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The vast size of chemical space necessitates computational approaches to automate and accelerate the design of molecular sequences to guide experimental efforts for drug discovery. Genetic algorithms provide a useful framework to incrementally generate molecules by applying mutations to known chemical structures. Recently, masked language models have been applied to automate the mutation process by leveraging large compound libraries to learn commonly occurring chemical sequences (i.e., using tokenization) and predict rearrangements (i.e., using mask prediction). Here, we consider how language models can be adapted to improve molecule generation for different optimization tasks. We use two different generation strategies for comparison, fixed and adaptive. The fixed strategy uses a pre-trained model to generate mutations; the adaptive strategy trains the language model on each new generation of molecules selected for target properties during optimization. Our results show that the adaptive strategy allows the language model to more closely fit the distribution of molecules in the population. Therefore, for enhanced fitness optimization, we suggest the use of the fixed strategy during an initial phase followed by the use of the adaptive strategy. We demonstrate the impact of adaptive training by searching for molecules that optimize both heuristic metrics, drug-likeness and synthesizability, as well as predicted protein binding affinity from a surrogate model. Our results show that the adaptive strategy provides a significant improvement in fitness optimization compared to the fixed pre-trained model, empowering the application of language models to molecular design tasks

Background: Pediatric cystic lung lesions represent a rare group of predominantly benign pulmonary anomalies with a broad spectrum of clinical disease and histopathology. We aimed to examine the clinical presentation, pathology data, and diagnostic evaluation of children undergoing resection of a cystic lung lesion diagnosed after birth. Methods: A multisite observational cohort study was conducted of children undergoing resection of a postnatally diagnosed primary cystic lung lesion between Jan 1, 2009 and Dec 31, 2015 at one of 11 United States children’s hospitals (Midwest Pediatric Surgery Consortium). Clinical presentation, perioperative findings, and pathologic diagnosis were reviewed and analyzed using non-parametric bivariate and multivariable logistic regression models. Findings: Of 521 children with resected lung lesions, 177 (34·0%) underwent resection for a lesion that was not diagnosed prenatally. Operations was performed with low morbidity at median ages of 4.4 months [interquartile range (IQR), 0·9-28·7], 10·9 months (IQR, 7·6-151·2), and 42·3 months (IQR, 11·1-86·2) for respiratory symptoms (n=89, 50·6%), asymptomatic disease (n=35, 19·9%), and pneumonia history (n=54, 30.7%), respectively. The most common pathologic diagnosis was congenital pulmonary airway malformation (n=59, 34·3%). Fifteen (8·5%) were classified as malignant tumors [type 1 pleuropulmonary blastoma (PPB), n=11; other PPB, n=3; adenocarcinoma, n=1) at a median resection age of 20.7 months (IQR, 7·9-58·1). The sensitivity of preoperative chest CT for detecting malignant pathology was 33.3% (95% CI: 15·2-58·3). Multivariable logistic regression showed that increased suspicion of malignancy by CT and bilateral disease were significant predictors of malignant pathology [odds ratios, 42·15 (95% CI: 7·43-340·3, p

Background Transcatheter aortic valve replacement (TAVR) is an established therapy in high-risk patients with severe aortic stenosis. Among patients with reduced left ventricular ejection fraction (LVEF), it is unclear which patients will derive maximal benefit from TAVR. Methods Clinical and echocardiographic data of patients with severe aortic stenosis and low LVEF (≤50%) who underwent TAVR at a single institution during 2009–2013 were retrospectively analyzed. Patients were divided into 2 groups post-TAVR based on improved LV function (Group A = ΔLVEF ≥ 10%) versus persistent LV dysfunction (Group B = ΔLVEF

Objective Transcatheter aortic valve replacement (TAVR) has emerged as an alternative to high-risk surgery in patients with comorbid conditions. The role of TAVR in patients with liver disease has not been examined. Methods We examined the procedural and intermediate to long-term follow-up outcomes of patients with severe symptomatic aortic valve stenosis and chronic liver disease, identified by liver biopsy or from a combination of clinical findings. All patients were treated with balloon-expandable transfemoral (TF) or transapical (TA) TAVR between November 2007 and February 2014. Results A total of 17 of 706 (2.41%) patients treated at our institution with TF [n = 14] or TA [n = 3] TAVR had chronic liver disease (mean age 77.65 ± 9.06 years, 7 women, mean STS score 8.37, mean Charlson score 5.00, mean MELD score 11.35, Child–Turcotte–Pugh (CTP) Class A [n = 11], B [n = 6], C [n = 0], biopsy proven liver disease [n = 5]). Median follow-up was 466 days (range = 12–1,403 days). The mean post-procedure length of hospital stay was 5.88 ± 3.08 days. Procedural success was achieved in all cases. In-hospital mortality was 5.88% and 90-day mortality was 17.65%. Safety and efficacy endpoints as defined by the valve academic research consortium (VARC) were significant for one perioperative death from a proximate cardiac cause (post-operative day 14), one death after hospital discharge of unknown cause (post-operative day 12), two late deaths from non-cardiac causes (post-operative days 50 and 487, respectively), and one late death of unknown cause (post-operative day 1,005). There were no life-threatening or major bleeding complications. One patient had an MI, one had a transient ischemic attack, four had transient, Stage I, acute kidney injury and one had transient, Stage II, acute kidney injury. Conclusion TF and TA TAVR are feasible methods for treating aortic stenosis in patients with chronic liver disease. In patients with mild to moderate chronic liver disease there are acceptable rates of early and late complications, however, outcomes in patients with advanced liver disease (MELD >20 or CTP class C) warrant further study. © 2015 Wiley Periodicals, Inc.

