Climate change, human health, and resilience in the Holocene.

Climate change is an indisputable threat to human health, especially for societies already confronted with rising social inequality, political and economic uncertainty, and a cascade of concurrent environmental challenges. Archaeological data about past climate and environment provide an important source of evidence about the potential challenges humans face and the long-term outcomes of alternative short-term adaptive strategies. Evidence from well-dated archaeological human skeletons and mummified remains speaks directly to patterns of human health over time through changing circumstances. Here, we describe variation in human epidemiological patterns in the context of past rapid climate change (RCC) events and other periods of past environmental change. Case studies confirm that human communities responded to environmental changes in diverse ways depending on historical, sociocultural, and biological contingencies. Certain factors, such as social inequality and disproportionate access to resources in large, complex societies may influence the probability of major sociopolitical disruptions and reorganizations-commonly known as "collapse." This survey of Holocene human-environmental relations demonstrates how flexibility, variation, and maintenance of Indigenous knowledge can be mitigating factors in the face of environmental challenges. Although contemporary climate change is more rapid and of greater magnitude than the RCC events and other environmental changes we discuss here, these lessons from the past provide clarity about potential priorities for equitable, sustainable development and the constraints of modernity we must address.

"Peace of Mind" After Mastectomy: A Scoping Review.

BACKGROUND: Many women eligible for breast conservation therapy (BCT) elect unilateral mastectomy (UM) with or without contralateral prophylactic mastectomy (CPM) and cite a desire for "peace of mind." This study aimed to characterize how peace of mind is defined and measured and how it relates to surgical choice. METHODS: Nine databases were searched for relevant articles through 8 October 2023, and data were extracted from articles meeting the inclusion criteria. RESULTS: The inclusion criteria were met by 20 studies. Most were prospective cohort studies (65%, 13/20). In the majority of the studies (72%, 13/18), Non-Hispanic white/Caucasian women comprised 80 % or more of the study's sample. Almost half of the studies used the phrase "peace of mind" in their publication (45%, 9/20), and few directly defined the construct (15%, 3/20). Instead, words representing an absence of peace of mind were common, specifically, "anxiety" (85%, 17/20), "fear" (75%, 15/20), and "concern" (75%, 15/20). Most of the studies (90%, 18/20) measured peace of mind indirectly using questionnaires validated for anxiety, fear, worry, distress, or concern, which were administered at multiple postoperative time points (55%, 11/20). Most of the studies (95%, 18/19) reported at least one statistically significant result showing no difference in peace of mind between BCT, UM, and/or CPM at their latest time of assessment. CONCLUSION: Peace of mind is largely framed around concepts that suggest its absence, namely, anxiety, fear, and concern. Existing literature suggests that peace of mind does not differ among average-risk women undergoing BCT, UM, or CPM. Shared surgical decisions should emphasize at least comparable emotional and/or psychosocial well-being between CPM and breast conservation.

A Dual Role for Cysteinyl Leukotriene Receptors in the Pathogenesis of Corneal Infection.

Cysteinyl leukotrienes (CysLTs) have been defined as central mediators of inflammation. Despite our extensive understanding of these bioactive lipid mediators in the pathogenesis of diseases such as asthma, allergic rhinitis, and even neurological disorders, information regarding the eye is markedly lacking. As a result, this study examined the expression profiles of two major CysLT receptors, CysLT1 and CysLT2, in the cornea using experimental mouse models of Pseudomonas aeruginosa-induced keratitis with contrasting outcomes: susceptible C57BL/6 (B6) and resistant BALB/c. Postinfection, disparate levels of CysLT receptors were accompanied by distinct expression profiles for select proinflammatory and anti-inflammatory cell surface markers detected on macrophages and polymorphonuclear neutrophils between the two strains. Further, inhibition of either CysLT receptor converted the disease response of both strains, where corneal perforation was prevented in B6 mice, and BALB/c mice fared significantly worse. In addition, receptor antagonist studies revealed changes in inflammatory cell infiltrate phenotypes and an influence on downstream CysLT receptor signaling pathways. Although the B6 mouse model highlights the established proinflammatory activities related to CysLT receptor activation, results generated from BALB/c mice indicate a protective mechanism that may be essential to disease resolution. Further, basal expression levels of CysLT1 and CysLT2 were significantly higher in uninfected corneas of both mouse strains as opposed to during infection, suggestive of a novel role in homeostatic maintenance within the eye. In light of these findings, therapeutic targeting of CysLT receptors extends beyond inhibition of proinflammatory activities and may impact inflammation resolution, as well as corneal surface homeostasis.

