Steroid receptor coactivator 3 is a key modulator of regulatory T cell-mediated tumor evasion.

Steroid receptor coactivator 3 (SRC-3) is most strongly expressed in regulatory T cells (Tregs) and B cells, suggesting that it plays an important role in the regulation of Treg function. Using an aggressive E0771 mouse breast cell line syngeneic immune-intact murine model, we observed that breast tumors were "permanently eradicated" in a genetically engineered tamoxifen-inducible Treg-cell-specific SRC-3 knockout (KO) female mouse that does not possess a systemic autoimmune pathological phenotype. A similar eradication of tumor was noted in a syngeneic model of prostate cancer. A subsequent injection of additional E0771 cancer cells into these mice showed continued resistance to tumor development without the need for tamoxifen induction to produce additional SRC-3 KO Tregs. SRC-3 KO Tregs were highly proliferative and preferentially infiltrated into breast tumors by activating the chemokine (C-C motif) ligand (Ccl) 19/Ccl21/chemokine (C-C motif) receptor (Ccr)7 signaling axis, generating antitumor immunity by enhancing the interferon-γ/C-X-C motif chemokine ligand (Cxcl) 9 signaling axis to facilitate the entrance and function of effector T cells and natural killer cells. SRC-3 KO Tregs also show a dominant effect by blocking the immune suppressive function of WT Tregs. Importantly, a single adoptive transfer of SRC-3 KO Tregs into wild-type E0771 tumor-bearing mice can completely abolish preestablished breast tumors by generating potent antitumor immunity with a durable effect that prevents tumor reoccurrence. Therefore, treatment with SRC-3-deleted Tregs represents an approach to completely block tumor growth and recurrence without the autoimmune side effects that typically accompany immune checkpoint modulators.

Transcriptional coactivation of NRF2 signaling in cardiac fibroblasts promotes resistance to oxidative stress.

We recently discovered that steroid receptor coactivators (SRCs) SRCs-1, 2 and 3, are abundantly expressed in cardiac fibroblasts (CFs) and their activation with the SRC small molecule stimulator MCB-613 improves cardiac function and dramatically lowers pro-fibrotic signaling in CFs post-myocardial infarction. These findings suggest that CF-derived SRC activation could be beneficial in the mitigation of chronic heart failure after ischemic insult. However, the cardioprotective mechanisms by which CFs contribute to cardiac pathological remodeling are unclear. Here we present studies designed to identify the molecular and cellular circuitry that governs the anti-fibrotic effects of an MCB-613 derivative, MCB-613-10-1, in CFs. We performed cytokine profiling and whole transcriptome and proteome analyses of CF-derived signals in response to MCB-613-10-1. We identified the NRF2 pathway as a direct MCB-613-10-1 therapeutic target for promoting resistance to oxidative stress in CFs. We show that MCB-613-10-1 promotes cell survival of anti-fibrotic CFs exposed to oxidative stress by suppressing apoptosis. We demonstrate that an increase in HMOX1 expression contributes to CF resistance to oxidative stress-mediated apoptosis via a mechanism involving SRC co-activation of NRF2, hence reducing inflammation and fibrosis. We provide evidence that MCB-613-10-1 acts as a protectant against oxidative stress-induced mitochondrial damage. Our data reveal that SRC stimulation of the NRF2 transcriptional network promotes resistance to oxidative stress and highlights a mechanistic approach toward addressing pathologic cardiac remodeling.

Negotiated Rates for Surgical Cancer Care in the Era of Price Transparency-Prices Reflect Market Competition.

OBJECTIVE: To measure commercial price variation for cancer surgery within and across hospitals. BACKGROUND: Surgical care for solid-organ tumors is costly, and negotiated commercial rates have been hidden from public view. The Hospital Price Transparency Rule, enacted in 2021, requires all hospitals to list their negotiated rates on their website, thus opening the door for an examination of pricing for cancer surgery. METHODS: This was a cross-sectional study using 2021 negotiated price data disclosed by US hospitals for the 10 most common cancers treated with surgery. Price variation was measured using within-hospital and across-hospital ratios. Commercial rates relative to cancer center designation and the Herfindahl-Hirschman Index at the facility level were evaluated with mixed effects linear regression with random intercepts per procedural code. RESULTS: In all, 495,200 unique commercial rates from 2232 hospitals resulted for the 10 most common solid-organ tumor cancers. Gynecologic cancer operations had the highest median rates at $6035.8/operation compared with bladder cancer surgery at $3431.0/operation. Compared with competitive markets, moderately and highly concentrated markets were associated with significantly higher rates (HHI 1501, 2500, coefficient $513.6, 95% CI, $295.5, $731.7; HHI >2500, coefficient $1115.5, 95% CI, $913.7, $1317.2). National Cancer Institute designation was associated with higher rates, coefficient $3,451.9 (95% CI, $2853.2, $4050.7). CONCLUSIONS: Commercial payer-negotiated prices for the surgical management of 10 common, solid tumor malignancies varied widely both within and across hospitals. Higher rates were observed in less competitive markets. Future efforts should facilitate price competition and limit health market concentration.

