Microbiota and metabolic adaptation shape Staphylococcus aureus virulence and antimicrobial resistance during intestinal colonization.

Depletion of microbiota increases susceptibility to gastrointestinal colonization and subsequent infection by opportunistic pathogens such as methicillin-resistant Staphylococcus aureus (MRSA). How the absence of gut microbiota impacts the evolution of MRSA is unknown. The present report used germ-free mice to investigate the evolutionary dynamics of MRSA in the absence of gut microbiota. Through genomic analyses and competition assays, we found that MRSA adapts to the microbiota-free gut through sequential genetic mutations and structural changes that enhance fitness. Initially, these adaptations increase carbohydrate transport; subsequently, evolutionary pathways largely diverge to enhance either arginine metabolism or cell wall biosynthesis. Increased fitness in arginine pathway mutants depended on arginine catabolic genes, especially nos and arcC, which promote microaerobic respiration and ATP generation, respectively. Thus, arginine adaptation likely improves redox balance and energy production in the oxygen-limited gut environment. Findings were supported by human gut metagenomic analyses, which suggest the influence of arginine metabolism on colonization. Surprisingly, these adaptive genetic changes often reduced MRSA's antimicrobial resistance and virulence. Furthermore, resistance mutation, typically associated with decreased virulence, also reduced colonization fitness, indicating evolutionary trade-offs among these traits. The presence of normal microbiota inhibited these adaptations, preserving MRSA's wild-type characteristics that effectively balance virulence, resistance, and colonization fitness. The results highlight the protective role of gut microbiota in preserving a balance of key MRSA traits for long-term ecological success in commensal populations, underscoring the potential consequences on MRSA's survival and fitness during and after host hospitalization and antimicrobial treatment.

Refining Parent SMART: User feedback to optimize a multi-modal intervention.

INTRODUCTION: The continuing care period following residential substance use treatment is a time when adolescents are at especially high risk for relapse, yet few families engage in traditional office-based care. Parent SMART (Substance Misuse among Adolescents in Residential Treatment) is a multi-component continuing care intervention for parents that combines three digital health technologies - an "off the shelf" online parenting program, daily phone notifications, and an online parent networking forum - with support from a parent coach. The current study solicited both qualitative and quantitative user feedback about Parent SMART to ensure responsivity to user preferences, refinement, and continuous improvement of the intervention. METHODS: Exit interviews were conducted with 30 parents who received Parent SMART, which includes (1) a parent networking forum; (2) daily text messages reminders of skills, (3) an "off-the-shelf" online parenting program; and (4) in-person or telehealth parent coaching sessions. The study collected qualitative feedback using semi-structured interviews and obtained quantitative feedback via a series of ratings of each Parent SMART component on a 5-point Likert scale administered at each follow-up assessment. RESULTS: Quantitative feedback suggest that parents rated all four elements of Parent SMART as easy to use. Qualitative feedback revealed that parents valued several aspects of Parent SMART including the brevity and structure of the intervention elements, the reminders to use parenting skills, and the sense of social connectedness fostered by different components. Recommended refinements included a number of strategies to enhance personalization and ease of navigation. CONCLUSIONS: Parent feedback informed enhancements to the Parent SMART intervention prior to implementation in a larger, ongoing pragmatic effectiveness trial. The current study serves as a model for applying a staged person-centered approach and eliciting both quantitative and qualitative feedback to refine digital health technologies.

Practice Consolidation Among US Medical Oncologists, 2015-2022.