Ancillary Treatment Referrals and Visits After Breast Cancer Surgery in a Sociodemographically Diverse Population.

BACKGROUND: Ancillary therapies with rehabilitative, palliative, and survivorship specialists mitigate adverse effects of breast cancer surgery. Existing data suggest that patients from disadvantaged backgrounds may be less likely to receive these services. This study aimed to assess variations in ancillary provider referrals and patient visits at a high-volume urban cancer center. METHODS: Electronic health records of breast cancer surgical patients at the Yale-New Haven Health System between 2010 and 2017 were reviewed. The primary end points were postoperative referral to ancillary service providers and patient use of ancillary services (defined as attending ≥ 1 consultation). Associations between end points and demographic/disease variables were identified in uni- and multivariable logistic regression analyses. RESULTS: The study identified 5496 patients: 2288 patients (41.6%) referred to ancillary services and 1572 patients (28.6%) who attended one or more consultations. Referrals were highest among the patients with Hispanic (57.5%) or black (54.9%) ancestry, no health insurance (57.6%), lowest percentage of high school degrees for the zip code area (50.5%), and poorest median income bracket (50.7%). Associations remained significant in the multivariable analysis (p < 0.05). Minority race remained associated with referrals in analyses of each ancillary service individually. Visits to ancillary specialists were greatest among the patients with private insurance (70.7%), highest percentage of high school degrees (72.8%), highest median household income (72.2%), and Hispanic ethnicity (73.5%). Highest median household income (odds ratio [OR] 1.45; p = 0.02) and Hispanic ethnicity (OR, 1.50; p = 0.05) remained associated in the multivariable analysis. CONCLUSIONS: In a well-resourced health system serving a demographically diverse population, traditional markers of poor health care access were associated with referral for ancillary treatment after breast cancer surgery but not with utilization of ancillary treatment. Health care access remains a critical barrier to adjunctive therapies that target postoperative morbidity and elevate quality of life.

Comparison of Outcomes Between BRCA Pathogenic Variant Carriers Undergoing Breast-Conserving Surgery Versus Mastectomy.

INTRODUCTION: Although outcomes are similar following breast-conserving surgery (BCS) or mastectomy among sporadic breast cancer patients, data are mixed for women with a germline BRCA mutation. We sought to compare outcomes among a modern cohort of BRCA mutation carriers undergoing BCS versus mastectomy. METHODS: Women with a BRCA mutation and an index breast cancer from 2006-2015 were retrospectively identified from institutional databases. Factors, including date of genetic testing, clinicopathologic details, and treatment characteristics, were identified. Subsequent locoregional recurrence (LRR), distant recurrence, contralateral breast cancer (CBC), breast cancer-specific survival (BCSS), and overall survival (OS) events were compared between groups. RESULTS: A total of 395 BRCA mutation carriers with 424 cancers were identified. Surgical treatment included BCS for 99 cancers and mastectomy for 325 cancers. Patients choosing mastectomy were more likely to have bilateral breast cancer, be younger/premenopausal, and be aware of their genetic status before surgery, and were less likely to receive radiation therapy (p < 0.001). At 7.9 years median follow-up, LRR, distant recurrence, BCSS, and OS rates did not differ between groups. CBC occurred in 5 versus 0 women treated with unilateral versus bilateral surgery, respectively, resulting is a 10-year estimated CBC risk of 14% among unilateral breast surgery patients (p < 0.001). CONCLUSIONS: With nearly 8 years follow-up, we report no difference in LRR, BCSS, and OS among BRCA mutation carriers who underwent BCS or mastectomy; however, we report a higher incidence of CBC among those undergoing unilateral breast surgery. These data support BCS as an option for BRCA mutation carriers willing to continue high-risk screening.

