Telemedicine appointments are more likely to be completed than in-person healthcare appointments: a retrospective cohort study.

Objectives: Missed appointments can lead to treatment delays and adverse outcomes. Telemedicine may improve appointment completion because it addresses barriers to in-person visits, such as childcare and transportation. This study compared appointment completion for appointments using telemedicine versus in-person care in a large cohort of patients at an urban academic health sciences center. Materials and Methods: We conducted a retrospective cohort study of electronic health record data to determine whether telemedicine appointments have higher odds of completion compared to in-person care appointments, January 1, 2021, and April 30, 2023. The data were obtained from the University of South Florida (USF), a large academic health sciences center serving Tampa, FL, and surrounding communities. We implemented 1:1 propensity score matching based on age, gender, race, visit type, and Charlson Comorbidity Index (CCI). Results: The matched cohort included 87 376 appointments, with diverse patient demographics. The percentage of completed telemedicine appointments exceeded that of completed in-person care appointments by 9.2 points (73.4% vs 64.2%, P < .001). The adjusted odds ratio for telemedicine versus in-person care in relation to appointment completion was 1.64 (95% CI, 1.59-1.69, P < .001), indicating that telemedicine appointments are associated with 64% higher odds of completion than in-person care appointments when controlling for other factors. Discussion: This cohort study indicated that telemedicine appointments are more likely to be completed than in-person care appointments, regardless of demographics, comorbidity, payment type, or distance. Conclusion: Telemedicine appointments are more likely to be completed than in-person healthcare appointments.

Patient satisfaction with women vs men surgical interns and senior residents.

BACKGROUND: Patient satisfaction is critical for referrals and reimbursement of surgical faculty but remains poorly characterized for residents. We investigated whether patient evaluations of surgical trainees vary by resident gender. METHODS: Surgical inpatients evaluated surgical resident care postoperatively after positively identifying trainees. Evaluations (Consumer Assessment of Healthcare Providers and Systems Surgical Care Surveys (S-CAHPS)) were scored by the "top-box" method, stratified by training level, and compared between women and men residents. RESULTS: Ninety-one percent of patients participated (n â€‹= â€‹324/357). Patients recognized women interns less than men (75.0 â€‹% vs 87.2 â€‹%, p â€‹= â€‹0.01). S-CAHPS scores for women vs men interns were equivalent except for spending sufficient time with patients (75.6 â€‹% vs 88.0 â€‹%, p â€‹= â€‹0.02). For senior residents, there was no difference in patient recognition of women vs men (83.9 â€‹% vs 85.2 â€‹%, p â€‹= â€‹0.91) or in any S-CAHPS scores (p â€‹> â€‹0.05). CONCLUSIONS: Gendered differences in patient evaluations of surgical trainees exist for interns but resolve by senior years. Future work should explore how patient evaluations can support trainee development while ensuring patients recognize the role of surgical residents regardless of gender.

Impact of pre-operative abdominal MRI on survival for patients with resected pancreatic carcinoma: a population-based study.

Background: This study determined the impact of pre-operative abdominal MRI on all-cause mortality for patients with resected PDAC. Methods: All adult (≥18 years) PDAC patients who underwent pancreatectomy between January 2011 and December 2022 in Ontario, Canada, were identified for this population-based cohort study (ICD-O-3 codes: C250, C251, C252, C253, C257, C258). Patient demographics, comorbidities, PDAC stage, medical and surgical management, and survival data were sourced from multiple linked provincial administrative databases at ICES. All-cause mortality was compared between patients with and without a pre-operative abdominal MRI after controlling for multiple covariates. Findings: A cohort of 4579 patients consisted of 2432 men (53.1%) and 2147 women (46.9%) with a mean age of 65.2 years (standard deviation: 11.2 years); 2998 (65.5%) died while 1581 (34.5%) survived. Median follow-up duration post-resection was 22.4 months (interquartile range: 10.8-48.8 months), and median survival post-pancreatectomy was 25.9 months (95% confidence interval [95% CI]: 24.8, 27.5). Patients who underwent a pre-operative abdominal MRI had a median survival of 33.1 months (95% CI: 30.7, 37.2) compared to 21.1 months (95% CI: 19.8, 22.6) for all others. A total of 2354/4579 (51.4%) patients underwent a pre-operative abdominal MRI, which was associated with a 17.2% (95% CI: 11.0, 23.1) decrease in the rate of all-cause mortality, with an adjusted hazard ratio (aHR) of 0.828 (95% CI: 0.769, 0.890). Interpretation: Pre-operative abdominal MRI was associated with improved overall survival for PDAC patients who underwent pancreatectomy, possibly due to better detection of liver metastases than CT. Funding: Northern Ontario Academic Medicine Association (NOAMA) Clinical Innovation Fund.

