Senescence is a developmental mechanism that contributes to embryonic growth and patterning.

Senescence is a form of cell-cycle arrest linked to tumor suppression and aging. However, it remains controversial and has not been documented in nonpathologic states. Here we describe senescence as a normal developmental mechanism found throughout the embryo, including the apical ectodermal ridge (AER) and the neural roof plate, two signaling centers in embryonic patterning. Embryonic senescent cells are nonproliferative and share features with oncogene-induced senescence (OIS), including expression of p21, p15, and mediators of the senescence-associated secretory phenotype (SASP). Interestingly, mice deficient in p21 have defects in embryonic senescence, AER maintenance, and patterning. Surprisingly, the underlying mesenchyme was identified as a source for senescence instruction in the AER, whereas the ultimate fate of these senescent cells is apoptosis and macrophage-mediated clearance. We propose that senescence is a normal programmed mechanism that plays instructive roles in development, and that OIS is an evolutionarily adapted reactivation of a developmental process.

Belonging in Surgery: A Validated Instrument and Single Institutional Pilot.

OBJECTIVE: The aim of this study was to develop and validate an instrument to measure Belonging in Surgery among surgical residents. BACKGROUND: Belonging is the essential human need to maintain meaningful relationships and connections to one's community. Increased belongingness is associated with better well-being, job performance, and motivation to learn. However, no tools exist to measure belonging among surgical trainees. METHODS: A panel of experts adapted a belonging instrument for use among United States surgery residents. After administration of the 28-item instrument to residents at a single institution, a Cronbach alpha was calculated to measure internal consistency, and exploratory principal component analyses were performed. Multiple iterations of analyses with successively smaller item samples suggested the instrument could be shortened. The expert panel was reconvened to shorten the instrument. Descriptive statistics measured demographic factors associated with Belonging in Surgery. RESULTS: The overall response rate was 52% (114 responses). The Cronbach alpha among the 28 items was 0.94 (95% CI: 0.93-0.96). The exploratory principal component analyses and subsequent Promax rotation yielded 1 dominant component with an eigenvalue of 12.84 (70% of the variance). The expert panel narrowed the final instrument to 11 items with an overall Cronbach alpha of 0.90 (95% CI: 0.86, 0.92). Belonging in Surgery was significantly associated with race (Black and Asian residents scoring lower than White residents), graduating with one's original intern cohort (residents who graduated with their original class scoring higher than those that did not), and inversely correlated with resident stress level. CONCLUSIONS: An instrument to measure Belonging in Surgery was validated among surgical residents. With this instrument, Belonging in Surgery becomes a construct that may be used to investigate surgeon performance and well-being.

Non-English Primary Language: A Growing Population's Access to Cholecystectomy.

OBJECTIVE: To examine access to cholecystectomy and postoperative outcomes among non-English primary-speaking patients. BACKGROUND: The population of U.S. residents with limited English proficiency is growing. Language affects health literacy and is a well-recognized barrier to health care in the United States of America. Historically marginalized communities are at greater risk of requiring emergent gallbladder operations. However, little is known about how primary language affects surgical access and outcomes of common surgical procedures, such as cholecystectomy. METHODS: We conducted a retrospective cohort study of adult patients after receipt of cholecystectomy in Michigan, Maryland, and New Jersey utilizing the Healthcare Cost and Utilization Project State Inpatient Database and State Ambulatory Surgery and Services Database (2016-2018). Patients were classified by primary spoken language: English or non-English. The primary outcome was admission type. Secondary outcomes included operative setting, operative approach, in-hospital mortality, postoperative complications, and length of stay. Multivariable logistics and Poisson regression were used to examine outcomes. RESULTS: Among 122,013 patients who underwent cholecystectomy, 91.6% were primarily English speaking and 8.4% were non-English primary language speaking. Primary non-English speaking patients had a higher likelihood of emergent/urgent admissions (odds ratio: 1.22, 95% CI: 1.04-1.44, P = 0.015) and a lower likelihood of having an outpatient operation (odds ratio: 0.80, 95% CI: 0.70-0.91, P = 0.0008). There was no difference in the use of a minimally invasive approach or postoperative outcomes based on the primary language spoken. CONCLUSIONS: Non-English primary language speakers were more likely to access cholecystectomy through the emergency department and less likely to receive outpatient cholecystectomy. Barriers to elective surgical presentation for this growing patient population need to be further studied.

