"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.

Higher Waitlist Mortality in Pediatric Acute-on-chronic Liver Failure in the UNOS Database.

OBJECTIVES: Acute-on-chronic liver failure (ACLF), whereas increasingly well-defined in adults, has been poorly characterized in pediatric patients other than having a poor prognosis. This study aimed to identify ACLF and evaluate prognosis in the American pediatric population. METHODS: Modified ACLF definitions (p-CLIF) were applied to 11,300 children listed for liver transplantation from March 2002 through 2017 in the Organ Procurement and Transplantation Network (OPTN) database. RESULTS: Pediatric ACLF patients have greater mortality within 90 days from listing (46.6% by p-CLIF) than other types of failure (<30%), including acute liver failure, as well as greater mortality within the first 30 and 90 days after transplantation than all other types of liver failure, but do not have increased mortality rates relative to other groups between 90 and 365 days from transplant. Although some ACLF listings also received 1B status, ACLF mortality at 90 days was greater than the general 1B population (50 vs 29.4%). Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease scores of ACLF patients are lower than 1B listings, and do not predict waitlist or posttransplant death. Greater number of organ failures does correlate with increased mortality. Biliary atresia is the leading etiology of pediatric chronic liver disease, accounting for over 30% of chronic and 45% of ACLF listings, yet is protective against mortality (hazard ratio [HR] = 0.142 for ACLF). Receiving exception approval is independently but similarly protective in ACLF (HR = 0.145). CONCLUSIONS: These findings pose a challenge for allocation decisions but indicate greater attention to ACLF is needed, as scoring systems may not capture these children's risk of early death, which appears to currently be mitigated by exceptions. Multicenter, clinical, preferably prospective study of ACLF is necessary to determine how to prioritize ACLF relative to other liver failure types to address its relatively higher early mortality.

Pediatric discard risk index for predicting pediatric liver allograft discard.

BACKGROUND: Of the 600 pediatric candidates added to the liver waiting list annually, 100 will remain waiting while over 100 liver allografts are discarded, often for subjective reasons. METHODS: We created a risk index to predict discard to better optimize donor supply. We used the UNOS database to retrospectively analyze 17 367 deceased donors (≤18 years old) through univariate and multivariate logistic regression models. Deceased donor clinical characteristics and laboratory values were independent variables with discard being the dependent variable in the analysis. Significant univariate factors (P-value < .05) comprised the multivariate analysis. Significant variables from the multivariate analysis were incorporated into the pDSRI, producing a risk score for discard. RESULTS: From 17 potential factors, 11 were identified as significant predictors (P < .05) of pediatric liver allograft discard. The most significant risk factors were as follows: DCD; total bilirubin >10 mg/dL, and alanine transaminase (ALT) ≥500 IU/L. The pDSRI has a C-statistic of 0.846 for the training set and 0.840 for the validation set. CONCLUSION: The pDSRI uses 11 significant risk factors, including elevated liver function tests, donor demographics, and donor risk/type to accurately predict risk of pediatric liver allograft discard and serve as a tool that may maximize donor yield.

The decreasing predictive power of MELD in an era of changing etiology of liver disease.

The field of liver transplantation has shifted considerably in the MELD era, including changing allocation, immunosuppression, and liver failure etiologies, as well as better supportive therapies. Our aim was to evaluate the predictive accuracy of the MELD score over time. The United Network for Organ Sharing provided de-identified data on 120 156 patients listed for liver transplant from 2002-2016. The ability of the MELD score to predict 90-day mortality was evaluated by a concordance (C-) statistic and corroborated with competing risk analysis. The MELD score's concordance with 90-day mortality has downtrended from 0.80 in 2003 to 0.70 in 2015. While lab MELD scores at listing and transplant climbed in that interval, score at waitlist death remained steady near 35. Listing age increased from 50 to 54 years. HCV-positive status at listing dropped from 33 to 17%. The concordance of MELD and mortality does not differ with age (>60 = 0.73, <60 = 0.74), but is lower in diseases that are increasing most rapidly-alcoholic liver disease and non-alcoholic fatty liver disease-and higher in those that are declining, particularly in HCV-positive patients (HCV positive = 0.77; negative = 0.73). While MELD still predicts mortality, its accuracy has decreased; changing etiology of disease may contribute.