Association of Medicaid Expansion with Post-mastectomy Reconstruction Rates.

BACKGROUND: The Affordable Care Act sought to improve access to health care for low-income individuals. This study aimed to assess whether expansion of Medicaid coverage increased rates of post-mastectomy reconstruction (PMR) for patients who had Medicaid or no insurance. METHODS: A retrospective analysis performed through the National Cancer Database examined women who underwent PMR and were uninsured or had Medicaid, private insurance, or Medicare, and whose race/ethnicity, age, and state expansion status were known. Trends in the use of PMR after passage of Medicaid expansion in 2014 were evaluated. RESULTS: In all states and at all time periods, patients with private insurance were about twice as likely to undergo PMR as patients who had Medicaid or no insurance. In 2016, only 28.7 % of patients with Medicaid or no insurance in nonexpansion states underwent PMR (p < 0.001) compared with 38.5 % of patients in expansion states (p < 0.001). Patients in expansion states also have higher levels of education, higher income, and greater likelihood of living in metropolitan areas. Additionally, patients in all states saw an increase in early-stage disease, with a concomitant reduction in late disease, but this change was greater in expansion states than in non-expansion states. CONCLUSIONS: Expansion states have larger proportions of patients undergoing PMR than non-expansion states. This difference stems from significant differences in income, education, comorbidities, race, and location. Large metropolitan areas have the largest number of patients undergoing PMR, whereas rural areas have the least.

Breast conservation among older patients with early-stage breast cancer: Locoregional recurrence following adjuvant radiation or hormonal therapy.

BACKGROUND: For patients with breast cancer undergoing breast-conserving surgery (BCS), adjuvant radiation (RT) and hormonal therapy (HT) reduce the risk of locoregional recurrence (LRR). Although several studies have evaluated adjuvant HT ± RT, the outcomes of HT versus RT monotherapy remain less clear. In this study, the risk of LRR is characterized among older patients with early-stage breast cancer following adjuvant RT alone, HT alone, neither, or both. METHODS: This study included female patients from the Memorial Sloan Kettering Cancer Center (New York, New York) who were aged ≥65 years with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) T1N0 breast cancer treated with BCS. The primary endpoint was time to LRR evaluated by Cox regression analysis. RESULTS: There were 888 women evaluated with a median age of 71 years (range, 65-100 years) and median follow-up of 4.9 years (range, 0.0-9.5 years). There were 27 LRR events (3.0%). Five-year LRR was 11% for those receiving no adjuvant treatment, 3% for HT alone, 4% for RT alone, and 1% for HT and RT. LRR rates were significantly different between the groups (P < .001). Compared with neither HT nor RT, HT or RT monotherapy each yielded similar LRR reductions: HT alone (HR, 0.27; 95% CI, 0.10-0.68; P = .006) and RT alone (HR, 0.32; 95% CI, 0.11-0.92; P = .034). Distant recurrence and breast cancer-specific survival rates did not significantly differ between groups. CONCLUSIONS: LRR risk following BCS is low among women aged ≥65 years with T1N0, ER+/HER2- breast cancer. Adjuvant RT and HT monotherapy each similarly reduce this risk; the combination yields a marginal improvement. Further study is needed to elucidate whether appropriate patients may feasibly receive adjuvant RT monotherapy versus the current standards of HT monotherapy or combined RT/HT.

Assessing Interobserver Variability of Cosmetic Outcome Assessment in Breast Cancer Patients Undergoing Breast-Conservation Surgery.