NRF2-dependent regulation of the prostacyclin receptor PTGIR drives CD8 T cell exhaustion.

The progressive decline of CD8 T cell effector function-also known as terminal exhaustion-is a major contributor to immune evasion in cancer. Yet, the molecular mechanisms that drive CD8 T cell dysfunction remain poorly understood. Here, we report that the Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) signaling axis, which mediates cellular adaptations to oxidative stress, directly regulates CD8 T cell exhaustion. Transcriptional profiling of dysfunctional CD8 T cells from chronic infection and cancer reveals enrichment of NRF2 activity in terminally exhausted (Texterm) CD8 T cells. Increasing NRF2 activity in CD8 T cells (via conditional deletion of KEAP1) promotes increased glutathione production and antioxidant defense yet accelerates the development of terminally exhausted (PD-1+TIM-3+) CD8 T cells in response to chronic infection or tumor challenge. Mechanistically, we identify PTGIR, a receptor for the circulating eicosanoid prostacyclin, as an NRF2-regulated protein that promotes CD8 T cell dysfunction. Silencing PTGIR expression restores the anti-tumor function of KEAP1-deficient T cells. Moreover, lowering PTGIR expression in CD8 T cells both reduces terminal exhaustion and enhances T cell effector responses (i.e. IFN-γ and granzyme production) to chronic infection and cancer. Together, these results establish the KEAP1-NRF2 axis as a metabolic sensor linking oxidative stress to CD8 T cell dysfunction and identify the prostacyclin receptor PTGIR as an NRF2-regulated immune checkpoint that regulates CD8 T cell fate decisions between effector and exhausted states.

Web Site Accessibility Among Doctor of Physical Therapy Programs in the United States.

INTRODUCTION: Given the impetus to improve accessibility for diverse learners seeking physical therapist education, it is critical that all entry points to access information have minimal barriers. This study identified Web site accessibility barriers among Doctor of Physical Therapy (DPT) programs in the United States. REVIEW OF LITERATURE: Web site accessibility has been evaluated among many institutions of higher education, but none focused on DPT education. Individuals with disabilities may be adversely affected by Web site accessibility barriers. SUBJECTS: This cross-sectional study included 262 DPT programs in the United States. Doctor of Physical Therapy program characteristics collected were geographic region, institutional control type (public/private), medical school affiliation, accreditation status, total institutional enrollment, and DPT class size. METHODS: The Web Accessibility Evaluation (WAVE) Tool assessed data related to accessibility barriers among DPT program homepage Uniform Resource Locators. Three primary outcomes from the WAVE Tool included WAVE Total Errors, Error Density, and Total Alerts. RESULTS: Web site homepage accessibility barriers varied among programs for WAVE Total Errors (range 0-150), Error Density (range 0-14.6%), and Total Alerts (range 1-331). Median Total Errors were greater among private (9.0) versus public (5.0) institution Web sites (P < .001). Median Total Errors were greater among those institutions not affiliated with a medical school (9.0) compared with those that had an affiliated medical school (7.0) (P = .04). No differences in accessibility barriers were identified according to geographic region or accreditation status (P > .05). Median Total Errors were significantly different between institutional enrollment quartiles (H[3] = 17.9, P < .001), with no differences noted between DPT class size quartiles for any outcome (P > .05). Generally, weak-fair inverse correlations were observed between student enrollment for the institution and Web site accessibility barrier outcomes. DISCUSSION AND CONCLUSION: Homepage accessibility barriers varied greatly among DPT programs in the United States. Factors, including being a private institution, no medical school affiliation, and lower institutional enrollment, were related to increased accessibility barriers.

Kinesin-1-transported liposomes prefer to go straight in 3D microtubule intersections by a mechanism shared by other molecular motors.