Diminished airway host innate response in people with cystic fibrosis who experience frequent pulmonary exacerbations.

RATIONALE: Pulmonary exacerbations are clinically impactful events that accelerate cystic fibrosis (CF) lung disease progression. The pathophysiological mechanisms underlying an increased frequency of pulmonary exacerbations have not been explored. OBJECTIVES: To compare host immune response during intravenous antibiotic treatment of pulmonary exacerbations in people with CF who have a history of frequent versus infrequent exacerbations. METHODS: Adults with CF were recruited at onset of antibiotic treatment of a pulmonary exacerbation and were categorised as infrequent or frequent exacerbators based on their pulmonary exacerbation frequency in the previous 12 months. Clinical parameters, sputum bacterial load and sputum inflammatory markers were measured on day 0, day 5 and at the end of treatment. Shotgun proteomic analysis was performed on sputum using liquid chromatography-mass spectrometry. MEASUREMENTS AND MAIN RESULTS: Many sputum proteins were differentially enriched between infrequent and frequent exacerbators (day 0 n=23 and day 5 n=31). The majority of these proteins had a higher abundance in infrequent exacerbators and were secreted innate host defence proteins with antimicrobial, antiprotease and immunomodulatory functions. Several differentially enriched proteins were validated using ELISA and Western blot including secretory leukocyte protease inhibitor (SLPI), lipocalin-1 and cystatin SA. Sputum from frequent exacerbators demonstrated potent ability to cleave exogenous recombinant SLPI in a neutrophil elastase dependent manner. Frequent exacerbators had increased sputum inflammatory markers (interleukin (IL)-1ß and IL-8) and total bacterial load compared to infrequent exacerbators. CONCLUSIONS: A diminished innate host protein defence may play a role in the pathophysiological mechanisms of frequent CF pulmonary exacerbations. Frequent exacerbators may benefit from therapies targeting this dysregulated host immune response.

A transgenic mouse model of Down syndrome acute lymphoblastic leukemia identifies targetable vulnerabilities.

Not available.

Updated Trends and Outcomes in Autologous Breast Reconstruction in the United States, 2016-2019.

INTRODUCTION: Autologous breast reconstruction (ABR) has increased in recent decades, although concerns for access remain. As such, our goal is to trend national demographics and operative characteristics of ABR in the United States. METHODS: Using the National Inpatient Sample, 2016-2019, the International Classification of Disease , Tenth Edition codes identified adult female encounters undergoing ABR. Demographics and procedure-related characteristics were recorded. Discharge weights generated national estimates. Statistical analysis included univariate testing and multivariate regression modeling. RESULTS: A total of 52,910 weighted encounters met the criteria (mean age, 51.5 ± 10.0 years). Autologous breast reconstruction utilization increased (Δ = +5%), 2016-2019, primarily driven by a rise in deep inferior epigastric perforator (DIEP) reconstructions (Δ = +28%; incidence rate ratio [IRR], 1.070; P < 0.001), which were predominant throughout the study period (69%). More recent surgery year, bilateral reconstruction, higher income levels, commercial insurance, and care in the South US region increased the odds of DIEP-based ABR ( P ≤ 0.036). Transverse rectus abdominis myocutaneous flaps, bilateral reconstructions, higher comorbidity levels, and experiencing complications increased the length of stay ( P ≤ 0.038). Most ABRs (75%) were privately insured. The rates of immediate reconstructions increased over the study period (from 26% to 46%; IRR, 1.223; P < 0.001), as did the rates of bilateral reconstructions (from 54% to 57%; IRR, 1.026; P = 0.030). The rates of ABRs performed at teaching hospitals remained high (90% to 93%; P = 0.242). CONCLUSIONS: As of 2019, ABR has become more prevalent, with the DIEP flap constituting the most common modality. With the increasing ABR popularity, efforts should be made to ensure geographic and financial accessibility.