BACKGROUND: Inter-rater reliability between breast surgical oncologists and reconstructive surgeons using cosmesis scales, and the correlation between their observations and patients' own subjective assessments, is poorly understood. METHODS: Patients undergoing BCS in a prospective trial rated their cosmetic outcome on a Likert scale (poor/fair/good/excellent) at the postoperative and 1-year time points; photographs were also taken. Three breast surgical oncologists (not involved in these cases) and two reconstructive surgeons were asked to independently rate cosmesis using the Harvard/NSABP/RTOG scale. RESULTS: Overall, 55 and 17 patients had photographs and Likert self-evaluations at the postoperative and 1-year time points, respectively. There was poor agreement between surgeon and patient ratings postoperatively [kappas - 0.042 (p = 0.659), 0.069 (p = 0.226), and 0.076 (p = 0.090) for the breast surgical oncologists; and 0.018 (p = 0.689) and 0.112 (p = 0.145) for the reconstructive surgeons], and poor interobserver agreement between surgeons of the same specialty (kappa - 0.087, 95% confidence interval [CI] - 0.091 to - 0.082, p = 0.223 for breast surgical oncologists; and kappa - 0.150, 95% CI - 0.157 to - 0.144, p = 0.150, for reconstructive surgeons). At 1 year, the interobserver agreement between breast surgical oncologists was better (kappa 0.507, 95% CI 0.501-0.512, p < 0.001); however, there was still poor correlation between the reconstructive surgeons (kappa - 0.040, 95% CI - 0.049 to - 0.031, p = 0.772). Agreement between surgeon and patient ratings remained poor at this time point [kappas - 0.115 (p = 0.477), 0.177 (p = 0.245), and 0.101 (p = 0.475) for breast surgical oncologists; and 0.335 (p = 0.037) and -0.118 (p = 0.221) for reconstructive surgeons]. CONCLUSION: Despite gradation scales for measuring cosmesis after BCS, high levels of agreement between surgeons is lacking and these do not always reflect patients' subjective assessments.

Apocrine Breast Cancer: Unique Features of a Predominantly Triple-Negative Breast Cancer.

INTRODUCTION: Invasive apocrine carcinoma is a rare breast cancer that is frequently triple negative. Little is known about the characteristics of its molecular subtypes. We compared the incidence, demographics, and clinicopathologic features of this cancer with non-apocrine carcinomas stratified by molecular subtype. METHODS: Women with invasive apocrine cancer were retrospectively identified from the Surveillance, Epidemiology, and End Results (SEER) database. Clinicopathologic and demographic features were compared with non-apocrine carcinomas, both overall using data from 2004 to 2017 and stratified by molecular subtypes using data from 2010 to 2017. The life table method was used to determine the 7-year breast cancer-specific survival. RESULTS: Compared with non-apocrine cancers, apocrine cancers presented at a younger age, with larger, higher-grade tumors that were much more likely to be triple negative (50% vs. 11%) or human epidermal growth factor receptor 2 (HER2)-positive (28% vs. 15%) and less likely to be luminal (22% vs. 74%); however, the 7-year survival was the same at 85%. The characteristics varied dramatically by molecular type. Compared with non-apocrine triple-negative, apocrine triple-negative patients were less likely to be African American and were much older, with smaller, lower-grade tumors and much better survival (86% vs. 74%). In contrast, compared with luminal non-apocrine, apocrine luminal patients had larger, higher-grade tumors and worse survival (79% vs. 89%). CONCLUSIONS: Invasive apocrine carcinomas have more aggressive features than non-apocrine carcinomas but the breast cancer-specific survival is the same. Half of these apocrine tumors are triple negative but these have more favorable features and much better survival than non-apocrine triple-negative cancers.

Moral Injury and Burnout in Health Care Professionals During the COVID-19 Pandemic.