Regulation of valve endothelial cell vasculogenic network architectures with ROCK and Rac inhibitors.

OBJECTIVE: The age- and disease-dependent presence of microvessels within heart valves is an understudied characteristic of these tissues. Neovascularization involves endothelial cell (EC) migration and cytoskeletal reorientation, which are heavily regulated by the Rho family of GTPases. Given that valve ECs demonstrate unique mesenchymal transdifferentiation and cytoskeletal mechanoresponsiveness, compared to vascular ECs, this study quantified the effect of inhibiting two members of the Rho family on vasculogenic network formation by valve ECs. APPROACH AND RESULTS: A tubule-like structure vasculogenesis assay (assessing lacunarity, junction density, and vessel density) was performed with porcine aortic valve ECs treated with small molecule inhibitors of Rho-associated serine-threonine protein kinase (ROCK), Y-27632, or the Rac1 inhibitor, NSC-23766. Actin coordination, cell number, and cell migration were assessed through immunocytochemistry, MTT assay, and scratch wound healing assay. ROCK inhibition reduced network lacunarity and interrupted proper cell-cell adhesion and actin coordination. Rac1 inhibition increased lacunarity and delayed actin-mediated network formation. ROCK inhibition alone significantly inhibited migration, whereas both ROCK and Rac1 inhibition significantly reduced cell number over time compared to controls. Compared to a vascular EC line, the valve ECs generated a network with larger total vessel length, but a less smooth appearance. CONCLUSIONS: Both ROCK and Rac1 inhibition interfered with key processes in vascular network formation by valve ECs. This is the first report of manipulation of valve EC vasculogenic organization in response to small molecule inhibitors. Further study is warranted to comprehend this facet of valvular cell biology and pathology and how it differs from vascular biology.

Is Liver Transplant Justified at Any MELD Score?

BACKGROUND: Assessing the survival benefit of transplantation in patients with end-stage liver disease is critical in guiding the decision-making process for liver allocation. Previous studies established increased mortality risk for those transplanted below Model for End-Stage Liver Disease (MELD) 18 compared with candidates who remained on the waitlist; however, improved outcomes of liver transplantation and a changing landscape in the donor supply warrant re-evaluation of this idea. METHODS: Using the United Network for Organ Sharing database, we analyzed 160 290 candidates who were waitlisted for liver transplantation within MELD cohorts. We compared patients who were transplanted in a MELD cohort with those listed but not transplanted in that listed MELD cohort with an intent-to-treat analysis. RESULTS: Those transplanted at a MELD between 6 and 11 showed a 31% reduction in adjusted mortality (HR = 0.69 [95% confidence interval [CI], 0.66-0.75]; P < 0.001) compared with the intent-to-treat cohort in a Cox multivariate regression. This mortality benefit increased to a 37% adjusted reduction for those transplanted at MELD between 12 and 14 (HR = 0.63 [95% CI, 0.60-0.66]; P < 0.001) and a 46% adjusted reduction for those transplanted at a MELD between 15 and 17 (HR = 0.54 [95% CI, 0.52-0.57]; P < 0.001), effects that remained in sensitivity analyses excluding patients with hepatocellular carcinoma, encephalopathy, ascites, and variceal bleeds. A multivariate analysis of patients transplanted at MELD < 18 found younger age and cold ischemia time were protective, whereas older age, lower functional status, and socioeconomic factors increased mortality risk. CONCLUSIONS: These findings challenge the current practice of deferring liver transplants below a particular MELD score by demonstrating survival benefits for most transplant patients at the lowest MELD scores and providing insight into who benefits within these subgroups.