Early Cleft Palate Repair is Associated With Lower Incidence of Velopharyngeal Insufficiency Surgery.

BACKGROUND: The timing of primary repair in nonsyndromic cleft palate remains controversial. Recent evidence suggests earlier repair is associated with a lower incidence of velopharyngeal insufficiency (VPI). The authors aim to evaluate these findings in a large cohort study using causal inference. METHODS: All nonsyndromic cleft palate repairs in California were extracted between 2000 and 2021 from the California Health Care Access and Information (HCAI) database. Cases were linked with VPI surgery following cleft palate repair based on unique identifiers. The main outcome measure was incidence of VPI surgery evaluated with propensity score matching. Early cleft palate repair was defined as <7 months of age versus traditional cleft palate repair at >11 months of age. Standardized mean differences (SMD) were measured before and after matching for potential confounders including sex, race, payer, and distance from patient home to hospital. RESULTS: In all, 52,007 cleft palate repairs were included, of which 12,169 (23.3%) were repaired early and 39,838 (76.7%) were repaired traditionally. Early cleft palate repairs underwent VPI surgery in 1.2% (13/1,000) of cases, compared with 6.1% (61/1000) in the traditional repair cohort. Post-matching, the average treatment effect of early repair was a 6.3% reduction in VPI surgery (P<0.001, 95% CI -6.3, -5.4%). All covariate SMDs were <|0.1| after matching. CONCLUSION: Our cohort study demonstrates a significantly reduced incidence of VPI surgery in children with primary cleft palate repair <7 months of age. Craniofacial centers should consider early cleft palate repair in appropriate patients.

Neutrophil-Derived Proteases in Lung Inflammation: Old Players and New Prospects.

Neutrophil-derived proteases are critical to the pathology of many inflammatory lung diseases, both chronic and acute. These abundant enzymes play roles in key neutrophil functions, such as neutrophil extracellular trap formation and reactive oxygen species release. They may also be released, inducing tissue damage and loss of tissue function. Historically, the neutrophil serine proteases (NSPs) have been the main subject of neutrophil protease research. Despite highly promising cell-based and animal model work, clinical trials involving the inhibition of NSPs have shown mixed results in lung disease patients. As such, the cutting edge of neutrophil-derived protease research has shifted to proteases that have had little-to-no research in neutrophils to date. These include the cysteine and serine cathepsins, the metzincins and the calpains, among others. This review aims to outline the previous work carried out on NSPs, including the shortcomings of some of the inhibitor-orientated clinical trials. Our growing understanding of other proteases involved in neutrophil function and neutrophilic lung inflammation will then be discussed. Additionally, the potential of targeting these more obscure neutrophil proteases will be highlighted, as they may represent new targets for inhibitor-based treatments of neutrophil-mediated lung inflammation.

PTEN Depletion Increases Radiosensitivity in Response to Ataxia Telangiectasia-Related-3 (ATR) Inhibition in Non-Small Cell Lung Cancer (NSCLC).

Radiotherapy (RT) treatment is an important strategy for the management of non-small cell lung cancer (NSCLC). Local recurrence amongst patients with late-stage NSCLC remains a challenge. The loss of PTEN has been associated with radio-resistance. This study aimed to examine the efficacy of RT combined with ataxia telangiectasia-mutated Rad3-related (ATR) inhibition using Ceralasertib in phosphatase and tensin homolog (PTEN)-depleted NSCLC cells and to assess early inflammatory responses indicative of radiation pneumonitis (RP) after combined-modality treatment. Small hairpin RNA (shRNA) transfections were used to generate H460 and A549 PTEN-depleted models. Ceralasertib was evaluated as a single agent and in combination with RT in vitro and in vivo. Histological staining was used to assess immune cell infiltration in pneumonitis-prone C3H/NeJ mice. Here, we report that the inhibition of ATR in combination with RT caused a significant reduction in PTEN-depleted NSCLC cells, with delayed DNA repair and reduced cell viability, as shown by an increase in cells in Sub G1. Combination treatment in vivo significantly inhibited H460 PTEN-depleted tumour growth in comparison to H460 non-targeting PTEN-expressing (NT) cell-line-derived xenografts (CDXs). Additionally, there was no significant increase in infiltrating macrophages or neutrophils except at 4 weeks, whereby combination treatment significantly increased macrophage levels relative to RT alone. Overall, our study demonstrates that ceralasertib and RT combined preferentially sensitises PTEN-depleted NSCLC models in vitro and in vivo, with no impact on early inflammatory response indicative of RP. These findings provide a rationale for evaluating ATR inhibition in combination with RT in NSCLC patients with PTEN mutations.

