we demonstrate that T cells play a critical role in driving GBM sex differences. Male mice exhibited accelerated tumor growth, with decreased frequency and increased exhaustion of CD8+ T cells in the tumor. Furthermore, a higher frequency of progenitor exhausted T cells was found in males, with improved responsiveness to anti-PD-1 treatment. Moreover, increased T-cell exhaustion was observed in male GBM patients. Bone marrow chimera and adoptive transfer models indicated that T cell-mediated tumor control was predominantly regulated in a cell-intrinsic manner, partially mediated by the X chromosome inactivation escape gene Kdm6a. These findings demonstrate that sex-biased predetermined behavior of T cells is critical for inducing sex differences in GBM progression and immunotherapy response. SIGNIFICANCE: Immunotherapies in patients with GBM have been unsuccessful due to a variety of factors, including the highly immunosuppressive tumor microenvironment in GBM. This study demonstrates that sex-biased T-cell behaviors are predominantly intrinsically regulated, further suggesting sex-specific approaches can be leveraged to potentially improve the therapeutic efficacy of immunotherapy in GBM. See related commentary by Alspach, p. 1966. This article is featured in Selected Articles from This Issue, p. 1949.

Clinical utility of multiple secondary combined tests in prostate cancer screening.

INTRODUCTION: The clinical utility of concurrent Prostate Health Index (PHI) and ExosomeDx Prostate Intelliscore (EPI) testing is unclear. We sought to examine the performance of combined PHI and EPI testing on men undergoing elevated PSA work up. MATERIALS AND METHODS: Patients who received both EPI and PHI testing were identified from an institutional database of men referred to urology for an elevated total PSA. Cut points of EPI > 15.6 and PHI ≥ 36 were used to denote a positive test. Patients were placed into one of four groups determined by combination of EPI and PHI results. Demographic variables and biopsy recommendations were compared between groups. The concordance of test positivity between EPI and PHI was compared by Cohen's kappa. Demographic variables and secondary testing results were compared between patients' compliant and non-compliant with prostate biopsy recommendation. Biopsy pathology was compared between groups. RESULTS: A total of 162 patients had both EPI and PHI testing. Median age was 65 years, with a median PSA of 6.64 ng/mL. Age (p = 0.001), PSA (< 0.001) and biopsy recommendation (< 0.001) differed between combined secondary screening test result groups. Seventy-five percent of patients with both a positive EPI and PHI were found to have prostate cancer, with 54.2% being ≥ Gleason 7. Cohen's kappa was 0.19, indicating poor concordance. The AUC of EPI and PHI for clinically significant cancer was 0.563 (95% CI: 0.4331-0.6923) and 0.685 (95% CI: 0.569-0.8) (p = 0.147). CONCLUSIONS: Concurrently positive EPI and PHI indicate increased prostate cancer risk, with combined usage potentially influencing biopsy recommendation and compliance.

GAP43-dependent mitochondria transfer from astrocytes enhances glioblastoma tumorigenicity.

The transfer of intact mitochondria between heterogeneous cell types has been confirmed in various settings, including cancer. However, the functional implications of mitochondria transfer on tumor biology are poorly understood. Here we show that mitochondria transfer is a prevalent phenomenon in glioblastoma (GBM), the most frequent and malignant primary brain tumor. We identified horizontal mitochondria transfer from astrocytes as a mechanism that enhances tumorigenesis in GBM. This transfer is dependent on network-forming intercellular connections between GBM cells and astrocytes, which are facilitated by growth-associated protein 43 (GAP43), a protein involved in neuron axon regeneration and astrocyte reactivity. The acquisition of astrocyte mitochondria drives an increase in mitochondrial respiration and upregulation of metabolic pathways linked to proliferation and tumorigenicity. Functionally, uptake of astrocyte mitochondria promotes cell cycle progression to proliferative G2/M phases and enhances self-renewal and tumorigenicity of GBM. Collectively, our findings reveal a host-tumor interaction that drives proliferation and self-renewal of cancer cells, providing opportunities for therapeutic development.

Evaluating Disparities in Pathways to Breast Reconstruction.