Trends in Survival for Pediatric Transplantation.

OBJECTIVES: Progress in pediatric transplantation measured in the context of waitlist and posttransplant survival is well documented but falls short of providing a complete perspective for children and their families. An intent-to-treat analysis, in which we measure survival from listing to death regardless of whether a transplant is received, provides a more comprehensive perspective through which progress can be examined. METHODS: Univariable and multivariable Cox regression was used to analyze factors impacting intent-to-treat survival in 12 984 children listed for heart transplant, 17 519 children listed for liver transplant, and 16 699 children listed for kidney transplant. The Kaplan-Meier method and log-rank test were used to assess change in waitlist, posttransplant, and intent-to-treat survival. Wait times and transplant rates were compared by using χ2 tests. RESULTS: Intent-to-treat survival steadily improved from 1987 to 2017 in children listed for heart (hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.96-0.97), liver (HR 0.95, 95% CI 0.94-0.97), and kidney (HR 0.97, 95% CI 0.95-0.99) transplant. Waitlist and posttransplant survival also improved steadily for all 3 organs. For heart transplant, the percentage of patients transplanted within 1 year significantly increased from 1987 to 2017 (60.8% vs 68.7%); however, no significant increase was observed in liver (68.9% vs 72.5%) or kidney (59.2% vs 62.7%) transplant. CONCLUSIONS: Intent-to-treat survival, which is more representative of the patient perspective than individual metrics alone, steadily improved for heart, liver, and kidney transplant over the study period. Further efforts to maximize the donor pool, improve posttransplant outcomes, and optimize patient care while on the waitlist may contribute to future progress.

Survival on the Heart Transplant Waiting List.

Importance: With continuing improvements in medical devices and more than a decade since the 2006 United Network for Organ Sharing (UNOS) allocation policy, it is pertinent to assess survival among patients on the heart transplantation waiting list, especially given the recently approved 2018 UNOS allocation policy. Objectives: To assess survival outcomes among patients on the heart transplant waiting list during the past 3 decades and to examine the association of ventricular assist devices (VADs) and the 2006 UNOS allocation policy with survival. Design, Setting, and Participants: A retrospective cross-sectional used the UNOS database to perform an analysis of 95 323 candidates wait-listed for heart transplantation between January 1, 1987, and December 29, 2017. Candidates for all types of combined transplants were excluded (n = 2087). Patients were followed up from the time of listing to death, transplantation, or removal from the list due to clinical improvement. Competing-risk, Kaplan-Meier, and multivariable Cox proportional hazards regression analyses were used. Main Outcomes and Measures: The analysis involved an unadjusted and adjusted survival analysis in which the primary outcome was death on the waiting list. Because of changing waiting list preferences and policies during the study period, the intrinsic risk of death for wait-listed candidates was assessed by individually analyzing, comparing, and adjusting for several candidate risk factors. Results: In total, 95 323 candidates (72 915 men [76.5%]; mean [SD] age, 51.9 [12.0] years) were studied. In the setting of changes in listing preferences, 1-year survival on the waiting list increased from 34.1% in 1987-1990 to 67.8% in 2011-2017 (difference in proportions, 0.34%; 95% CI, 0.32%-0.36%; P < .001). The 1-year waiting list survival for candidates with VADs increased from 10.2% in 1996-2000 to 70.0% in 2011-2017 (difference in proportions, 0.60%; 95% CI, 0.58%-0.62%; P < .001). Similarly, in the setting of changing mechanical circulatory support indications, the 1-year waiting list survival for patients without VADs increased from 53.9% in 1996-2000 to 66.5% in 2011-2017 (difference in proportions, 0.13%; 95% CI, 0.12%-0.14%; P < .001). In the decade prior to the 2006 UNOS allocation policy, the 1-year waiting list survival was 51.1%, while in the decade after it was 63.9% (difference in proportions, 0.13%; 95% CI, 0.12%-0.14%; P < .001). In adjusted analysis, each time period after 1987-1990 had a marked decrease in waiting list mortality. Conclusions and Relevance: This study found temporally associated increases in heart transplant waiting list survival for all patient groups (with or without VADs, UNOS status 1 and status 2 candidates, and candidates with poor functional status).