Endogenous CRISPR/Cas9 arrays for scalable whole-organism lineage tracing.

The past decade has seen a renewed appreciation of the central importance of cellular lineages to many questions in biology (especially organogenesis, stem cells and tumor biology). This has been driven in part by a renaissance in genetic clonal-labeling techniques. Recent approaches are based on accelerated mutation of DNA sequences, which can then be sequenced from individual cells to re-create a 'phylogenetic' tree of cell lineage. However, current approaches depend on making transgenic alterations to the genome in question, which limit their application. Here, we introduce a new method that completely avoids the need for prior genetic engineering, by identifying endogenous CRISPR/Cas9 target arrays suitable for lineage analysis. In both mouse and zebrafish, we identify the highest quality compact arrays as judged by equal base composition, 5' G sequence, minimal likelihood of residing in the functional genome, minimal off targets and ease of amplification. We validate multiple high-quality endogenous CRISPR/Cas9 arrays, demonstrating their utility for lineage tracing. Our pragmatically scalable technique thus can produce deep and broad lineages in vivo, while removing the dependence on genetic engineering.

Patient Accessibility to Eye Care in the United States.

PURPOSE: The United States (US) federal government uses health provider shortage areas (HPSAs) to define patient accessibility to primary care physicians. It is unclear whether HPSAs can be applied to eye care providers (ECPs). Our study determined the applicability of federal HPSA designations to ECP availability in the US. DESIGN: Cross-sectional study. PARTICIPANTS: US general population and ophthalmologists/optometrists in the Medicare database. METHODS: The primary care HPSA score, visual impairment prevalence, and ECP location were determined for each census tract or county using data from the US Department of Health and Human Services, the Centers for Disease Control and Prevention, and Centers for Medicare and Medicaid Services. MAIN OUTCOME MEASURES: Association of HPSA with vision loss and ECP density was examined. The 2-step floating catchment area approach was used to newly define eye care shortage areas (patient accessibility score [PAS], higher being worse accessibility) for every county in the US, by weighting the 2-step FCA scores by prevalence of vision loss and ECP density. Multivariable logistic regression was used to identify sociodemographic variables associated with areas of ECP shortage. RESULTS: Among 72 735 census tracts included, statistically significant but weak correlations of HPSA score with visual impairment (VI) (r = 0.38; P < 0.0001) and ECP density per county population (r = -0.18; P < 0.0001) were found. Only 54.0% of census tracts with < 25th percentile ECP density per county were HPSAs (P < 0.0001). Of census tracts > than 75th percentile for VI only 58.0% were HPSAs (P < 0.0001). Multivariable regression found a higher odds of ECP PAS ≥ 75th percentile (worse accessibility) in rural counties (adjusted odds ratio [aOR], 2.47; 95% confidence interval [CI], 1.93-3.67; P < 0.001) and counties with a greater prevalence of residents with less than a high school education (aOR, 1.21; 95% CI, 1.19-1.25; P < 0.001), residents ≥ 65 years of age (aOR, 1.10; 95% CI, 1.07-1.13; P < 0.001), and uninsured residents (aOR, 1.04; 95% CI, 1.01-1.06; P < 0.001). Counties with a greater proportion of men (aOR, 0.93; 95% CI, 0.89-0.967; P < 0.001) or White residents (aOR, 0.99; 95% CI, 0.98-0.99) had a lower odds of ECP PAS ≥ 75th percentile. CONCLUSIONS: Current HPSAs only weakly correlate with ECP supply. We propose a new approach to identify counties with high need but limited access to eye care. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Open-Globe Injury Repairs in the American Academy of Ophthalmology IRIS® Registry 2014 - 2018: Incidence, Risk Factors, and Visual Outcomes.