Kinesin-1 ensembles maneuver vesicular cargoes through the three-dimensional (3D) intracellular microtubule (MT) network. To define how such cargoes navigate MT intersections, we first determined how many kinesins from an ensemble on a lipid-based cargo simultaneously engage a MT, and then determined the directional outcomes (straight, turn, terminate) for liposome cargoes at perpendicular MT intersections. Run lengths of 350-nm diameter liposomes decorated with up to 20, constitutively active, truncated kinesin-1 KIF5B (K543) were longer than single motor transported cargo, suggesting multiple motor engagement. However, detachment forces of lipid-coated beads with ~20 kinesins, measured using an optical trap, showed no more than three simultaneously engaged motors, with a single engaged kinesin predominating, indicating anticooperative MT binding. At two-dimensional (2D) and 3D in vitro MT intersections, liposomes frequently paused (~2 s), suggesting kinesins simultaneously bind both MTs and engage in a tug-of-war. Liposomes showed no directional outcome bias in 2D (1.1 straight:turn ratio) but preferentially went straight (1.8 straight:turn ratio) in 3D intersections. To explain these data, we developed a mathematical model of liposome transport incorporating the known mechanochemistry of kinesins, which diffuse on the liposome surface, and have stiff tails in both compression and extension that impact how motors engage the intersecting MTs. Our model predicts the ~3 engaged motor limit observed in the optical trap and the bias toward going straight in 3D intersections. The striking similarity of these results to our previous study of liposome transport by myosin Va suggests a "universal" mechanism by which cargoes navigate 3D intersections.

A systematic review of animal feeding operations including concentrated animal feeding operations (CAFOs) for exposure, health outcomes, and environmental justice.

BACKGROUND: Despite growing literature on animal feeding operations (AFOs) including concentrated animal feeding operations (CAFOs), research on disproportionate exposure and associated health burden is relatively limited and shows inconclusive findings. OBJECTIVE: We systematically reviewed previous literature on AFOs/CAFOs, focusing on exposure assessment, associated health outcomes, and variables related to environmental justice (EJ) and potentially vulnerable populations. METHODS: We conducted a systematic search of databases (MEDLINE/PubMed and Web of Science) and performed citation screening. Screening of titles, abstracts, and full-text articles and data extraction were performed independently by pairs of reviewers. We summarized information for each study (i.e., study location, study period, study population, study type, study design, statistical methods, and adjusted variables (if health association was examined), and main findings), AFO/CAFO characteristics and exposure assessment (i.e., animal type, data source, measure of exposure, and exposure assessment), health outcomes or symptoms (if health association was examined), and information related to EJ and potentially vulnerable populations (in relation to exposure and/or health associations, vulnerable populations considered, related variables, and main findings in relation to EJ and vulnerable populations). RESULTS: After initial screening of 10,963 papers, we identified 76 eligible studies. This review found that a relatively small number of studies (20 studies) investigated EJ and vulnerability issues related to AFOs/CAFOs exposure and/or associated health outcomes (e.g., respiratory diseases/symptoms, infections). We found differences in findings across studies, populations, the metrics used for AFO/CAFO exposure assessment, and variables related to EJ and vulnerability. The most commonly used metric for AFO/CAFO exposure assessment was presence of or proximity to facilities or animals. The most investigated variables related to disparities were race/ethnicity and socioeconomic status. CONCLUSION: Findings from this review provide suggestive evidence that disparities exist with some subpopulations having higher exposure and/or health response in relation to AFO/CAFO exposure, although results varied across studies.

Impact of Bariatric Surgery on Asthma Severity and Medication Use.