Liver Transplantation for Alcoholic Liver Disease: An Update.

Alcoholic liver disease is a serious and increasing contributor to the global liver disease burden. Extensive selection criteria, including a minimum abstinence period, has previously been used to secure good outcomes but new research questions the effectiveness of abstinence periods and has recommended changes in integrated alcohol use treatment to effectively prevent relapse. Patients have unique health concerns, including posttransplantation risks of malignancy and metabolic complications, but overall very good long-term outcomes. Severe alcoholic hepatitis has been increasingly treated with early transplantation without a set sobriety period, with overall favorable outcomes, even with respect to recidivism.

The Man with 2 Hearts: 25 Years from Heterotopic to Orthotopic Heart Transplantation.

Substantial technological advances in mechanical circulatory support have caused a shift in the management of end-stage heart failure. From the 1970s through the 1990s, heterotopic heart transplantation was routinely performed in patients in whom orthotopic transplantation was likely to fail. Heterotopic heart transplantation is now performed less often because modern mechanical circulatory assist devices are routinely used as bridges to orthotopic transplantation; regardless, the operation has helped numerous patients who would not otherwise have received adequate allografts. We describe the case of a man with idiopathic nonischemic cardiomyopathy who, at age 17, was given an ABO- and size-matched heterotopic allograft that was a complete human leukocyte antigen mismatch. The graft functioned normally for 20 years until the patient had a myocardial infarction that necessitated placement of a coronary artery stent. Subsequent treatments involved many interventions, including insertion of an intra-aortic balloon pump, medical therapy for heart failure, implantation of a total artificial heart, and, ultimately, orthotopic transplantation. To our knowledge, our patient is the longest surviving recipient of a heterotopic heart transplant, with a remarkable 25-year graft survival despite poor histocompatibility and an almost complete lack of native heart function. The strategies used for his treatment make him a living case study that can add valuable information to the history of cardiac support.

An Infertile Couple's Long and Expensive Path to Varicocele Repair.

OBJECTIVE: To characterize the pathways to care that infertile couples requiring varicocele repair (VR) pursue prior to presenting to a male fertility clinic. METHODS: An IRB-approved single center retrospective review of patients undergoing VR after presentation to an academic male fertility clinic was performed. Patients whose charts included partner histories were assessed for duration of attempting conception, prior workup, and assisted reproductive technology (ART) use. RESULTS: A total of 405 couples were included. At presentation, mean age was 34.4 (SD ± 6.5) years for men and 31.1 (SD ± 4.3) years for women (P < .0001). A couple's first visit to a physician was a gynecologist in 59% (198/334) of couples, a reproductive endocrinologist (REI) in 25% (83/334) of cases, with 14% (47/334) presenting without a previous female workup and were self-referred, and 2% (6/334) seeing both a gynecologist and REI prior to presentation. On average, couples attempted pregnancy for 22.3 (SD ± 21.1, range 0-120) months prior to presentation. Eighteen percent of couples underwent ART prior to presentation. Couples who had undergone ART had lower pre-VR total motile sperm counts compared to couples not pursuing ART prior to presentation (P = 0.031). The majority (70.4%) of females had no abnormality in their workup, making varicocele the only correctable factor for infertility in the couple. CONCLUSIONS: Our findings show a significant delay in referral of infertile men requiring VR. Eighteen percent of couples underwent costly ART prior to an inexpensive male workup. In an era of medical cost containment, early referral to a male infertility specialist is imperative.