PURPOSE: Health care consolidation has significantly affected cancer care delivery, with oncology practices undergoing substantial consolidation over the past two decades. This study investigates practice consolidation trends among medical oncologists (MOs), factors associated with consolidation, and changes in MO geographic distribution. METHODS: Medicare data from 2015 to 2022 were used to assess MO practice consolidation in hospital referral regions (HRRs), linked with regional health care market data and physician demographics. The Herfindahl-Hirschman Index (HHI) was used to measure consolidation, and the Gini coefficient was used to measure MO distribution across counties. Multivariable linear regression explored factors associated with MO practice consolidation. RESULTS: Between 2015 and 2022, the number of MOs increased by 14.5% (11,727-13,433), whereas the number of MO practices decreased by 18.0% (2,774-2,276). The mean number of MOs per practice increased by 40% (4.26-5.95; P < .001). The percentage of MOs in small practices decreased, whereas larger practices saw an increase. MO consolidation, as indicated by the HHI, increased by 9% (median HHI, 0.3204-0.3480). HRRs with higher baseline hospital consolidation and more hospital beds per capita were more likely to have MO practice consolidation. Despite MO practice consolidation, the county-level distribution of MOs did not change substantially. CONCLUSION: On the basis of Federal Trade Commission classifications, MO practices were highly concentrated in 2015 and consolidated even further by 2022. While distribution of MOs at the county level remained stable, further research is needed to assess the effects of rapid consolidation on cancer care cost, quality, and access. These data have important implications for policymakers and payers as they design programs that ensure high-quality, affordable cancer care.

Accreditation Standards-An Untapped Lever for Cancer Equity.

This Viewpoint describes how the Commission on Cancer and the National Cancer Institute can incorporate health equity benchmarks into existing standards to improve care and outcomes for all patients with cancer.

Prefrontal Regulation of Safety Learning during Ethologically Relevant Thermal Threat.

Learning and adaptation during sources of threat and safety are critical mechanisms for survival. The prelimbic (PL) and infralimbic (IL) subregions of the medial prefrontal cortex (mPFC) have been broadly implicated in the processing of threat and safety. However, how these regions regulate threat and safety during naturalistic conditions involving thermal challenge still remains elusive. To examine this issue, we developed a novel paradigm in which adult mice learned that a particular zone that was identified with visuospatial cues was associated with either a noxious cold temperature ("threat zone") or a pleasant warm temperature ("safety zone"). This led to the rapid development of avoidance behavior when the zone was paired with cold threat or approach behavior when the zone was paired with warm safety. During a long-term test without further thermal reinforcement, mice continued to exhibit robust avoidance or approach to the zone of interest, indicating that enduring spatial-based memories were formed to represent the thermal threat and thermal safety zones. Optogenetic experiments revealed that neural activity in PL and IL was not essential for establishing the memory for the threat zone. However, PL and IL activity bidirectionally regulated memory formation for the safety zone. While IL activity promoted safety memory during normal conditions, PL activity suppressed safety memory especially after a stress pretreatment. Therefore, a working model is proposed in which balanced activity between PL and IL is favorable for safety memory formation, whereas unbalanced activity between these brain regions is detrimental for safety memory after stress.

Trends in Utilization and Medicare Spending on Short-Course Radiation Therapy for Breast and Prostate Cancer: An Episode-Based Analysis From 2015 to 2019.

PURPOSE: Evidence supports the value of shorter, similarly efficacious, and potentially more cost-effective hypofractionated radiation therapy (RT) regimens in many clinical scenarios for breast cancer (BC) and prostate cancer (PC). However, practice patterns vary considerably. We used the most recent Centers for Medicare and Medicaid Services data to assess trends in RT cost and practice patterns among episodes of BC and PC. METHODS AND MATERIALS: We performed a retrospective cohort analysis of all external beam RT episodes for BC and PC from 2015 to 2019 to assess predictors of short-course RT (SCRT) use and calculated spending differences. Multivariable logistic regression defined adjusted odds ratios of receipt of SCRT over longer-course RT (LCRT) by treatment modality, age, year of diagnosis, type of practice, and the interaction between year and treatment setting. Medicare spending was evaluated using multivariable linear regression controlling for duration of RT regimen (SCRT vs LCRT) in addition to the above covariables. RESULTS: Of 143,729 BC episodes and 114,214 PC episodes, 63,623 (44.27%) and 25,955 (22.72%) were SCRT regimens, respectively. Median total spending for SCRT regimens among BC episodes was $9418 (interquartile range [IQR], $7966-$10,983) versus $13,602 (IQR, $11,814-$15,499) for LCRT. Among PC episodes, median total spending was $6924 (IQR, $4,509-$12,905) for stereotactic body RT, $18,768 (IQR, $15,421-$20,740) for moderate hypofractionation, and $27,319 (IQR, $25,446-$29,421) for LCRT. On logistic regression, receipt of SCRT was associated with older age among both BC and PC episodes as well as treatment at hospital-affiliated over freestanding sites (P < .001 for all). CONCLUSIONS: In this evaluation of BC and PC RT episodes from 2015 to 2019, we found that shorter-course RT resulted in lower costs than longer-course RT. SCRT was also more common in hospital-affiliated sites. Future research focusing on potential payment incentives encouraging SCRT when clinically appropriate in the 2 most common cancers treated with RT will be valuable as the field continues to prospectively evaluate cost-effective hypofractionation in other disease sites.