INTRODUCTION: Bariatric surgery improves many obesity-related comorbidities, yet the literature remains inconclusive on the impact of bariatric surgery on asthma. Our primary objective was to identify the long-term impact of bariatric surgery on asthma severity and medication use. METHODS: A retrospective review was completed of all patients with a diagnosis of asthma who underwent bariatric surgery over 10 years at a single institution. Primary outcomes were the number of asthma medications prescribed at five time points (preoperative, postoperative < 18 months, 19-36 months, 37-60 months, 60 + months) after bariatric surgery. Secondary outcomes were spirometry results and BMI. RESULTS: There were 260 patients with 84.6% female predominance. There were 168 sleeve gastrectomy patients and 92 Roux-en-Y gastric bypass patients. Mean age was 47.6 ± 10.7 years, mean BMI was 46.0 ± 6.8 kg/m2, and 54.2% were previous tobacco users. The total number of patients on two or more asthma medications decreased from 46% preoperatively to 41% at 18 months, to 36% at 36 months, and to 32% at 60 months after surgery. The total number of patients free from asthma medication increased from 25% preoperatively to 33% at 60 months postoperatively. Asthma medication use decreased in both surgery groups, and neither operation demonstrated superiority. No significant improvement nor differences were found between groups at any time point regarding FEV1/FVC ratio spirometry measures. CONCLUSION: Bariatric surgery reduces the use of medications taken for management of asthma. The amount of asthma medication usage decreases with time and is sustained at 60 months after bariatric surgery.

Blockade of IL-1ß and PD-1 with combination chemotherapy reduces systemic myeloid suppression in metastatic pancreatic cancer with heterogeneous effects in the tumor.

Innate inflammation promotes tumor development, although the role of innate inflammatory cytokines in established human tumors is unclear. Here we report clinical and translational results from a phase Ib trial testing whether IL-1ß blockade in human pancreatic cancer would alleviate myeloid immunosuppression and reveal antitumor T-cell responses to PD-1 blockade. Patients with treatment-naïve advanced pancreatic ductal adenocarcinoma (n=10) were treated with canakinumab, a high-affinity monoclonal human anti-interleukin-1ß (IL-1ß), the PD-1 blocking antibody spartalizumab, and gemcitabine/n(ab)paclitaxel. Analysis of paired peripheral blood from patients in the trial versus patients receiving multiagent chemotherapy showed a modest increase in HLA-DR+CD38+ activated CD8+ T cells and a decrease in circulating monocytic myeloid-derived suppressor cells (MDSCs) by flow cytometry for patients in the trial, but not in controls. Similarly, we used patient serum to differentiate monocytic MDSCs in vitro and showed that functional inhibition of T-cell proliferation was reduced when using on-treatment serum samples from patients in the trial but not when using serum from patients treated with chemotherapy alone. Within the tumor we observed few changes in suppressive myeloid-cell populations or activated T cells as assessed by single-cell transcriptional profiling or multiplex immunofluorescence, although increases in CD8+ T cells suggest that improvements in the tumor immune microenvironment might be revealed by a larger study. Overall, the data indicate that exposure to PD-1 and IL-1ß blockade induced a modest reactivation of peripheral CD8+ T cells and decreased circulating monocytic MDSCs; however, these changes did not lead to similarly uniform alterations in the tumor microenvironment.

High-throughput discovery of MHC class I- and II-restricted T cell epitopes using synthetic cellular circuits.

Antigen discovery technologies have largely focused on major histocompatibility complex (MHC) class I-restricted human T cell receptors (TCRs), leaving methods for MHC class II-restricted and mouse TCR reactivities relatively undeveloped. Here we present TCR mapping of antigenic peptides (TCR-MAP), an antigen discovery method that uses a synthetic TCR-stimulated circuit in immortalized T cells to activate sortase-mediated tagging of engineered antigen-presenting cells (APCs) expressing processed peptides on MHCs. Live, tagged APCs can be directly purified for deconvolution by sequencing, enabling TCRs with unknown specificity to be queried against barcoded peptide libraries in a pooled screening context. TCR-MAP accurately captures self-reactivities or viral reactivities with high throughput and sensitivity for both MHC class I-restricted and class II-restricted TCRs. We elucidate problematic cross-reactivities of clinical TCRs targeting the cancer/testis melanoma-associated antigen A3 and discover targets of myocarditis-inciting autoreactive T cells in mice. TCR-MAP has the potential to accelerate T cell antigen discovery efforts in the context of cancer, infectious disease and autoimmunity.

Cross-Sectional Melt Pool Geometry of Laser Scanned Tracks and Pads on Nickel Alloy 718 for the 2022 Additive Manufacturing Benchmark Challenges.

