Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism.

Tumor maintenance relies on continued activity of driver oncogenes, although their rate-limiting role is highly context dependent. Oncogenic Kras mutation is the signature event in pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible Kras(G12D)-driven PDAC mouse model establishes that advanced PDAC remains strictly dependent on Kras(G12D) expression. Transcriptome and metabolomic analyses indicate that Kras(G12D) serves a vital role in controlling tumor metabolism through stimulation of glucose uptake and channeling of glucose intermediates into the hexosamine biosynthesis and pentose phosphate pathways (PPP). These studies also reveal that oncogenic Kras promotes ribose biogenesis. Unlike canonical models, we demonstrate that Kras(G12D) drives glycolysis intermediates into the nonoxidative PPP, thereby decoupling ribose biogenesis from NADP/NADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in PDAC.

Ultrabroadband two-dimensional electronic spectroscopy in the pump-probe geometry using conventional optics.

We report ultrabroadband two-dimensional electronic spectroscopy (2D ES) measurements obtained in the pump-probe geometry using conventional optics. A phase-stabilized Michelson interferometer provides the pump-pulse delay interval, τ1, necessary to obtain the excitation-frequency dimension. Spectral resolution of the probe beam provides the detection-frequency dimension, ω3. The interferometer incorporates active phase stabilization via a piezo stage and feedback from interference of a continuous-wave reference laser detected in quadrature. To demonstrate the method, we measured a well-characterized laser dye sample and obtained the known peak structure. The vibronic peaks are modulated as a function of the waiting time, τ2, by vibrational wave packets. The interferometer simplifies ultrabroadband 2D ES measurements and analysis.

Dynamics of Chromatin Accessibility During Hematopoietic Stem Cell Differentiation Into Progressively Lineage-Committed Progeny.

Epigenetic mechanisms regulate the multilineage differentiation capacity of hematopoietic stem cells (HSCs) into a variety of blood and immune cells. Mapping the chromatin dynamics of functionally defined cell populations will shed mechanistic insight into 2 major, unanswered questions in stem cell biology: how does epigenetic identity contribute to a cell type's lineage potential, and how do cascades of chromatin remodeling dictate ensuing fate decisions? Our recent work revealed evidence of multilineage gene priming in HSCs, where open cis-regulatory elements (CREs) exclusively shared between HSCs and unipotent lineage cells were enriched for DNA binding motifs of known lineage-specific transcription factors. Oligopotent progenitor populations operating between the HSCs and unipotent cells play essential roles in effecting hematopoietic homeostasis. To test the hypothesis that selective HSC-primed lineage-specific CREs remain accessible throughout differentiation, we used ATAC-seq to map the temporal dynamics of chromatin remodeling during progenitor differentiation. We observed epigenetic-driven clustering of oligopotent and unipotent progenitors into distinct erythromyeloid and lymphoid branches, with multipotent HSCs and MPPs associating with the erythromyeloid lineage. We mapped the dynamics of lineage-primed CREs throughout hematopoiesis and identified both unique and shared CREs as potential lineage reinforcement mechanisms at fate branch points. Additionally, quantification of genome-wide peak count and size revealed overall greater chromatin accessibility in HSCs, allowing us to identify HSC-unique peaks as putative regulators of self-renewal and multilineage potential. Finally, CRISPRi-mediated targeting of ATACseq-identified putative CREs in HSCs allowed us to demonstrate the functional role of selective CREs in lineage-specific gene expression. These findings provide insight into the regulation of stem cell multipotency and lineage commitment throughout hematopoiesis and serve as a resource to test functional drivers of hematopoietic lineage fate.

Compound Activity Prediction with Dose-Dependent Transcriptomic Profiles and Deep Learning.