PURPOSE: To estimate incidence and evaluate demographic risk factors and visual acuity (VA) outcomes of open-globe injuries requiring surgical repair in the IRIS® Registry (Intelligent Research in Sight). DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with open-globe injury repairs (OGRs) were identified by Current Procedural Terminology codes (65275, 65280, 65285, 65286, 65235, 65260, and 65265) from 2014 through 2018 in the IRIS Registry. METHODS: Logistic regression models adjusting for age, sex, race, ethnicity, United States region, concurrent and subsequent surgeries, and baseline VA. MAIN OUTCOME MEASURES: Outcomes included annual and 5-year incidence rates per 100 000 people and factors associated with OGR, VA better than 20/40, and VA of 20/200 or worse at final follow-up (3-12 months after OGR). RESULTS: Thirteen thousand seven hundred sixty-six OGRs were identified; 5-year cumulative incidence was 28.0 per 100 000 patients. Open-globe repair was associated with age 21 to 40 years compared with younger than 21 years (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.5-1.7]), male sex (OR, 2.8; 95% CI, 2.7-2.9), Black versus White race (OR, 1.3; 95% CI, 1.2-1.4), Hispanic versus non-Hispanic ethnicity (OR, 1.7; 95% CI, 1.6-1.8), and South (OR, 1.4; 95% CI, 1.3-1.5) and West (OR, 1.3; 95% CI, 1.2-1.4) versus Midwest regions and associated inversely with Asian versus White race (OR, 0.6; 95% CI, 0.6-0.7). Visual acuity outcomes, analyzed in a subset of 2966 patients with VA data available, showed vision impairment (VA < 20/40) at final follow-up was associated with VA of 20/200 or worse at presentation (20/200 better than 20/40; OR, 11.1; 95% CI, 8.0-15.7), older age (e.g., > 80 years vs. < 21 years; OR, 5.8; 95% CI, 3.2-10.7), and Black versus White race (OR, 1.8; 95% CI, 1.3-2.6). Risk factors were similar for VA of 20/200 or worse after OGR. Among the 1063 patients undergoing OGR with VA of 20/200 or worse at presentation, VA did not improve to better than 20/200 at follow-up in 35% of patients (1063/2996). CONCLUSIONS: Our findings bring to light racial disparities in risk of OGR and poor visual outcomes that warrant further exploration. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Impact of Medicaid expansion on outcomes after abdominal aortic aneurysm repair.

OBJECTIVE: Lack of insurance has been independently associated with an increased risk of in-hospital mortality after abdominal aortic aneurysm repair, possibly due to worse control of comorbidities and delays in diagnosis and treatment. Medicaid expansion has improved insurance rates and access to care, potentially benefiting these patients. We sought to assess the association between Medicaid expansion and outcomes after abdominal aortic aneurysm repair. METHODS: A retrospective analysis of Healthcare Cost and Utilization Project State Inpatient Databases data from 14 states between 2012 and 2018 was conducted. The sample was restricted to first-record abdominal aortic aneurysm repairs in adults under age 65 in states that expanded Medicaid on January 1, 2014 (Medicaid expansion group) or had not expanded before December 31, 2018 (non-expansion group). The Medicaid expansion and non-expansion groups were compared between pre-expansion (2012-2013) and post-expansion (2014-2018) time periods to assess baseline demographic and operative differences. We used difference-in-differences multivariable logistic regression adjusted for patient factors, open vs endovascular repair, and standard errors clustered by state. Our primary outcome was in-hospital mortality. Outcomes were stratified by insurance type. RESULTS: We examined 8995 patients undergoing abdominal aortic aneurysm repair, including 3789 (42.1%) in non-expansion states and 5206 (57.9%) in Medicaid expansion states. Rates of Medicaid insurance were unchanged in non-expansion states but increased in Medicaid expansion states post-expansion (non-expansion: 10.9% to 9.8%; P = .346; expansion: 9.7% to 19.7%; P < .001). One in 10 patients from both non-expansion and Medicaid expansion states presented with ruptured aneurysms, which did not change over time. Rates of open repair decreased in both non-expansion and Medicaid expansion states over time (non-expansion: 25.1% to 19.2%; P < .001; expansion: 25.2% to 18.4%; P < .001). On adjusted difference-in-differences analysis between expansion and non-expansion states pre-to post-expansion, Medicaid expansion was associated with a 1.02% absolute reduction in in-hospital mortality among all patients (95% confidence interval, -1.87% to -0.17%; P = .019). Additionally, among patients who were either on Medicaid or were uninsured (ie, the patients most likely to be impacted by Medicaid expansion), a larger 4.17% decrease in in-hospital mortality was observed (95% confidence interval, -6.47% to -1.87%; P < .001). In contrast, no significant difference-in-difference in mortality was observed for privately insured patients. CONCLUSIONS: Medicaid expansion was associated with decreased in-hospital mortality after abdominal aortic aneurysm repair among all patients and particularly among patients who were either on Medicaid or were uninsured. Our results provide support for improved access to care for patients undergoing abdominal aortic aneurysm repair through Medicaid expansion.