Travel Distance and Spanish-Speaking are Associated with Delays in the Treatment of Cleft Palate.

OBJECTIVE: Delayed repair of cleft palate is associated with worse speech outcomes. Social determinants of health may influence the timing of surgery; however, there are no population health investigations to evaluate factors such as travel distance, language barriers, and payer. This study sought to identify factors that may interfere with timely cleft palate repair. DESIGN: Retrospective cohort. SETTING: National/multi-center. PATIENTS/PARTICIPANTS: All cleft palate repairs within California were extracted from 2000-2021. MAIN OUTCOMES MEASURES: The primary outcome was age at surgical repair, which was modeled with linear regression. Covariates included race, primary language, distance from patient home to hospital, socioeconomic status, primary payer, and managed care enrollment status. RESULTS: 11 260 patients underwent surgical repair of a cleft palate. Black race was associated with delayed repair (22 additional days, P = .004, 95% CI 67.00-37.7) along with Asian/Pacific-Islander race (11 additional days, P = .006, 95% CI 3.26-18.9) compared to white race. Spanish-speaking patients had significantly later cleft palate repairs by 19 days, (P < .001, 95% CI 10.8-27.7) compared with English-speaking. Further distances from the hospital were significantly associated with later cleft surgeries with out-of-state patients undergoing surgery 52 days later (P < .001, 95% CI 11.3-24.3). Managed care plans and Medi-Cal were significantly associated with earlier surgical repair compared with private insurance. CONCLUSION: Black, Asian Pacific Islander, and Spanish-speaking patients and greater distance traveled to hospital were associated with delayed cleft palate repairs. These results underscore the importance of addressing structural and social barriers to care to improve outcomes and reduce health disparities for patients with cleft palate.

Evolution of cisplatin resistance through coordinated metabolic reprogramming of the cellular reductive state.

BACKGROUND: Cisplatin (CDDP) is a mainstay treatment for advanced head and neck squamous cell carcinomas (HNSCC) despite a high frequency of innate and acquired resistance. We hypothesised that tumours acquire CDDP resistance through an enhanced reductive state dependent on metabolic rewiring. METHODS: To validate this model and understand how an adaptive metabolic programme might be imprinted, we performed an integrated analysis of CDDP-resistant HNSCC clones from multiple genomic backgrounds by whole-exome sequencing, RNA-seq, mass spectrometry, steady state and flux metabolomics. RESULTS: Inactivating KEAP1 mutations or reductions in KEAP1 RNA correlated with Nrf2 activation in CDDP-resistant cells, which functionally contributed to resistance. Proteomics identified elevation of downstream Nrf2 targets and the enrichment of enzymes involved in generation of biomass and reducing equivalents, metabolism of glucose, glutathione, NAD(P), and oxoacids. This was accompanied by biochemical and metabolic evidence of an enhanced reductive state dependent on coordinated glucose and glutamine catabolism, associated with reduced energy production and proliferation, despite normal mitochondrial structure and function. CONCLUSIONS: Our analysis identified coordinated metabolic changes associated with CDDP resistance that may provide new therapeutic avenues through targeting of these convergent pathways.

Tracheostomy in children is associated with neutrophilic airway inflammation.

BACKGROUND: Tracheostomies in children are associated with significant morbidity, poor quality of life, excess healthcare costs and excess mortality. The underlying mechanisms facilitating adverse respiratory outcomes in tracheostomised children are poorly understood. We aimed to characterise airway host defence in tracheostomised children using serial molecular analyses. METHODS: Tracheal aspirates, tracheal cytology brushings and nasal swabs were prospectively collected from children with a tracheostomy and controls. Transcriptomic, proteomic and metabolomic methods were applied to characterise the impact of tracheostomy on host immune response and the airway microbiome. RESULTS: Children followed up serially from the time of tracheostomy up to 3 months postprocedure (n=9) were studied. A further cohort of children with a long-term tracheostomy were also enrolled (n=24). Controls (n=13) comprised children without a tracheostomy undergoing bronchoscopy. Long-term tracheostomy was associated with airway neutrophilic inflammation, superoxide production and evidence of proteolysis when compared with controls. Reduced airway microbial diversity was established pre-tracheostomy and sustained thereafter. CONCLUSIONS: Long-term childhood tracheostomy is associated with a inflammatory tracheal phenotype characterised by neutrophilic inflammation and the ongoing presence of potential respiratory pathogens. These findings suggest neutrophil recruitment and activation as potential exploratory targets in seeking to prevent recurrent airway complications in this vulnerable group of patients.