Pragmatic Implementation of a Music Intervention in Nursing Homes Before and During COVID-19.

OBJECTIVES: We conducted 2 trials of a music intervention for managing behaviors in nursing home (NH) residents with dementia, before (2019) and during (2021) the pandemic. In this report, we compare adherence fidelity across the trials using the Framework for Implementation Fidelity (FIF). DESIGN: Cross-sectional, descriptive implementation comparison. SETTING AND PARTICIPANTS: Fifty-four NHs randomized to receive the intervention (27 pre-COVID, 27 during COVID) METHODS: We compare the trials on the following FIF criteria: coverage (number of residents receiving the intervention); duration (minutes of music received per exposed day); frequency (percentage of residents with nursing staff use of music in the past week); and details of content (adherence to core components of the intervention). We report NH-level performance in each domain and compare characteristics of NHs in the bottom (low) and top (high) terciles of adherence. RESULTS: Across FIF domains, adherence fidelity was lower during COVID compared with pre-COVID: coverage, residents exposed (COVID: 7.5, SD 5.6; pre-COVID: 12.7, SD 3.6); duration, music minutes per exposed day (COVID: 2.5, SD 5.1; pre-COVID: 27.1, SD 23.9); frequency, percentage of residents with nursing use of intervention in the past week (COVID: 15.0, SD 31.5; pre-COVID 40.4, SD 25.6); and details of content, compliance with core components of the intervention (COVID: 8.3, SD 1.9; pre-COVID 9.6, SD 2.0). In both trials, high-adherence fidelity NHs had better nursing staff ratios, greater percentages of Medicare residents, and lower percentages of Black residents, compared with low-fidelity NHs. CONCLUSIONS AND IMPLICATIONS: Adherence fidelity was worse in the COVID vs pre-COVID trial, despite adaptations between trials intended to reduce staff burden and increase clinical targeting of the intervention. Results may point to the long-term effects of COVID on quality improvement capacity in NHs and/or a lack of available resources in most NHs to implement complex behavioral interventions without direct research support.

Incidence and Reimbursement Trends for Facial Fracture Repair in the Elderly: A Medicare Analysis.

OBJECTIVES: The aim was to describe incidence and reimbursement trends of surgical repair of facial fractures among the Medicare population. METHODS: The annual procedure data from the Centers for Medicare and Medicaid Service National Part B Data File from 2000 to 2019 were queried. RESULTS: The total number of surgically corrected facial fractures increased from 10,148 in 2000 to 19,631 in 2019 in a linear pattern (r = 0.924). Specifically, nasal bone/septum fracture repairs increased the most by 200.6% (n = 4682 to n = 14,075), whereas operations for TMJ dislocations, malar/zygoma fractures, and alveolar ridge/mandibular fractures decreased by 27.9%, 12.3%, and 3.2%, respectively, between 2000 and 2019. Correspondingly, the total Medicare reimbursement rose from $2,574,317 in 2000 to $4,129,448 in 2019 (r = 0.895). However, the mean reimbursement for all procedures decreased from $376.63 to $210.35 (44.1% fall) over the same time after adjusting for inflation, with this trend holding for individual fracture types as well. CONCLUSIONS: Given the population's increasing age, there has been a significant increase in the number of surgical repairs of facial fractures in Medicare patients between 2000 and 2019. However, this is largely driven by an increase in nasal bone/septum closed reductions, with stagnant and, in some cases, declining incidence among other fracture repairs. The reason is unclear and may be related to an increase in nonoperative management or poor outcomes. Nevertheless, like other subfields within otolaryngology and medicine at large, payments have lagged far behind, which may play some role. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:659-665, 2024.