Predicting compound activity in assays is a long-standing challenge in drug discovery. Computational models based on compound-induced gene expression signatures from a single profiling assay have shown promise toward predicting compound activity in other, seemingly unrelated, assays. Applications of such models include predicting mechanisms-of-action (MoA) for phenotypic hits, identifying off-target activities, and identifying polypharmacologies. Here, we introduce transcriptomics-to-activity transformer (TAT) models that leverage gene expression profiles observed over compound treatment at multiple concentrations to predict the compound activity in other biochemical or cellular assays. We built TAT models based on gene expression data from a RASL-seq assay to predict the activity of 2692 compounds in 262 dose-response assays. We obtained useful models for 51% of the assays, as determined through a realistic held-out set. Prospectively, we experimentally validated the activity predictions of a TAT model in a malaria inhibition assay. With a 63% hit rate, TAT successfully identified several submicromolar malaria inhibitors. Our results thus demonstrate the potential of transcriptomic responses over compound concentration and the TAT modeling framework as a cost-efficient way to identify the bioactivities of promising compounds across many assays.

Temporal changes in the utilization of kidneys from hepatitis C virus-infected donors in the United States.

Despite data demonstrating increased utilization of kidneys from hepatitis C virus (HCV)-infected donors, it is unknown whether this is due to an increase in the donor pool or improved organ utilization and whether data from early pilot trials were temporally associated with changes in organ utilization. We used data from the Organ Procurement and Transplantation Network on all kidney donors and recipients of kidney transplants from January 1, 2015, to March 31, 2022 to evaluate temporal changes using joinpoint regression. Our primary analyses compared donors on the basis of their HCV viremic status (HCV-infected vs HCV-negative). Kidney utilization changes were assessed by evaluating the kidney discard rate and kidneys transplanted per donor. A total of 81 833 kidney donors were included in the analysis. There was a statistically significant decrease in the discard rates of HCV-infected kidney donors from 40% to just over 20% over a 1-year period, with a concurrent increase in kidneys transplanted per donor. This increased utilization occurred in tandem with the publication of pilot trials involving HCV-infected kidney donors in HCV-negative recipients rather than an increase in the donor pool. Ongoing clinical trials may strengthen existing data, which could result in this practice becoming the accepted standard of care.

A Pilot Single-Blinded, Randomized, Controlled Trial Comparing BNT162b2 vs. JNJ-78436735 Vaccine as the Third Dose After Two Doses of BNT162b2 Vaccine in Solid Organ Transplant Recipients.

Solid Organ Transplant (SOT) recipients are at significant higher risk for COVID-19 and due to immunosuppressive medication, the immunogenicity after vaccination is suboptimal. In the previous studies, booster method showed significant benefit in this population. In the current study, we compared using a mix-and-match method vs. same vaccine as a third dose in SOT recipients. This was a patient-blinded, single center, randomized controlled trial comparing BNT162b2 vs. JNJ-78436735 vaccine as the third dose after two doses of BNT162b2 vaccine. We included adult SOT recipients with functional graft who had received two doses of BNT162b2 vaccine. Participants were randomly assigned to receive either BNT162b2 or JNJ-78436735 in one-to-one ratio. Primary outcome was SARS-CoV-2 IgG positivity at 1 month after the third dose. Sixty SOT recipients, including 36 kidney, 12 liver, 2 lung, 3 heart, and 5 combined transplants, were enrolled, and 57 recipients were analyzed per protocol. There were no statistically significant differences between the two vaccine protocols for IgG positivity (83.3% vs. 85.2% for BNT162b2 and JNJ-78436735, respectively, p = 0.85, Odds Ratio 0.95, 95% Confidence Interval 0.23-4.00). Comparison of the geometric mean titer demonstrated a higher trend with BNT162b2 (p = 0.09). In this pilot randomized controlled trial comparing mix and match method vs. uniform vaccination in SOT recipients, both vaccines were safely used. Since this was a small sample sized study, there was no statistically significant difference in immunogenicity; though, the mix and match method showed relatively lower geometric mean titer, as compared to uniform vaccine. Further studies need to be conducted to determine duration of this immunogenicity. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT05047640?term=20210641&draw=2&rank=1, identifier 20210641.

Clinical characteristics and outcomes in CMV infection in intestinal transplant recipients: A single-center experience.