The Additive Manufacturing Benchmark Series (AM Bench) is a NIST-led organization that provides a continuing series of additive manufacturing benchmark measurements, challenge problems, and conferences with the primary goal of enabling modelers to test their simulations against rigorous, highly controlled additive manufacturing benchmark measurement data. To this end, single-track (1D) and pad (2D) scans on bare plate nickel alloy 718 were completed with thermography, cross-sectional grain orientation and local chemical composition maps, and cross-sectional melt pool size measurements. The laser power, scan speed, and laser spot size were varied for single tracks, and the scan direction was varied for pads. This article focuses on the cross-sectional melt pool size measurements and presents the predictions from challenge problems. Single-track depth correlated with volumetric energy density while width did not (within the studied parameters). The melt pool size for pad scans was greater than single tracks due to heat buildup. Pad scan melt pool depth was reduced when the laser scan direction and gas flow direction were parallel. The melt pool size in pad scans showed little to no trend against position within the pads. Uncertainty budgets for cross-sectional melt pool size from optical micrographs are provided for the purpose of model validation.

The Effect of Shift Timing on Cesarean Delivery Outcomes and Operative Noise Levels.

OBJECTIVE: Intraoperative noise exposure has been associated with an increased risk of complications, communication errors, and stress among surgical team members. This study evaluates intraoperative noise levels in cesarean deliveries during different shift times, for example, night shifts, day shifts, and hand-off times between shifts. STUDY DESIGN: This is a secondary analysis of a prospective observational study which measured volume in decibels, percentage of time above safe levels (>60 dB), startle noise events (events with rapid increase of decibel level above baseline noise), and peak levels (>75 dB) for cesarean deliveries during a 3-month preintervention and postintervention study. This secondary analysis of noise data evaluated whether there were differences in noise for cases occurring during day shifts (6:31 a.m.-4:59 p.m.), night shifts (6:01 p.m.-5:29 a.m.), and hand-off times (5:30 a.m.-6:30 a.m. and 5:00 p.m.-6:00 p.m.). Correlates and postoperative complications during the respective shifts were additionally analyzed. RESULTS: Noise data were collected for a total of 312 cesarean deliveries; 203 occurred during the day shift, 94 during the night shift, and 15 during hand-off times. Median noise in decibels, median noise at various key intraoperative points, number of startle events, percentage of time above 60 dB, and above 75 dB had no significant differences throughout the various shift times. Significantly larger numbers of postpartum hemorrhages, unscheduled, urgent, and STAT cesarean deliveries occurred at hand-off times and on night shifts. CONCLUSION: Noise levels during cesarean deliveries did not significantly vary when comparing night shifts, day shifts, and hand-off times, despite significantly higher numbers of urgent and STAT cases occurring overnight and during hand-off times. However, more than 60% of case time had noise levels exceeding those considered safe. This suggests that ambient background noise may be contributing more to overall noise levels rather than the specific clinical scenario at hand. KEY POINTS: · Noise in cesarean delivery operating rooms frequently exceeded recommended levels.. · Noise in cesarean delivery operating rooms did not vary with shift type.. · Hand-off times had higher rates of urgent and STAT cesareans.. · Night shifts had higher rates of urgent and STAT cesareans..

Nontypeable Haemophilus influenzae challenge during gammaherpesvirus infection enhances viral reactivation and latency.

Gammaherpesviruses are ubiquitous, lifelong pathogens associated with multiple cancers that infect over 95% of the adult population. Increases in viral reactivation, due to stress and other unknown factors impacting the immune response, frequently precedes lymphomagenesis. One potential stressor that could promote viral reactivation and increase viral latency would be the myriad of infections from bacterial and viral pathogens that we experience throughout our lives. Using murine gammaherpesvirus 68 (MHV68), a mouse model of gammaherpesvirus infection, we examined the impact of bacterial challenge on gammaherpesvirus infection. We challenged MHV68 infected mice during the establishment of latency with nontypeable Haemophilus influenzae (NTHi) to determine the impact of bacterial infection on viral reactivation and latency. Mice infected with MHV68 and then challenged with NTHi, saw increases in viral reactivation and viral latency. These data support the hypothesis that bacterial challenge can promote gammaherpesvirus reactivation and latency establishment, with possible consequences for viral lymphomagenesis.

Effectiveness of Autologous Skin Cell Suspension in Large Total Body Surface Area Burns: Analysis of Clinical Outcomes and Patient Charges.