BACKGROUND: Rates of postmastectomy breast reconstruction have been shown to vary by racial, ethnic, and socioeconomic factors. In this study, we evaluated disparities across pathways toward breast reconstruction. METHODS: All women who underwent mastectomy for breast cancer at a single institution from 2017 to 2018 were reviewed. Rates of discussions about reconstruction with breast surgeons, plastic surgery referrals, plastic surgery consultations, and ultimate decisions to pursue reconstruction were compared by race/ethnicity. RESULTS: A total of 218 patients were included, with the racial/ethnic demographic of 56% white, 28% Black, 1% American Indian/Native Alaskan, 4% Asian, and 4% Hispanic/Latina. The overall incidence of postmastectomy breast reconstruction was 48%, which varied by race (white: 58% vs. Black: 34%; p < 0.001). Plastic surgery was discussed by the breast surgeon with 68% of patients, and referrals were made in 62% of patients. While older age (p < 0.001) and nonprivate insurance (p < 0.05) were associated with lower rates of plastic surgery discussion and referral, it did not vary by race/ethnicity. The need for an interpreter was associated with lower rates of discussion (p < 0.05). After multivariate adjustment, a lower reconstruction rate was associated with the Black race (odds ratio [OR] = 0.33; p = 0.014) and body mass index (BMI) ≥ 35 (OR = 0.14; p < 0.001). Elevated BMI did not disproportionately lower breast reconstruction rates in Black versus white women (p = 0.27). CONCLUSION: Despite statistically equivalent rates of plastic surgery discussions and referrals, black women had lower breast reconstruction rates versus white women. Lower rates of breast reconstruction in Black women likely represent an amalgamation of barriers to care; further exploration within our community is warranted to better understand the racial disparity observed.

Mapping Patient Encounters in Breast Cancer Care: An Analysis of 8800 Clinical Encounters Among Patients Undergoing Mastectomy.

BACKGROUND: Transitions toward value-based systems require a comprehensive definition of the complexity and duration of provider effort required for a given diagnosis. This study modeled the numbers of clinical encounters involved in various treatment pathways among breast cancer patients undergoing mastectomy. METHODS: Clinical encounters with medical oncologists, radiation oncologists, breast surgeons, or plastic surgeons ≤4 years after diagnosis among all patients undergoing mastectomy from 2017 to 2018 were reviewed. Relative encounter volumes were modeled each 90-day period after diagnosis. RESULTS: A total of 8807 breast cancer-related encounters from 221 patients were analyzed, with mean (SD) encounter volume 39.9 (27.2) encounters per patient. Most encounters occurred in the first year after diagnosis (70.0%), with years 2, 3, and 4 representing 15.8%, 9.1%, and 3.5% of encounters, respectively. Overall stage was associated with encounter volume, with higher encounter volume with increasing stage (stages 0: 27.4 vs I: 28.5 vs II: 48.4 vs III: 61.1 vs IV: 80.8 mean encounters). Body mass index (odds ratio [OR], 0.22), adjuvant radiation (OR, 6.8), and receipt of breast reconstruction (OR, 3.5) were also associated with higher encounter volume (all P 's < 0.01). Duration of encounter volume varied by treatment phases, with medical oncology and plastic surgery sustaining high clinical encounter volume 3 years after diagnosis. CONCLUSIONS: Encounter utilization in breast cancer care persists 3 years after index diagnosis and is influenced by overall stage and treatment characteristics, including receipt of breast reconstruction. These results may inform the design of episode durations within value-based models and institutional resource allocation for breast cancer care.

Lactiplantibacillus plantarum PS128 Alleviates Exaggerated Cortical Beta Oscillations and Motor Deficits in the 6-Hydroxydopamine Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by midbrain dopaminergic neuronal loss and subsequent physical impairments. Levodopa manages symptoms best, while deep brain stimulation (DBS) is effective for advanced PD patients; however, side effects occur with the diminishing therapeutic window. Recently, Lactiplantibacillus plantarum PS128 (PS128) was found to elevate dopamine levels in rodent brains, suggesting its potential to prevent PD. Here, the therapeutic efficacy of PS128 was examined in the 6-hydroxydopamine rat PD model. Suppression of the power spectral density of beta oscillations (beta PSD) in the primary motor cortex (M1) was recorded as the indicator of disease progression. We found that 6 weeks of daily PS128 supplementation suppressed M1 beta PSD as well as did levodopa and DBS. Long-term normalization of M1 beta PSD was found in PS128-fed rats, whereas levodopa and DBS showed only temporal effects. PS128 + levodopa and PS128 + DBS exhibited better therapeutic effects than did levodopa + DBS or either alone. Significantly improved motor functions in PS128-fed rats were correlated with normalization of M1 beta PSD. Brain tissue analyses further demonstrated the role of PS128 in dopaminergic neuroprotection and the enhanced availability of neurotransmitters. These findings suggest that psychobiotic PS128 might be used alongside conventional therapies to treat PD patients.