12-h clock regulation of genetic information flow by XBP1s.

Our group recently characterized a cell-autonomous mammalian 12-h clock independent from the circadian clock, but its function and mechanism of regulation remain poorly understood. Here, we show that in mouse liver, transcriptional regulation significantly contributes to the establishment of 12-h rhythms of mRNA expression in a manner dependent on Spliced Form of X-box Binding Protein 1 (XBP1s). Mechanistically, the motif stringency of XBP1s promoter binding sites dictates XBP1s's ability to drive 12-h rhythms of nascent mRNA transcription at dawn and dusk, which are enriched for basal transcription regulation, mRNA processing and export, ribosome biogenesis, translation initiation, and protein processing/sorting in the Endoplasmic Reticulum (ER)-Golgi in a temporal order consistent with the progressive molecular processing sequence described by the central dogma information flow (CEDIF). We further identified GA-binding proteins (GABPs) as putative novel transcriptional regulators driving 12-h rhythms of gene expression with more diverse phases. These 12-h rhythms of gene expression are cell autonomous and evolutionarily conserved in marine animals possessing a circatidal clock. Our results demonstrate an evolutionarily conserved, intricate network of transcriptional control of the mammalian 12-h clock that mediates diverse biological pathways. We speculate that the 12-h clock is coopted to accommodate elevated gene expression and processing in mammals at the two rush hours, with the particular genes processed at each rush hour regulated by the circadian and/or tissue-specific pathways.

Plastic surgery market share of breast reconstructive procedures: An analysis of two nationwide databases.

BACKGROUND AND OBJECTIVES: Given advances that streamline breast reconstruction (e.g., prepectoral placement, acellular dermal matrix [ADM], oncoplastic surgery), there is concern that nonplastic surgeons are performing a growing proportion of breast reconstructive procedures. The purpose of this study was to evaluate US trends in the market share of breast reconstruction performed by plastic compared to general surgeons. METHODS: IBM® MarketScan® Commercial Claims 2006-2017 and NSQIP 2005-2020 were queried to identify women who underwent mastectomy with alloplastic (tissue expander or implant-based) or free flap reconstruction, or lumpectomy with oncoplastic reconstruction (breast reduction, mastopexy, or local/regional flap). MarketScan included immediate and delayed reconstructions, while all NSQIP reconstructions were immediate. Poisson regression with incident rate ratios (IRRs) modeled trends in surgeon type over time. RESULTS: The cohort included 65 168 encounters from MarketScan and 73 351 from NSQIP. Plastic surgeons performed 95.8% of free flap, 93.8% of alloplastic, and 64.9% of oncoplastic reconstructions. Plastic surgeons performed an increasing proportion of immediate oncoplastic reduction and mastopexy (MarketScan IRR: 1.077, 95% confidence interval [CI]: 1.060-1.094, p < 0.001; NSQIP IRR: 1.041, 95% CI: 1.030-1.052, p < 0.001). There were no clinically significant trends for delayed oncoplastic, alloplastic, or free flap reconstructions. Plastic surgeons were more likely to use ADM compared to general surgeons in NSQIP (p < 0.001). CONCLUSIONS: Plastic surgeons gained market share in immediate oncoplastic breast reduction and mastopexy over the past two decades without any loss in alloplastic or free flap breast reconstruction. Plastic surgeons should continue collaboration with breast surgical oncologists to reinforce the shared surgeon model for management of breast cancer.

Coactivator-Dependent Oscillation of Chromatin Accessibility Dictates Circadian Gene Amplitude via REV-ERB Loading.