Nerve block efficacy in breast augmentation: A systematic review and meta-analysis.

Breast augmentation is often performed as a day-case general anaesthetic operation, with postoperative, opioid-based analgesia regimens. However, it may also be performed using regional anaesthesia; a variety of nerve block techniques are available to reduce postoperative pain and analgesic requirements. This systematic review and meta-analysis were undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines comparing breast augmentation using regional anaesthesia with general anaesthesia, versus general anaesthesia alone or with local field infiltration. All randomised or quasi-randomised studies that recruited adult female patients undergoing breast augmentation using regional anaesthesia were considered. The primary outcome measures were postoperative pain and analgesic requirements. A randomised effects model was used, with standardised mean difference or mean difference outcomes used as appropriate. Thirteen studies were included for systematic review, out of which eight met the inclusion criteria for meta-analysis. Nerve blocks had statistically significant standardised mean difference reductions in postoperative pain scores across all time points: 0 h (-1.2 [-2.1 to -0.3], p = 0.01, I2 = 85%), 1 h (-1.3 [-2.1 to -0.5], p = 0.002, I2 = 89%), 2 h (-1.8 [-2.8 to -0.9], p = 0.0002, I2 = 88%), 4-6 h (-1.2 [-2.1 to -0.4], p = 0.006, I2 = 89%), 24 h (-1.4 [-2.5 to -0.2], p = 0.02, I2 = 94%). There was also a statistically significant reduction in postoperative opioid requirements: -150 mcg fentanyl (-259.2 to -40.9), p = 0.007. Although an element of study heterogeneity is noted, this systematic review and meta-analysis support the concept that regional anaesthesia using nerve blocks in breast augmentation surgery, reduces both postoperative pain and opioid requirements, compared with general anaesthesia.

Mayaro virus pathogenesis and immunity in rhesus macaques.

Mayaro virus (MAYV) is a mosquito-transmitted alphavirus that causes debilitating and persistent arthritogenic disease. While MAYV was previously reported to infect non-human primates (NHP), characterization of MAYV pathogenesis is currently lacking. Therefore, in this study we characterized MAYV infection and immunity in rhesus macaques. To inform the selection of a viral strain for NHP experiments, we evaluated five MAYV strains in C57BL/6 mice and showed that MAYV strain BeAr505411 induced robust tissue dissemination and disease. Three male rhesus macaques were subcutaneously challenged with 105 plaque-forming units of this strain into the arms. Peak plasma viremia occurred at 2 days post-infection (dpi). NHPs were taken to necropsy at 10 dpi to assess viral dissemination, which included the muscles and joints, lymphoid tissues, major organs, male reproductive tissues, as well as peripheral and central nervous system tissues. Histological examination demonstrated that MAYV infection was associated with appendicular joint and muscle inflammation as well as presence of perivascular inflammation in a wide variety of tissues. One animal developed a maculopapular rash and two NHP had viral RNA detected in upper torso skin samples, which was associated with the presence of perivascular and perifollicular lymphocytic aggregation. Analysis of longitudinal peripheral blood samples indicated a robust innate and adaptive immune activation, including the presence of anti-MAYV neutralizing antibodies with activity against related Una virus and chikungunya virus. Inflammatory cytokines and monocyte activation also peaked coincident with viremia, which was well supported by our transcriptomic analysis highlighting enrichment of interferon signaling and other antiviral processes at 2 days post MAYV infection. The rhesus macaque model of MAYV infection recapitulates many of the aspects of human infection and is poised to facilitate the evaluation of novel therapies and vaccines targeting this re-emerging virus.

Ten simple rules for students navigating summer research experiences for undergraduates (REU) programs: From application to program completion.