Comparative quantum mechanics/molecular mechanics (QM/MM) and density functional theory calculations on the oxo-iron species of taurine/alpha-ketoglutarate dioxygenase.

We present here the first quantum mechanical/molecular mechanics (QM/MM) studies of taurine/alpha-ketoglutarate dioxygenase (TauD) enzymes. Our studies are focused on the chemical properties of the oxo-iron species and the effect of the protein environment on its structural and electronic behavior. Although the active site region of TauD is very polar with many key hydrogen bonding interactions and salt bridges, the actual effect of the protein environment on the ordering and relative energies of the possible spin state structures is found to be quite small. Optimized geometries are very close to ones observed with density functional theory models that did not take the protein environment into consideration. The calculations show that protonation of the histidine ligands of iron is essential to reproduce the correct electronic representations of the enzyme. Hydroxylation studies of taurine by the oxo-iron active species predict that it is a very efficient catalyst that reacts with substrates via low reaction barriers.

MELD-Na (the new MELD) and peri-operative outcomes in emergency surgery.

BACKGROUND: The new Model for End-Stage Liver Disease includes serum sodium (MELD-Na). To evaluate its predictive power in non-transplant surgery, we analyzed emergency surgery outcomes of cirrhotic patients, hypothesizing that negative outcomes could be associated with discrete MELD-Na score thresholds. METHODS: Retrospective chart review was conducted of patients with cirrhosis undergoing emergency surgery at our institution from 2001 to 2013 (n = 85). Risk thresholds and predictors of peri-operative outcomes were identified using univariate and multivariate regression. RESULTS: MELD-Na scores of 19, 17, and 12 were identified as predictors of 30-day mortality (OR = 3.44), post-operative complications (OR = 3.08), and discharge to home (inverse relationship, OR = 0.31). Post-operative complications were independent negative predictors of discharge to home (OR = 0.21). CONCLUSION: Although emergency surgery in patients with cirrhosis can be life-saving, knowledge of the significant peri-operative risk should drive decision-making, informed by the increased risk associated with these score thresholds. Further study is needed to establish definitive MELD-Na thresholds.

Valve Interstitial Cells Act in a Pericyte Manner Promoting Angiogensis and Invasion by Valve Endothelial Cells.

Neovascularization is an understudied aspect of calcific aortic valve disease (CAVD). Within diseased valves, cells along the neovessels' periphery stain for pericyte markers, but it is unclear whether valvular interstitial cells (VICs) can demonstrate a pericyte-like phenotype. This investigation examined the perivascular potential of VICs to regulate valve endothelial cell (VEC) organization and explored the role of Angiopoeitin1-Tie2 signaling in this process. Porcine VECs and VICs were fluorescently tracked and co-cultured in Matrigel over 7 days. VICs regulated early VEC network organization in a ROCK-dependent manner, then guided later VEC network contraction through chemoattraction. Unlike vascular control cells, the valve cell cultures ultimately formed invasive spheroids with 3D angiogenic-like sprouts. VECs co-cultured with VICs displayed significantly more invasion than VECs alone; with VICs generally leading and wrapping around VEC invasive sprouts. Lastly, Angiopoietin1-Tie2 signaling was found to regulate valve cell organization during VEC/VIC spheroid formation and invasion. VICs demonstrated pericyte-like behaviors toward VECs throughout sustained co-culture. The change from a vasculogenic network to an invasive sprouting spheroid suggests that both cell types undergo phenotypic changes during long-term culture in the model angiogenic environment. Valve cells organizing into spheroids and undergoing 3D invasion of Matrigel demonstrated several typical angiogenic-like phenotypes dependent on basal levels of Angiopoeitin1-Tie2 signaling and ROCK activation. These results suggest that the ectopic sustained angiogenic environment during the early stages of valve disease promotes organized activity by both VECs and VICs, contributing to neovessel formation and the progression of CAVD.