A central mechanism for controlling circadian gene amplitude remains elusive. We present evidence for a "facilitated repression (FR)" model that functions as an amplitude rheostat for circadian gene oscillation. We demonstrate that ROR and/or BMAL1 promote global chromatin decondensation during the activation phase of the circadian cycle to actively facilitate REV-ERB loading for repression of circadian gene expression. Mechanistically, we found that SRC-2 dictates global circadian chromatin remodeling through spatial and temporal recruitment of PBAF members of the SWI/SNF complex to facilitate loading of REV-ERB in the hepatic genome. Mathematical modeling highlights how the FR model sustains proper circadian rhythm despite fluctuations of REV-ERB levels. Our study not only reveals a mechanism for active communication between the positive and negative limbs of the circadian transcriptional loop but also establishes the concept that clock transcription factor binding dynamics is perhaps a central tenet for fine-tuning circadian rhythm.

Cathepsin S Contributes to Lung Inflammation in Acute Respiratory Distress Syndrome.

Rationale: Although the cysteine protease cathepsin S has been implicated in the pathogenesis of several inflammatory lung diseases, its role has not been examined in the context of acute respiratory distress syndrome, a condition that still lacks specific and effective pharmacological treatments. Objectives: To characterize the status of cathepsin S in acute lung inflammation and examine the role of cathepsin S in disease pathogenesis. Methods: Human and mouse model BAL fluid samples were analyzed for the presence and activity of cathepsin S and its endogenous inhibitors. Recombinant cathepsin S was instilled directly into the lungs of mice. The effects of cathepsin S knockout and pharmacological inhibition were examined in two models of acute lung injury. Protease-activated receptor-1 antagonism was used to test a possible mechanism for cathepsin S-mediated inflammation. Measurements and Main Results: Pulmonary cathepsin S concentrations and activity were elevated in acute respiratory distress syndrome, a phenotype possibly exacerbated by the loss of the endogenous antiprotease cystatin SN. Direct cathepsin S instillation into the lungs induced key pathologies of acute respiratory distress syndrome, including neutrophilia and alveolar leakage. Conversely, in murine models of acute lung injury, genetic knockdown and prophylactic or therapeutic inhibition of cathepsin S reduced neutrophil recruitment and protein leakage. Cathepsin S may partly mediate its pathogenic effects via protease-activated receptor-1, because antagonism of this receptor abrogated cathepsin S-induced airway inflammation. Conclusions: Cathepsin S contributes to acute lung injury and may represent a novel therapeutic target for acute respiratory distress syndrome.

A steroid receptor coactivator stimulator (MCB-613) attenuates adverse remodeling after myocardial infarction.

Progressive remodeling of the heart, resulting in cardiomyocyte (CM) loss and increased inflammation, fibrosis, and a progressive decrease in cardiac function, are hallmarks of myocardial infarction (MI)-induced heart failure. We show that MCB-613, a potent small molecule stimulator of steroid receptor coactivators (SRCs) attenuates pathological remodeling post-MI. MCB-613 decreases infarct size, apoptosis, hypertrophy, and fibrosis while maintaining significant cardiac function. MCB-613, when given within hours post MI, induces lasting protection from adverse remodeling concomitant with: 1) inhibition of macrophage inflammatory signaling and interleukin 1 (IL-1) signaling, which attenuates the acute inflammatory response, 2) attenuation of fibroblast differentiation, and 3) promotion of Tsc22d3-expressing macrophages-all of which may limit inflammatory damage. SRC stimulation with MCB-613 (and derivatives) is a potential therapeutic approach for inhibiting cardiac dysfunction after MI.

The Geographical Impact of Plastic Surgery Residency to Fellowship and Residency/Fellowship to First Job Placement.

INTRODUCTION: The location of trainees' plastic surgery residency or fellowship has implications on their subsequent careers, which can inform future trainees and faculty decisions, and may affect access to care nationwide. This study explores historic geographic trends of the location where trainees complete residency or fellowship and where they pursue a fellowship program or first job. METHODS: Graduates from US integrated plastic surgery residency or fellowship programs from 2015 to 2021 were identified along with their proximity to fellowship or first job. Location was categorized based on whether the graduate's fellowship/first job location to residency/fellowship was within 100 miles, the same state, the same geographic region, the United States, or international. A χ2 value was calculated to determine the significance of relative geographical location after training. RESULTS: Three hundred sixty-five graduates that attended fellowship were included, representing 76.5% (65/85) of integrated plastic surgery residency programs. There were 47.7% (n = 174) that stayed within the same geographic region and 3.6% (n = 13) pursued training internationally. The location of the residency or fellowship program appears to have an influence on the location of the graduate's fellowship or first job. CONCLUSION: Graduates who completed integrated residency or fellowship in a certain geographic location were more likely to stay in that area for their fellowship or first job. This may be explained by graduates continuing training with their original program, the established network, and personal factors such as family and friends.