ObjectivesPatients often present for aortic root replacement surgery with concomitant mitral valve pathology. Moderate mitral regurgitation is the point of clinical equipoise where the benefits of intervention compared with observation are currently unknown. This study compares outcomes in patients undergoing aortic root replacement surgery who did or did not receive a mitral valve repair for their preoperative moderate mitral regurgitation.MethodsA total of 1316 patients who underwent aortic root replacement surgery between 2000 and 2011 were evaluated, with 104 patients meeting the inclusion criteria by presenting with moderate preoperative mitral regurgitation. A total of 73 patients (70%) received no mitral intervention, and 31 patients (30%) received a mitral repair. Patients underwent preoperative, postoperative, and greater than 6-month follow-up echocardiograms. Average clinical follow-up was 6.5 years.ResultsThe mitral repair group had increased preoperative New York Heart Association III/IV and heart failure, longer crossclamp times, and more postoperative renal failure (P = .0003, P = .04, P

Transcatheter aortic valve replacement (TAVR) is an established therapy in high-risk patients with severe aortic stenosis. Among patients with reduced left ventricular ejection fraction (LVEF), it is unclear which patients will derive maximal benefit from TAVR.Clinical and echocardiographic data of patients with severe aortic stenosis and low LVEF (≤50%) who underwent TAVR at a single institution during 2009-2013 were retrospectively analyzed. Patients were divided into 2 groups post-TAVR based on improved LV function (Group A = ΔLVEF ≥ 10%) versus persistent LV dysfunction (Group B = ΔLVEF10%). Echocardiographic parameters were assessed for their association with LVEF change post-TAVR. Kaplan-Meier analysis was performed to generate survival estimates.Of 382 patients who underwent TAVR, 60 patients had low LVEF, LV function failed to improve ≥10% in 50% of patients following the procedure (Group B). At baseline echocardiograms, Group B had higher LVEF, stroke volume (SV), SV index; and lower E, E/E', and estimated pulmonary arterial systolic pressure (PASP) compared to Group A. Higher mortality was found in Group B compared to the Group A (p = 0.003) with a significantly shorter survival (Group A = 3.3 ± 0.1 years vs Group B = 2.7 ± 0.2 years, p = 0.003). One-year event free survival was 53.3% in Group B compared to 93.3% in Group A, with a stable trend over ensuing years (5-year survival; 53.3% versus 90.0%, p = 0.003).In patients undergoing TAVR with depressed LV function, those who failed to improve were more likely to have relatively higher LVEF, SV, and SVI; and lower E, E/E', and PASP at baseline. Mortality rates were found to be higher in persistent LV dysfunction group. © 2015 Wiley Periodicals, Inc.

Transcatheter aortic valve replacement (TAVR) has emerged as an alternative to high-risk surgery in patients with comorbid conditions. The role of TAVR in patients with liver disease has not been examined.We examined the procedural and intermediate to long-term follow-up outcomes of patients with severe symptomatic aortic valve stenosis and chronic liver disease, identified by liver biopsy or from a combination of clinical findings. All patients were treated with balloon-expandable transfemoral (TF) or transapical (TA) TAVR between November 2007 and February 2014.A total of 17 of 706 (2.41%) patients treated at our institution with TF [n=14] or TA [n=3] TAVR had chronic liver disease (mean age 77.65±9.06 years, 7 women, mean STS score 8.37, mean Charlson score 5.00, mean MELD score 11.35, Child-Turcotte-Pugh (CTP) Class A [n=11], B [n=6], C [n=0], biopsy proven liver disease [n=5]). Median follow-up was 466 days (range=12-1,403 days). The mean post-procedure length of hospital stay was 5.88±3.08 days. Procedural success was achieved in all cases. In-hospital mortality was 5.88% and 90-day mortality was 17.65%. Safety and efficacy endpoints as defined by the valve academic research consortium (VARC) were significant for one perioperative death from a proximate cardiac cause (post-operative day 14), one death after hospital discharge of unknown cause (post-operative day 12), two late deaths from non-cardiac causes (post-operative days 50 and 487, respectively), and one late death of unknown cause (post-operative day 1,005). There were no life-threatening or major bleeding complications. One patient had an MI, one had a transient ischemic attack, four had transient, Stage I, acute kidney injury and one had transient, Stage II, acute kidney injury.TF and TA TAVR are feasible methods for treating aortic stenosis in patients with chronic liver disease. In patients with mild to moderate chronic liver disease there are acceptable rates of early and late complications, however, outcomes in patients with advanced liver disease (MELD20 or CTP class C) warrant further study.