ABSTRACT: The coronavirus pandemic (COVID-19) is predicted to increase burnout in health professionals (HPs), but little is known about moral injury (MI) in this context. We administered the Moral Injury Symptoms Scale for Health Professionals (MISS-HP) and the abbreviated Maslach Burnout Inventory via online survey to a global sample of 1831 HPs in April and October 2020. Mean MISS-HP increased from 27.4 (SD, 11.6) in April to 36.4 (SD, 13.8) in October (p < 0.001), with an accompanying increase in personal accomplishment (April: 4.7; SD, 3.1; October: 9.3; SD, 3.1; p < 0.001) and no change in other burnout subscales. In April, 26.7% of respondents reported at least moderate functional impairment from MI, increasing to 45.7% in October (p < 0.001). Predictors of MISS-HP included younger age and being a nurse. Odds of functional impairment were higher in respondents who were widowed, divorced, never married, or had direct experience caring for patients with COVID-19. COVID-19 has increased MI but not burnout in HPs; younger or unmarried individuals, nurses, and frontline workers may benefit from targeted outreach to reduce downstream effects of MI, depression, and/or posttraumatic stress disorder.

Adjunctive Thymosin Beta-4 Treatment Influences MΦ Effector Cell Function to Improve Disease Outcome in Pseudomonas aeruginosa-Induced Keratitis.

Our previous work has shown that topical thymosin beta 4 (Tß4) as an adjunct to ciprofloxacin treatment reduces inflammatory mediators and inflammatory cell infiltrates (neutrophils/PMN and macrophages/MΦ) while enhancing bacterial killing and wound healing pathway activation in an experimental model of P. aeruginosa-induced keratitis. This study aimed to mechanistically examine how Tß4 influences MΦ function in particular, leading to reduced inflammation and enhanced host defense following P. aeruginosa-induced infection of the cornea. Flow cytometry was conducted to profile the phenotype of infiltrating MΦ after infection, while generation of reactive nitrogen species and markers of efferocytosis were detected to assess functional activity. In vitro studies were performed utilizing RAW 264.7 cells to verify and extend the in vivo findings. Tß4 treatment decreases MΦ infiltration and regulates the activation state in response to infected corneas. MΦ functional data demonstrated that the adjunctive Tß4 treatment group significantly downregulated reactive nitrogen species (RNS) production and efferocytotic activity. In addition, the in vitro studies showed that both Tß4 alone and adjunctive Tß4 treatment influenced MΦ cellular function following LPS stimulation. Collectively, these data provide further evidence that adjunctive Tß4 + ciprofloxacin treatment offers a more efficacious option for treating bacterial keratitis. Not only does the adjunctive therapy address both the infectious pathogen and corneal wound healing response, but it also influences MΦ infiltration, activation, and function, as revealed by the current study.

Real-Time Monitoring the Effect of Cytopathic Hypoxia on Retinal Pigment Epithelial Barrier Functionality Using Electric Cell-Substrate Impedance Sensing (ECIS) Biosensor Technology.

Disruption of retinal pigment epithelial (RPE barrier integrity is a hallmark feature of various retinal blinding diseases, including diabetic macular edema and age-related macular degeneration, but the underlying causes and pathophysiology are not completely well-defined. One of the most conserved phenomena in biology is the progressive decline in mitochondrial function with aging leading to cytopathic hypoxia, where cells are unable to use oxygen for energy production. Therefore, this study aimed to thoroughly investigate the role of cytopathic hypoxia in compromising the barrier functionality of RPE cells. We used Electric Cell-Substrate Impedance Sensing (ECIS) system to monitor precisely in real time the barrier integrity of RPE cell line (ARPE-19) after treatment with various concentrations of cytopathic hypoxia-inducing agent, Cobalt(II) chloride (CoCl2). We further investigated how the resistance across ARPE-19 cells changes across three separate parameters: Rb (the electrical resistance between ARPE-19 cells), α (the resistance between the ARPE-19 and its substrate), and Cm (the capacitance of the ARPE-19 cell membrane). The viability of the ARPE-19 cells and mitochondrial bioenergetics were quantified with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and seahorse technology, respectively. ECIS measurement showed that CoCl2 reduced the total impedance of ARPE-19 cells in a dose dependent manner across all tested frequencies. Specifically, the ECIS program's modelling demonstrated that CoCl2 affected Rb as it begins to drastically decrease earlier than α or Cm, although ARPE-19 cells' viability was not compromised. Using seahorse technology, all three concentrations of CoCl2 significantly impaired basal, maximal, and ATP-linked respirations of ARPE-19 cells but did not affect proton leak and non-mitochondrial bioenergetic. Concordantly, the expression of a major paracellular tight junction protein (ZO-1) was reduced significantly with CoCl2-treatment in a dose-dependent manner. Our data demonstrate that the ARPE-19 cells have distinct dielectric properties in response to cytopathic hypoxia in which disruption of barrier integrity between ARPE-19 cells precedes any changes in cells' viability, cell-substrate contacts, and cell membrane permeability. Such differences can be used in screening of selective agents that improve the assembly of RPE tight junction without compromising other RPE barrier parameters.