Autologous skin cell suspension (ASCS) is an adjunct to conventional split-thickness skin grafts (STSG) for acute burns, enhancing healing and reducing donor site requirements. This study validates ASCS's predictive benefits in hospital stay reduction and cost savings by analyzing outcomes and real-world charges post-ASCS implementation at a single institution. A retrospective study (2018-2022) included burn patients with ≥10% TBSA. The study population comprised two groups: burns treated either with a combination of ASCS ± STSG or with STSG alone. Outcomes included LOS, surgeries, infection, complications, days on antibiotics, and adjusted charge per TBSA. The ASCS ± STSG group demonstrated significantly shorter LOS (Mdn: 16.0 days, IQR: 10-26) than the STSG group (Mdn: 20.0 days, IQR: 14-36; P = 0.017), and fewer surgeries (Mdn: 1.0, IQR: 1-2) versus the STSG group (Mdn: 1.0, IQR: 1-4; P = 0.020). Postoperative complications were significantly lower in ASCS ± STSG (11% vs. 36%; P < 0.001). The STSG group had a longer distribution of antibiotic days (IQR: 0-7.0, min-max: 0-76) than the ASCS ± STSG group (IQR: 0-0, min-max: 0-37; P = 0.014). Wound infection incidence did not differ (P = 0.843). ASCS ± STSG showed a lower distribution of adjusted charge per TBSA (IQR: $10,788.5 - $28,332.6) compared to the STSG group (IQR: $12,336.8 - $29,507.3; P = 0.602) with a lower mean adjusted charge per TBSA ($20,995.0 vs. $24,882.3), although this was not statistically significant. ASCS ± STSG utilization demonstrated significant reductions in LOS, surgeries, postoperative complications, antibiotics, and potential cost savings. These findings underscore the practicality of integrating ASCS in burn management, offering substantial benefits to patients and healthcare institutions.

Initiatives to improve lung and sleep health in children: Delphi consensus from the pediatrics, pulmonary, and sleep conference.

BACKGROUND AND OBJECTIVES: The lung and sleep health of adults is heavily influenced by early factors, both genetic and environmental; therefore, optimizing respiratory health begins in childhood. Multiple barriers impede improvements in lung and sleep health for children. First, the traditional siloing between general pediatric care in the community, pediatric pulmonary and sleep subspecialty care, and the research community limits the translation of knowledge into practice. Additionally, identifying and addressing health disparities remains a challenge. The 2021 NHLBI-sponsored workshop "Defining and Promoting Pediatric Pulmonary Health (DAP3H)" was a first step in defining critical gaps in our current healthcare system in identifying and optimizing lung and sleep health in children. The workshop identified key opportunities including measuring pulmonary function in young children, sleep-focused outcomes, developing biomarkers, and longitudinal research cohorts. To expand on the work of DAP3H and continue initiatives to improve childhood lung and sleep health, the Pediatrics & Pulmonary Network: Improving Health Together conference was held in 2023. STUDY DESIGN: A modified Delphi process was applied to form consensus surrounding gaps, barriers, and action items, with the goal of identifying the most urgent opportnities for improving childhood lung and sleep health. RESULTS: Cross-cutting foundational principles were identified as: (1) Authentic Stakeholder Collaboration & Engagement, (2) Reach & Implementation in Real World Settings, (3) Understanding Current Landscape & Resources and (4) Purposeful Diversity, Equity, & Inclusion Initiatives. CONCLUSIONS: To improve lung and sleep health in children, these principles should be the foundation for research design, development, and implementation.

Profiling Proteins and Phosphorylation Sites During T Cell Activation Using an Integrated Thermal Shift Assay.

T cell activation is a complex biological process of naïve cells maturing into effector cells. Proteomic and phospho-proteomic approaches have provided critical insights into this process, yet it is not always clear how changes in individual proteins or phosphorylation sites have functional significance. Here, we developed the Phosphorylation Integrated Thermal Shift Assay (PITSA) that combines the measurement of protein or phosphorylation site abundance and thermal stability into a single TMT experiment and apply this method to study T cell activation. We quantified the abundance and thermal stability of over 7,500 proteins and 5,000 phosphorylation sites, and identified significant differences in chromatin-related, TCR signaling, DNA repair, and proliferative phosphoproteins. PITSA may be applied to a wide range of biological contexts to generate hypotheses as to which proteins or phosphorylation sites are functionally regulated in a given system, as well as the mechanisms by which this regulation may occur.