A study analyzing outcomes after bariatric surgery by primary language.

BACKGROUND: Communication is key to success in bariatric surgery. This study aims to understand how outcomes after bariatric surgery differ between patients with a non-English primary language and those with English as their primary language. METHODS: This retrospective, observational cohort study of bariatric surgery patients age ≥ 18 years utilized the Michigan, Maryland, and New Jersey State Inpatient Databases and State Ambulatory Surgery and Services Databases, 2016 to 2018. Patients were classified by primary spoken language: English and non-English. Primary outcome was complications. Secondary outcomes included length of stay (LOS) and cost, with cost calculated using cost-to-charge ratios provided by Healthcare Cost and Utilization Project and reported in 2019 United States dollars. Multivariable regression models (logistic, Poisson, and quantile) were used to examine associations between primary language and outcomes. Given the uneven distribution of race by primary language, interaction terms were used to examine conditional effects of race. RESULTS: Among 69,749 bariatric surgery patients, 2811 (4.2%) spoke a non-English primary language. Covariates, notably race distribution, and unadjusted outcomes differed significantly by primary language. However, after adjustment, non-English primary language was not associated with significantly increased odds of complications (odds ratio 1.24, p = 0.389), significantly different LOS (- 0.02 days, p = 0.677), nor significantly different mean healthcare costs (- $265, p = 0.309). There were no significant conditional effects of race seen among outcomes. CONCLUSIONS: Though non-English primary language was associated with a significantly different distribution of observable characteristics (including race, income quartile, and insurance type), after adjustment, non-English primary language was not associated with significant differential risk of adverse outcomes after bariatric surgery, and there were no significant conditional effects of race. As such, this study suggests that disparities in bariatric surgery by primary spoken language more likely related to access to care, or the pre- and post-hospital care continuum, rather than index hospitalization after surgery.

RISK FACTORS FOR SURGERY OR BLINDNESS IN NEOVASCULAR GLAUCOMA EYES TREATED WITH ANTI-VEGF INJECTIONS BY A RETINA SPECIALIST.

PURPOSE: To determine baseline patient characteristics that predict the need for glaucoma surgery or blindness in eyes with neovascular glaucoma (NVG) despite intravitreal antivascular endothelial growth factor therapy. METHODS: This is a retrospective cohort study of patients with NVG who had not previously received glaucoma surgery and were treated with intravitreal antivascular endothelial growth factor injections at the time of diagnosis, from September 8, 2011, to May 8, 2020, at a large, retina subspecialty practice. RESULTS: Of 301 newly presenting NVG eyes, 31% required glaucoma surgery and 20% progressed to no light perception vision despite treatment. Patients with intraocular pressure >35 mmHg ( P < 0.001), two or more topical glaucoma medications ( P = 0.003), worse than 20/100 vision ( P = 0.024), proliferative diabetic retinopathy ( P = 0.001), eye pain or discomfort ( P = 0.010), and new patient status ( P = 0.015) at the time of NVG diagnosis were at a higher risk of glaucoma surgery or blindness regardless of antivascular endothelial growth factor therapy. The effect of panretinal photocoagulation was not statistically significant in a subgroup analysis of patients without media opacity ( P = 0.199). CONCLUSION: Several baseline characteristics at the time of presentation to a retina specialist with NVG seem to portend a higher risk of uncontrolled glaucoma despite the use of antivascular endothelial growth factor therapy. Prompt referral of these patients to a glaucoma specialist should be strongly considered.

Wolpert's French Flag: what's the problem?

Two phrases attributed to Lewis Wolpert - 'positional information' and 'The French Flag Model' - have become so intertwined that they are now used almost interchangeably. Here, I argue that this represents an unfortunate oversimplification of Wolpert's ideas that arose gradually in the developmental biology community, some significant time after his key papers were published. In contrast to common belief, Wolpert did not use the phrase French Flag 'Model' but instead introduced the French Flag 'Problem'. This famous metaphor was not a proposal of how patterning works, but rather an abstraction of the question to be addressed. More specifically, the French flag metaphor was an attempt to de-couple the problem from the multiple possible models that could solve it. In this spirit, Wolpert's first article on this topic also proposed (in addition to the well-known gradient model) an alternative solution to the French Flag Problem that was self-organising and had no gradients, and in which each cell 'cannot compute where it is in the system', i.e. there is no positional information. I discuss the history and evolution of these terms, and how they influence the way we study patterning.