Antimicrobial Effects of Thymosin Beta-4 and Ciprofloxacin Adjunctive Therapy in Pseudomonas aeruginosa Induced Keratitis.

Prior work has indicated that thymosin beta 4 (Tß4) administered with ciprofloxacin markedly improves disease outcome for Pseudomonas aeruginosa (PA)-induced keratitis. As a result, the goal of the current study was to elucidate mechanisms by which Tß4 mitigates the corneal response; specifically, regarding its bactericidal influence and potential synergy with ciprofloxacin. An in vitro approach was carried out using minimum inhibitory concentration (MIC) assays to assess bactericidal activity against PA. In addition, antimicrobial peptide (AMP) production was evaluated at the mRNA levels using human corneal epithelial cells in response to lipopolysaccharide (LPS) challenge. The results of the MIC assays did not show direct bactericidal activity with Tß4 alone, although ciprofloxacin exhibited significant killing at concentrations far lower than clinically dosed. Tß4, however, displayed an indirect effect on bacterial killing, as shown by an upregulation of AMPs and related molecules. The cumulative data from this study indicate an indirect bactericidal role of Tß4, as well as a synergistic relationship with ciprofloxacin. Furthermore, ciprofloxacin alone was found to influence cellular functions that otherwise have yet to be reported. These results highlight a mechanism of intracellular communication for Tß4 and further strengthen its development as an adjunct therapy with antibiotics for corneal infections.

A Contrast in Pathogenic Responses between C57BL/6J and BALB/cJ Mice Using a Model of Retinal Injury.

Ischemia is associated with the pathogenesis of retinal disease, including diabetic retinopathy and glaucoma. As a result, the retinal ischemia/reperfusion injury model has been used to study neurovascular changes. Historically, murine models of retinal disease are established in C57BL/6J (B6) mice, which have been described as type 1-dominant responders. In bacterial keratitis models, B6 mice are susceptible, whereas BALB/cJ (BALB/c; type 2-dominant) mice exhibit a resistant phenotype. As such, we questioned whether the type 1/type 2 paradigm could be extrapolated to events associated with retinal pathogenesis. The current study compares the retinal response of B6 with BALB/c mice to investigate strain-specific differences. Retinas were collected at 2 and 10 days after ischemia/reperfusion injury to examine differences in neurovascular degeneration, leukostasis, oxidative stress, glial activation, and select inflammatory mediators. Although both strains showed signs of retinal injury, significantly more damage was observed in B6 mice. Retinal thickness was reduced and vascular damage was more severe in B6 mice. Exacerbated response to injury in B6 versus BALB/c retinas was further supported by increased leukostasis, inflammatory mediators, reactive oxygen species, and lipid peroxidation. In addition, more terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells and increased glial activation were detected in B6 mice. These data indicate that B6 and BALB/c retinas differentially respond to injury, which has broader implications regarding the development and study of retinal diseases.

Immunoregulatory role of 15-lipoxygenase in the pathogenesis of bacterial keratitis.