For many emerging scientists, research experiences for undergraduates (REU) programs are an important gateway to graduate school and a career in science, technology, engineering, and mathematics (STEM). REUs provide guided mentorship and learning experiences in a summer-long program where students develop research skills, build scientific knowledge, and strengthen their scientific identity. While the benefits of REUs are abundant, the process is not always easy to navigate, especially for students who come from first-generation and/or low-income (FLI) backgrounds. This paper provides two-fold guidance for undergraduate students interested in participating in REUs. Rules 1 to 5 focus on demystifying the application process from beginning to end, and Rules 6 to 10 guide students who are on the other side of the application process. Thus, this paper will be most helpful for undergraduate students who are either considering applying for an REU or have been accepted into one and want to learn more about what to expect. It can also be a shareable resource for faculty, staff, and mentors who work directly with STEM undergraduates.

Opportunities for Savings in Risk Arrangements for Oncologic Care.

Importance: As the US accelerates adoption of alternative payment through global payment models such as Accountable Care Organizations (ACOs) or Medicare Advantage (MA), high spending for cancer care is a potential target for savings. Objective: To quantify the extent to which ACOs and other risk-bearing organizations operating in a specific geographic area (hospital referral region [HRR]) could achieve savings by steering patients to efficient medical oncology practices. Design, Setting, and Participants: This observational study included serial cross-sections of Medicare beneficiaries with cancer from 2010 to 2018. Data were analyzed from August 2021 to March 2023. Main Outcomes and Measures: Total spending and spending by category in the 1-year period following an index visit for a patient with newly diagnosed (incident) or poor-prognosis cancer. Results: The incident cohort included 1 309 825 patients with a mean age of 74.0 years; the most common cancer types were breast (21.4%), lung (16.7%), and colorectal cancer (10.0%). The poor prognosis cohort included 1 429 973 (mean age, 72.7 years); the most common cancer types were lung (26.6%), lymphoma (11.7%), and leukemia (7.3%). Options for steering varied across markets; the top quartile market had 10 or more oncology practices, but the bottom quartile had 3 or fewer oncology practices. Total spending (including Medicare Part D) in the incident cohort increased from a mean of $57 314 in 2009 to 2010 to $66 028 in 2016 to 2017. Within markets, total spending for practices in the highest spending quartile was 19% higher than in the lowest quartile. Hospital spending was the single largest component of spending in both time periods ($20 390 and $19 718, respectively) followed by Part B (infused) chemotherapy ($8022 and $11 699). Correlations in practice-level spending between the first-year (2009) and second-year (2010) spending were high (>0.90 in all categories with most >0.98), but these attenuated over time. Conclusions and Relevance: These results suggest there may be opportunities for ACOs and other risk-bearing organizations to select or drive referrals to lower-spending oncology practices in many local markets.

Private Equity Acquisition of Oncology Clinics in the US From 2003 to 2022.

This cross-sectional study examines private equity­backed acquisitions of medical and radiation oncology clinics in the US from 2003 to 2022 using financial databases and publicly available data.

Disruption of the early-life microbiota alters Peyer's patch development and germinal center formation in gastrointestinal-associated lymphoid tissue.

During postnatal development, both the maturing microbiome and the host immune system are susceptible to environmental perturbations such as antibiotic use. The impact of timing in which antibiotic exposure occurs was investigated by treating mice from days 5-9 with amoxicillin or azithromycin, two of the most commonly prescribed medications in children. Both early-life antibiotic regimens disrupted Peyer's patch development and immune cell abundance, with a sustained decrease in germinal center formation and diminished intestinal immunoglobulin A (IgA) production. These effects were less pronounced in adult mice. Through comparative analysis of microbial taxa, Bifidobacterium longum abundance was found to be associated with germinal center frequency. When re-introduced to antibiotic-exposed mice, B. longum partially rescued the immunological deficits. These findings suggest that early-life antibiotic use affects the development of intestinal IgA-producing B cell functions and that probiotic strains could be used to restore normal development after antibiotic exposure.