Arrested coalescence of multicellular aggregates.

Multicellular aggregates are known to exhibit liquid-like properties. The fusion process of two cell aggregates is commonly studied as the coalescence of two viscous drops. However, tissues are complex materials and can exhibit viscoelastic behaviour. It is known that elastic effects can prevent the complete fusion of two drops, a phenomenon known as arrested coalescence. Here we study this phenomenon in stem cell aggregates and provide a theoretical framework which agrees with the experiments. In addition, agent-based simulations show that active cell fluctuations can control a solid-to-fluid phase transition, revealing that arrested coalescence can be found in the vicinity of an unjamming transition. By analysing the dynamics of the fusion process and combining it with nanoindentation measurements, we obtain the effective viscosity, shear modulus and surface tension of the aggregates. More generally, our work provides a simple, fast and inexpensive method to characterize the mechanical properties of viscoelastic materials.

REFRACTIVE ERROR CHANGE DURING TREATMENT OF DIABETIC MACULAR EDEMA: A Post Hoc Analysis of the Diabetic Retinopathy Clinical Research Protocol T Trial.

PURPOSE: To evaluate the impact of anti-vascular endothelial growth factor therapy on the refractive error in eyes with diabetic macular edema. METHODS: Post hoc analysis of Diabetic Retinopathy Clinical Research protocol T. Spherical equivalent (SE) was calculated for study and fellow eyes at baseline, 1-year, and 2-year visits. The SE change of the eyes with edema was compared with those with resolved edema. The correlation between refractive error changes and central subfield thickness was evaluated. RESULTS: Among 543 study eyes, SE changed from -0.17 (2.04) D at baseline visit to -0.16 (2.14) D at 2 years giving a hyperopic shift of 0.04 (0.82) D (P = 0.022). Among fellow eyes, mean (SD) SE changed from -0.19 (2.1) D at baseline to -0.11 (2.1) D at 2 years, giving a hyperopic shift of 0.12 (0.84) D (P = 0.001). No significant difference in SE shift was found between eyes with and without edema at 2 years in phakic (0.12D and 0.08 D, P = 0.87) and pseudophakic eyes (-0.24D and -0.08D, P = 0.30). The SE shift was not correlated with central subfield thickness change at the end of the second year (r = 0.02, P = 0.62). CONCLUSION: Diabetic macular edema patients have minimal changes in refractive error. The correction of refractive error may be considered during treatment, regardless of the presence of edema.

A National Comparison of Operative Outcomes of New and Experienced Surgeons.

OBJECTIVE: To determine whether outcomes achieved by new surgeons are attributable to inexperience or to differences in the context in which care is delivered and patient complexity. BACKGROUND: Although prior studies suggest that new surgeon outcomes are worse than those of experienced surgeons, factors that underlie these phenomena are poorly understood. METHODS: A nationwide observational tapered matching study of outcomes of Medicare patients treated by new and experienced surgeons in 1221 US hospitals (2009-2013). The primary outcome studied is 30-day mortality. Secondary outcomes were examined. RESULTS: In total, 694,165 patients treated by 8503 experienced surgeons were matched to 68,036 patients treated by 2119 new surgeons working in the same hospitals. New surgeons' patients were older (25.8% aged ≥85 vs 16.3%,P<0.0001) with more emergency admissions (53.9% vs 25.8%,P<0.0001) than experienced surgeons' patients. Patients of new surgeons had a significantly higher baseline 30-day mortality rate compared with patients of experienced surgeons (6.2% vs 4.5%,P<0.0001;OR 1.42 (1.33, 1.52)). The difference remained significant after matching the types of operations performed (6.2% vs 5.1%, P<0.0001; OR 1.24 (1.16, 1.32)) and after further matching on a combination of operation type and emergency admission status (6.2% vs 5.6%, P=0.0007; OR 1.12 (1.05, 1.19)). After matching on operation type, emergency admission status, and patient complexity, the difference between new and experienced surgeons' patients' 30-day mortality became indistinguishable (6.2% vs 5.9%,P=0.2391;OR 1.06 (0.97, 1.16)). CONCLUSIONS: Among Medicare beneficiaries, the majority of the differences in outcomes between new and experienced surgeons are related to the context in which care is delivered and patient complexity rather than new surgeon inexperience.