Although autacoids primarily derived from the cyclooxygenase-2 and 5-lipoxygenase (LOX) pathways are essential mediators of inflammation, endogenous specialized proresolving mediators (SPMs) act as robust agonists of resolution. SPM biosynthesis is initiated by the conversion of arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid primarily via the 12/15-LOX pathway. Although 12/15-LOX activity is prominent in the cornea, the role of SPM pathway activation during infection remains largely unknown and is the focus of the current study. Pseudomonas keratitis was induced in resistant BALB/c and susceptible C57BL/6 (B6) mice. Biosynthetic pathways for proinflammatory autacoids and SPMs were assessed. Divergent lipid mediator profiles demonstrate the importance of 15-LOX pathways in the pathogenesis of ocular infectious disease. Results indicate that an imbalance of LOX enzymatic pathways contributes to susceptibility observed in B6 mice where deficient activation of SPM circuits, as indicated by reduced 15-hydroxy-eicosatetraenoic acid and 17-hydroxydocosahexaenoic acid levels, prevented transition toward resolution and led to chronic inflammation. In sharp contrast, BALB/c mice demonstrated a well-balanced axis of 5-LOX/12-LOX/15-LOX pathways, resulting in sufficient proresolving bioactive metabolite formation and immune homeostasis. Furthermore, a novel immunoregulatory role for 15-LOX was revealed in inflammatory cells (polymorphonuclear leukocytes and macrophages), which influenced phagocytic activity. These data provide evidence that SPM circuits are essential for host defense during bacterial keratitis.-Carion, T. W., Greenwood, M., Ebrahim, A. S., Jerome, A., Suvas, S., Gronert, K., Berger, E. A. Immunoregulatory role of 15-lipoxygenase in the pathogenesis of bacterial keratitis.

Assessment of hospital-level adjusted breast cancer sentinel lymph node positivity rates.

BACKGROUND/OBJECTIVES: Proficiency of performing sentinel lymph node biopsy (SLNB) for breast cancer varies among hospitals and may be reflected in the hospital's SLNB positivity rate. Our objectives were to examine whether hospital characteristics are associated with variation in SLNB positivity rates and whether hospitals with lower-than-expected SLNB positivity rates have worse patient survival. METHODS: Using the National Cancer Data Base, stage I to III breast cancer patients were identified (2004-2012). Hospital-level SLNB positivity rates were adjusted for tumor and patient factors. Hospitals were divided into terciles of SLNB positivity rates (lower-, higher-, as-expected). Hospital characteristics and survival were examined across terciles. RESULTS: Of 438 610 SLNB patients (from 1357 hospitals), 78 104 had one or more positive SLN (21.3%). Hospitals in the low and high terciles were more likely to be low volume (low: RRR, 4.40; 95% CI, 2.89-6.57; P < 0.001; and high: RRR, 1.79; 95% CI, 1.21-2.64; P < 0.001) compared to hospitals with as-expected (middle tercile) SLNB positivity rates. Stage I patients at low- and high-tercile hospitals had statistically worse survival. CONCLUSIONS: There is a wide variation in hospital SLNB positivity rates. Hospitals with lower- or higher-than-expected SLNB positivity rates were associated with survival differences. Hospital SLNB positivity rates may be a novel 'process measure' to report to hospitals for internal quality assessment.

VIP modulates the ALX/FPR2 receptor axis toward inflammation resolution in a mouse model of bacterial keratitis.

Vasoactive intestinal peptide (VIP) has been shown to regulate corneal inflammation. Formyl peptide receptor 2 (FPR2) is a transmembrane protein belonging to the GPCR family. Ligands include pro-resolving lipids, lipoxin A4 (LXA4) and resolvin D1 (RvD1). The current study focuses on the effect of VIP regarding the FPR2 receptor axis in improving disease outcome in a mouse model of bacterial keratitis. Infection was induced in C57BL/6 (B6) mice using P. aeruginosa (PA) ATCC 19660. Mice received topical treatment (VIP or PBS) 3× daily after infection. Mean clinical scores, bacterial plate counts, Griess and myeloperoxidase (MPO) assays indicate that topical VIP effectively abrogates the disease response. Findings also reveal that VIP influences FPR2 pathway activation independent of archetypal VIP receptors. Exploring the immunoresolving role of FPR2, its ligand RvD1 and related enzymes (5-LOX, 12/15-LOX), our results suggest a mechanism by which VIP treatment influences the disease response in bacterial keratitis, which could offer a therapeutic point of intervention for enhancing this pro-resolving circuit.