Progression Rates by Age, Sex, Treatment, and Disease Activity by AASLD and EASL Criteria: Data for Precision Medicine.

BACKGROUND & AIMS: Antiviral treatment criteria are based on disease progression risk, and hepatocellular carcinoma (HCC) surveillance recommendations for patients with chronic hepatitis B (CHB) without cirrhosis is based on an annual incidence threshold of 0.2%. However, accurate and precise disease progression estimate data are limited. Thus, we aimed to determine rates of cirrhosis and HCC development stratified by age, sex, treatment status, and disease activity based on the 2018 American Association for the Study of Liver Diseases and 2017 European Association for the Study of the Liver guidelines. METHODS: We analyzed 18,338 patients (8914 treated, 9424 untreated) from 6 centers from the United States and 27 centers from Asia-Pacific countries. The Kaplan-Meier method was used to estimate annual progression rates to cirrhosis or HCC in person-years. RESULTS: The cohort was 63% male, with a mean age of 46.19 years, with baseline cirrhosis of 14.3% and median follow up of 9.60 years. By American Association for the Study of Liver Diseases criteria, depending on age, sex, and disease activity, annual incidence rates ranged from 0.07% to 3.94% for cirrhosis, from 0.04% to 2.19% for HCC in patients without cirrhosis, and from 0.40% to 8.83% for HCC in patients with cirrhosis. Several subgroups of patients without cirrhosis including males younger than 40 years of age and females younger than 50 years of age had annual HCC risk near or exceeding 0.2%. Similar results were found using European Association for the Study of the Liver criteria. CONCLUSION: There is great variability in CHB disease progression rates even among "lower-risk" populations. Future CHB modeling studies, public health planning, and HCC surveillance recommendation should be based on more precise disease progression rates based on sex, age, and disease activity, plus treatment status.

Predictors of critical care, mechanical ventilation, and mortality among hospitalized patients with COVID-19 in an electronic health record database.

BACKGROUND: There are limited data on risk factors for serious outcomes and death from COVID-19 among patients representative of the U.S. POPULATION: The objective of this study was to determine risk factors for critical care, ventilation, and death among hospitalized patients with COVID-19. METHODS: This was a cohort study using data from Optum's longitudinal COVID-19 electronic health record database derived from a network of healthcare provider organizations across the US. The study included patients with confirmed COVID-19 (presence of ICD-10-CM code U07.1 and/or positive SARS-CoV-2 test) between January 2020 and November 2020. Patient characteristics and clinical variables at start of hospitalization were evaluated for their association with subsequent serious outcomes (critical care, mechanical ventilation, and death) using odds ratios (OR) and 95% confidence intervals (CI) from logistic regression, adjusted for demographic variables. RESULTS: Among 56,996 hospitalized COVID-19 patients (49.5% male and 72.4% ≥ 50 years), 11,967 received critical care, 9136 received mechanical ventilation, and 8526 died. The median duration of hospitalization was 6 days (IQR: 4, 11), and this was longer among patients that experienced an outcome: 11 days (IQR: 6, 19) for critical care, 15 days (IQR: 8, 24) for mechanical ventilation, and 10 days (IQR: 5, 17) for death. Dyspnea and hypoxemia were the most prevalent symptoms and both were associated with serious outcomes in adjusted models. Additionally, temperature, C-reactive protein, ferritin, lactate dehydrogenase, D-dimer, and oxygen saturation measured during hospitalization were predictors of serious outcomes as were several in-hospital diagnoses. The strongest associations were observed for acute respiratory failure (critical care: OR, 6.30; 95% CI, 5.99-6.63; ventilation: OR, 8.55; 95% CI, 8.02-9.11; death: OR, 3.36; 95% CI, 3.17-3.55) and sepsis (critical care: OR, 4.59; 95% CI, 4.39-4.81; ventilation: OR, 5.26; 95% CI, 5.00-5.53; death: OR, 4.14; 95% CI, 3.92-4.38). Treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers during hospitalization were inversely associated with death (OR, 0.57; 95% CI, 0.54-0.61). CONCLUSIONS: We identified several clinical characteristics associated with receipt of critical care, mechanical ventilation, and death among COVID-19 patients. Future studies into the mechanisms that lead to severe COVID-19 disease are warranted.