A quantitative method for staging mouse embryos based on limb morphometry.

To determine the developmental stage of embryonic mice, we apply a geometric morphometric approach to the changing shape of the mouse limb bud as it grows from embryonic day 10 to embryonic day 15 post-conception. As the ontogenetic sequence results in the de novo emergence of shape features not present in the early stages, we have created a standard ontogenetic trajectory for limb bud development - a quantitative characterization of shape change during limb morphogenesis. This trajectory of form as a function of time also gives us the reverse function: the ability to infer developmental stage from form, with a typical uncertainty of 2 h. We introduce eMOSS (embryonic mouse ontogenetic staging system) as a fast, reliable, convenient and freely available online tool for staging embryos from two-dimensional images of their limb buds, and illustrate its use in phenotyping early limb abnormalities.

Outcomes among pediatric patients with cancer who are treated on trial versus off trial: A matched cohort study.

BACKGROUND: Approximately 50% of children with cancer in the United States who are aged <15 years receive primary treatment on a therapeutic clinical trial. To the authors' knowledge, it remains unknown whether trial enrollment has a clinical benefit compared with the best alternative standard therapy and/or off trial (ie, clinical trial effect). The authors conducted a retrospective matched cohort study to compare the morbidity and mortality of pediatric patients with cancer who are treated on a phase 3 clinical trial compared with those receiving standard therapy and/or off trial. METHODS: Subjects were aged birth to 19 years; were diagnosed between 2000 and 2010 with acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), rhabdomyosarcoma, or neuroblastoma; and had received initial treatment at the Children's Hospital of Philadelphia. On-trial and off-trial subjects were matched based on age, race, ethnicity, a diagnosis of Down syndrome (for patients with ALL or AML), prognostic risk level, date of diagnosis, and tumor type. RESULTS: A total of 428 participants were matched in 214 pairs (152 pairs for ALL, 24 pairs for AML, 32 pairs for rhabdomyosarcoma, and 6 pairs for neuroblastoma). The 5-year survival rate did not differ between those treated on trial versus those treated with standard therapy and/or off trial (86.9% vs 82.2%; P = .093). On-trial patients had a 32% lower odds of having worse (higher) mortality-morbidity composite scores, although this did not reach statistical significance (odds ratio, 0.68; 95% confidence interval, 0.45-1.03 [P = .070]). CONCLUSIONS: There was no statistically significant difference in outcomes noted between those patients treated on trial and those treated with standard therapy and/or off trial. However, in partial support of the clinical trial effect, the results of the current study indicate a trend toward more favorable outcomes in children treated on trial compared with those treated with standard therapy and/or off trial. These findings can support decision making regarding enrollment in pediatric phase 3 clinical trials.

Duty Hour Reform and the Outcomes of Patients Treated by New Surgeons.

OBJECTIVE: The aim of the study was to address the controversy surrounding the effects of duty hour reform on new surgeon performance, we analyzed patients treated by new surgeons following the transition to independent practice. SUMMARY BACKGROUND DATA: In 2003, duty hour reform affected all US surgical training programs. Its impact on the performance of new surgeons remains unstudied. METHODS: We studied 30-day mortality among 1,483,074 Medicare beneficiaries undergoing general and orthopedic operations between 1999 and 2003 ("traditional" era) and 2009 and 2013 ("modern" era). The operations were performed by 2762 new surgeons trained before the reform, 2119 new surgeons trained following reform and 15,041 experienced surgeons. We used a difference-in-differences analysis comparing outcomes in matched patients treated by new versus experienced surgeons within each era, controlling for the hospital, operation, and patient risk factors. RESULTS: Traditional era odds of 30-day mortality among matched patients treated by new versus experienced surgeons were significantly elevated [odds ratio (OR) 1.13; 95% confidence interval (CI) (1.05, 1.22), P < 0.001). The modern era elevated odds of mortality were not significant [OR 1.06; 95% CI (0.97-1.16), P = 0.239]. Relative performance of new and experienced surgeons with respect to 30-day mortality did not appear to change from the traditional era to the modern era [OR 0.93; 95% CI (0.83-1.05), P = 0.233]. There were statistically significant adverse changes over time in relative performance to experienced surgeons in prolonged length of stay [OR 1.08; 95% CI (1.02-1.15), P = 0.015], anesthesia time [9 min; 95% CI (8-10), P < 0.001], and costs [255USD; 95% CI (2-508), P = 0.049]. CONCLUSIONS: Duty hour reform showed no significant effect on 30-day mortality achieved by new surgeons compared to their more experienced colleagues. Patients of new surgeons, however, trained after duty hour reform displayed some increases in the resources needed for their care.