Understanding the Role of Pro-resolving Lipid Mediators in Infectious Keratitis.

Keratitis is a sight-threatening inflammatory condition of the cornea that can be caused by both infectious and non-infectious agents. Physical or chemical trauma are typically related to non-infectious keratitis, which may then become secondarily infected or remain non-infected. Etiology of infectious keratitis is most often associated with bacteria; but viruses, fungi, and parasites are common causative pathogens as well. As a global concern, common risk factors include: systemic immunosuppression (secondary to malnutrition, alcoholism, diabetes, steroid use), previous corneal surgery (refractive corneal surgery, penetrating keratoplasty), extended wear contact lens use, pre-existing ocular surface diseases (dry eye, epithelial defect) and ocular trauma (agriculture- or farm-related) [1-8]. Annual rates of incidence include nearly one million clinical visits due to keratitis in the United States, while it has been reported that roughly two million people develop corneal ulcers in India. Clinically, patients may show signs of eye pain (ranging from mild to severe), blurred vision, photophobia, chemosis and redness. Pathogenesis is generally characterized by rapid progression, focal white infiltrates with underlying stromal inflammation, corneal thinning, stromal edema, mucopurulent discharge and hypopyon, which can lead to corneal scarring, endophthalmitis, and perforation. In fact, corneal opacity is not only a complication of keratitis, but among the leading causes of legal blindness worldwide. Despite that empirical treatment effectively controls most of the pathogens implicated in infectious keratitis, improved clinical outcomes are not guaranteed. Further, if treatment is not initiated in a timely manner, good visual outcome is reduced to approximately 50% of keratitis patients [9]. Moreover, resultant structural alterations, loss of tissue and an unresolved host response remain unaddressed through current clinical management of this condition.

Prevalence and Risk Factors for Bariatric Surgery Readmissions: Findings From 130,007 Admissions in the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program.

OBJECTIVE: To evaluate readmissions following laparoscopic adjustable gastric banding (LAGB), laparoscopic sleeve gastrectomy (LSG), and laparoscopic Roux-en-Y gastric bypass (LRYGB). BACKGROUND: Few studies have evaluated national readmission rates for primary bariatric surgery with national, bariatric-specific data. METHODS: Patients undergoing primary LAGB, LSG, or LRYGB from January 1, 2014 to December 31, 2014, at 698 centers were identified based upon Current Procedural Terminology codes. The primary outcome was 30-day readmission from date of initial operation. RESULTS: A total of 130,007 patients who underwent primary bariatric surgery were identified: 7378 LAGB (5.7%), 80,646 LSG (62.0%), and 41,983 LRYGB (32.3%). A total of 5663 (4.4%) patients were readmitted within 30 days for all causes. Patients undergoing LAGB had the lowest related readmission rate of 1.4%, followed by LSG (2.8%), and LRYGB (4.9%). Of patients who had a complication, 17.9% (n = 785) were readmitted, whereas those without readmission had a complication 1.9% of the time (P < 0.001). The most common cause of a related readmission was nausea, vomiting, fluid, electrolyte, and nutritional depletion (35.4%), followed by abdominal pain (13.5%), anastomotic leak (6.4%), and bleeding (5.8%), accounting for more than 61% of readmissions. When compared with LAGB, LSG, and LRYGB had significantly higher rates of readmission (LSG: odds ratio 1.89; 95% confidence interval 1.52-2.33; LRYGB: odds ratio 3.06; 95% confidence interval 2.46-3.81). CONCLUSIONS: National bariatric readmissions after primary procedures were closely associated with complications, varied based on the type of procedure, and were most commonly due to nausea, vomiting, electrolyte, and nutritional depletion.