Background— Vascular complications after transfemoral transcatheter aortic valve replacement are common and associated with significant morbidity and mortality. Little is known about the effect of access approach on vascular complications. Methods and Results— Between 2007 and 2013, 331 patients underwent transfemoral transcatheter aortic valve replacement via open surgical (OS) or fully percutaneous (PC) approaches. Patient data and clinical outcomes were collected. Valve Academic Research Consortium–defined vascular complications were noted. Multivariable analysis with propensity matching was performed, and vascular complications, mortality, and length of stay were assessed. One hundred twenty patients were treated with the OS approach and 211 patients via the PC approach. There were fewer major vascular complications (11% versus 20%; P =0.03) and shorter length of stay (7.5 versus 9.9 days; P =0.003) in the PC group when compared with those in the OS group. In multivariable analysis, vascular complications were more likely in women (odds ratio, 2.2; P =0.02) and with increasing differences between sheath outer diameter and minimal artery diameter (overall vascular complications: odds ratio, 1.4; P =0.02 and major vascular complications: odds ratio, 2.0; P P =0.73) but significantly reduced length of stay in the PC group (7.9 versus 10.0 days; P =0.04). Conclusions— Transfemoral transcatheter aortic valve replacement performed via the PC route is associated with similar risk of vascular complications and significantly lower postprocedural length of stay than the OS route. The degree of sheath oversizing with respect to iliofemoral minimal artery diameter and female sex are associated with vascular complications regardless of access approach.

Recent studies have suggested that transcatheter aortic valve replacement (TAVR) may have superior outcomes compared with aortic valve replacement (AVR) for high-risk patients with significant mitral regurgitation (MR). Considering significant MR is frequently addressed with a mitral valve repair or replacement (MVR) at the time of open aortic valve replacement, this study compares TAVR and AVR/MVR in propensity-matched pairs of patients with significant MR.We evaluated all patients presenting with moderate or greater MR undergoing either TAVR or AVR/MVR at a single institution from 2002 to 2012. Patients who underwent other cardiac operations or had preoperative endocarditis were excluded. Of 306 patients in the AVR/MVR group and 147 patients in the TAVR group, propensity analysis matched 40 pairs of patients. Standard univariate, logistic regression, and propensity matching techniques were used.There was no significant difference between TAVR patients and AVR/MVR patients, respectively, in preoperative average age (76 ± 7.4 versus 78 ± 6.9 years, p = 0.68), ejection fraction (53 ± 15 versus 51 ± 17, p = 0.68), The Society of Thoracic Surgeons score (9.9 ± 3.1 versus 9.3 ± 3.4, p = 0.61), or 30-day mortality (7.5% versus 2.5%, p = 0.6). Postoperative MR was significantly improved for both TAVR and AVR/MVR, but AVR/MVR showed significantly greater improvement (-2.33 ± 1.23 versus -0.88 ± 0.79, p0.001). Among 30-day survivors, midterm survival was significantly better in the AVR/MVR group compared with the TAVR group (log rank p = 0.04).In a propensity-matched analysis of patients with significant MR, AVR/MVR and TAVR had equivalent perioperative outcomes, but AVR/MVR had more reduction in MR and may have superior midterm survival when compared with TAVR among 30-day survivors.

This paper will apply the theory of institutional corruption to the world of private-activity bonds, which offer private entities access to tax-exempt borrowing, which generally provides lower interest rates. The bonds are issued by a public authority that requires the funds be used for a purpose that serves the public benefit. There is a long history of corruption in the bond market, the latest development being a 2011 Department of Justice investigation that exposed rampant bid-rigging by Bank of America, J.P. Morgan Chase and others. This paper will focus on bonds used for affordable housing, and explore whether the theory of institutional corruption might apply to either housing bonds or tax-exempt bonds writ large. Readers with real estate backgrounds should take care to note this paper, and institutional corruption theory, allege no impropriety whatsoever.