Computer modeling in developmental biology: growing today, essential tomorrow.

D'Arcy Thompson was a true pioneer, applying mathematical concepts and analyses to the question of morphogenesis over 100 years ago. The centenary of his famous book, On Growth and Form, is therefore a great occasion on which to review the types of computer modeling now being pursued to understand the development of organs and organisms. Here, I present some of the latest modeling projects in the field, covering a wide range of developmental biology concepts, from molecular patterning to tissue morphogenesis. Rather than classifying them according to scientific question, or scale of problem, I focus instead on the different ways that modeling contributes to the scientific process and discuss the likely future of modeling in developmental biology.

National Trends in Utilization and 1-Year Outcomes with Transplantation of HCV-Viremic Kidneys.

BACKGROUND: Recent pilot trials have demonstrated the safety of transplanting HCV-viremic kidneys into HCV-seronegative recipients. However, it remains unclear if allograft function is impacted by donor HCV-viremia or recipient HCV-serostatus. METHODS: We used national United States registry data to examine trends in HCV-viremic kidney use between 4/1/2015 and 3/31/2019. We applied advanced matching methods to compare eGFR for similar kidneys transplanted into highly similar recipients of kidney transplants. RESULTS: Over time, HCV-seronegative recipients received a rising proportion of HCV-viremic kidneys. During the first quarter of 2019, 200 HCV-viremic kidneys were transplanted into HCV-seronegative recipients, versus 69 into HCV-seropositive recipients, while 105 HCV-viremic kidneys were discarded. The probability of HCV-viremic kidney discard has declined over time. Kidney transplant candidates willing to accept a HCV-seropositive kidney increased from 2936 to 16,809 from during this time period. When transplanted into HCV-seronegative recipients, HCV-viremic kidneys matched to HCV-non-viremic kidneys on predictors of organ quality, except HCV, had similar 1-year eGFR (66.3 versus 67.1 ml/min per 1.73 m2, P=0.86). This was despite the much worse kidney donor profile index scores assigned to the HCV-viremic kidneys. Recipient HCV-serostatus was not associated with a clinically meaningful difference in 1-year eGFR (66.5 versus 71.1 ml/min per 1.73 m2, P=0.056) after transplantation of HCV-viremic kidneys. CONCLUSIONS: By 2019, HCV-seronegative patients received the majority of kidneys transplanted from HCV-viremic donors. Widely used organ quality scores underestimated the quality of HCV-viremic kidneys based on 1-year allograft function. Recipient HCV-serostatus was also not associated with worse short-term allograft function using HCV-viremic kidneys.

Synthetic circuits reveal how mechanisms of gene regulatory networks constrain evolution.

Phenotypic variation is the raw material of adaptive Darwinian evolution. The phenotypic variation found in organismal development is biased towards certain phenotypes, but the molecular mechanisms behind such biases are still poorly understood. Gene regulatory networks have been proposed as one cause of constrained phenotypic variation. However, most pertinent evidence is theoretical rather than experimental. Here, we study evolutionary biases in two synthetic gene regulatory circuits expressed in Escherichia coli that produce a gene expression stripe-a pivotal pattern in embryonic development. The two parental circuits produce the same phenotype, but create it through different regulatory mechanisms. We show that mutations cause distinct novel phenotypes in the two networks and use a combination of experimental measurements, mathematical modelling and DNA sequencing to understand why mutations bring forth only some but not other novel gene expression phenotypes. Our results reveal that the regulatory mechanisms of networks restrict the possible phenotypic variation upon mutation. Consequently, seemingly equivalent networks can indeed be distinct in how they constrain the outcome of further evolution.