Background Stentless porcine bioroots and pericardial composite roots were developed as prostheses that avoid the anticoagulation necessary for mechanical composite roots. Data on the hemodynamics of all root replacements are lacking and questions remain regarding comparative performance. Methods This study evaluated patients receiving a stentless porcine bioroot, a pericardial, or a mechanical composite root at a single institution from January 2000 to December 2008. All patients underwent preoperative, postoperative and greater than 1-year echocardiograms. All root replacements were performed for aortic insufficiency or aneurysm. Median follow-up was 3.3 years (1 to 8 years). Results There were no significant differences in preoperative left ventricular ejection fraction, aortic valve peak gradient, mean gradient, left ventricular end diastolic diameter, and left ventricular end systolic diameter. Postoperative peak and mean gradients in mechanical composite roots were significantly higher than stentless porcine bioroots. At greater than 1 year, stentless porcine bioroots had significantly lower peak and mean gradients than both mechanical composite roots and pericardial composite roots. The end diastolic diameter was also significantly smaller in stentless porcine bioroots at greater than 1 year than mechanical composite roots. Conclusions All prostheses resulted in favorable hemodynamic and ventricular remodeling. Stentless porcine bioroots had the lowest gradients at greater than 1 year of all root replacements, with significantly better ventricular remodeling when compared with mechanical composite roots. Pericardial roots also had favorable hemodynamics and ventricular remodeling, suggesting that they are a viable alternative.

In 2005, the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) anovaginal colonization in pregnant women at our center (Columbia University Medical Center) was 0.5%, and MRSA-colonized women were less likely to carry group B streptococcus (GBS). In this study, our objectives were to identify changing trends in the prevalence of MRSA and methicillin-susceptible S. aureus (MSSA) anovaginal colonization in pregnant women, to assess the association between MRSA and GBS colonization, and to characterize the MRSA strains. From February to July 2009, Lim broths from GBS surveillance samples were cultured for S. aureus . MRSA strains were identified by resistance to cefoxitin and characterized by MicroScan, staphylococcal cassette chromosome mec (SCC mec ) typing, pulsed-field gel electrophoresis (PFGE), spa typing, and Panton-Valentine leukocidin PCR. A total of 2,921 specimens from different patients were analyzed. The prevalences of MSSA, MRSA, and GBS colonization were 11.8%, 0.6% and 23.3%, respectively. GBS colonization was associated with S. aureus colonization (odds ratio [OR], 1.9; 95% confidence interval [95% CI], 1.5 to 2.4). The frequencies of GBS colonization were similar in MRSA-positive (34.2%) versus MRSA-negative patients (21.8%) ( P = 0.4). All MRSA isolates from 2009 and 13/14 isolates from 2005 were SCC mec type IV or V, consistent with community-associated MRSA; 12/18 (2009) and 0/14 (2005) isolates were the USA300 clone. Levofloxacin resistance increased from 14.3% (2005) to 55.6% (2009) ( P = 0.028). In conclusion, the prevalence of MRSA anovaginal colonization in pregnant women in New York City, NY, remained stable from 2005 to 2009, and USA300 emerged as the predominant clone with a significant increase in levofloxacin-resistant isolates.

By providing evidence for best practice, randomized clinical trials play a critical role in shaping the care of the public. We report the operational management systems that enabled the successful execution of a landmark randomized clinical trial. We propose a model for managing high-enrolling

Transcatheter Aortic Valve Replacement (TAVR) has emerged as an alternative to high-risk surgery in patients with comorbid conditions. The role of TAVR in patients with liver disease has not been fully examined. We examined the procedural and intermediate to long-term follow-up outcomes of patients

Artificial microbial consortia seek to leverage division-of-labour to optimize function and possess immense potential for bioproduction. Co-culturing approaches, the preferred mode of generating a consortium, remain limited in their ability to give rise to stable consortia having finely tuned compositions. Here, we present an artificial differentiation system in budding yeast capable of generating stable microbial consortia with custom functionalities from a single strain at user-defined composition in space and in time based on optogenetically-driven genetic rewiring. Owing to fast, reproducible, and light-tunable dynamics, our system enables dynamic control of consortia composition in continuous cultures for extended periods. We further demonstrate that our system can be extended in a straightforward manner to give rise to consortia with multiple subpopulations. Our artificial differentiation strategy establishes a novel paradigm for the creation of complex microbial consortia that are simple to implement, precisely controllable, and versatile to use., Artificial microbial consortia use division-of-labour to optimize production. Here the authors develop an optogenetic differentiation system in yeast to generate consortia from a single strain with tunable composition.