BACKGROUND: Cytomegalovirus (CMV) infection is one of the most common posttransplantation infections and has been associated with increased rejection and mortality. Data in intestinal transplants recipients are limited. METHODS: This is a single-center, retrospective cohort study of all intestinal transplants performed between January 1, 2009, and August 31, 2020. We included recipients of all ages who were at risk of CMV infection. To identify the risk factors, we conducted at first univariate and multivariate analysis. For the multivariate analysis, we developed a logistic regression model based on the result of univariate analysis. RESULTS: Ninety five patients with a median age of 32 (interquartile range [IQR] 4, 50) were included. CMV donor seropositive/recipient seronegative were 17 (17.9%). Overall, 22.1% of the recipients developed CMV infection at a median time of 155 (IQR 28-254) days from transplant, including 4 CMV syndrome and 6 CMV end-organ disease. Overall, 90.4%, (19/21) developed DNAemia while on prophylaxis. Median peak viral load and time to negativity was 16 000 (IQR 1034-43 892) IU/mL and 56 (IQR 49-109) days, respectively. (Val)ganciclovir and foscarnet were utilized in 17 (80.9%) and 1 (4.76%) recipients, respectively. Recurrences of CMV DNAemia and graft rejection were observed in three and six recipients, respectively. Younger age was identified as a risk factor (p = .032, odds ratio 0.97, 95% confidence interval 0.95-0.99) to develop CMV DNAemia. CONCLUSION: A significant proportion of intestinal transplant recipients developed CMV infection while on prophylaxis. Better methods such as CMV cell mediated immunity guided prophylaxis should be used to prevent infections in this population.

Mesenchymal Stem Cells and Regenerative Therapy with Bilateral Gracilis Flaps for Perineal Reconstruction of a Wound Infection in the Setting of Anal Squamous Cell Carcinoma.

ABSTRACT: Many patients are affected by HIV/AIDS, and these conditions are highly prevalent worldwide. Patients with HIV/AIDS can experience debilitating wound infections that often require flap reconstruction and become challenging for surgeons to treat. In the past 5 years, mesenchymal stem cells have been tested and used as regenerative therapy to promote the growth of tissues throughout the body because of their ability to successfully promote cellular mitogenesis. To the authors' knowledge, the use of mesenchymal stem cell grafting following necrosis of a myocutaneous gracilis flap (as part of perineal wound reconstruction) has never been reported in the literature.In addition, the use of mesenchymal stem cells and regenerative medicine combined in the setting of squamous cell carcinoma of the anus with prior radiation (along with comorbid AIDS) has not been previously documented.In this report, the authors outline the case of a 60-year-old patient who had a recipient bed (perineum) complication from prior radiation therapy. Complicating the clinical picture, the patient also developed a Pseudomonal organ space infection of the pelvis leading to the failure of a vertical rectus abdominis myocutaneous flap and myocutaneous gracilis flaps. As a result, the patient underwent serial operative debridements for source control, with the application of mesenchymal stem cells, fetal bovine dermis, porcine urinary bladder xenograft, and other regenerative medicine products, achieving a highly successful clinical outcome. A procedural description for future use and replication of this method is provided.

The Influence of Athletic Identity, Passion, and Perceptions of Severity of Concussions on Athletes' Willingness to Report Concussion Symptoms.

CONTEXT: The influence of several psychological characteristics on the willingness of athletes to report concussion behaviors has not been well explored. Therefore, the purpose of this study was to understand how athletic identity and sport passion predicted participants' willingness to report symptoms above what was explained by athlete demographics, concussion knowledge, and perceived seriousness of concussions. DESIGN: The study was cross-sectional. METHODS: Three-hundred and twenty-two male and female high school and club sport athletes completed survey measures of concussion knowledge, athletic identity, harmonious and obsessive passion, and degree to which athletes indicated they would report concussions and concussion symptoms. RESULTS: Athletes scored moderately high on their knowledge of symptoms and other concussion information (mean = 16.21; ± = 2.88) and above the midpoint on their attitudes and behaviors toward reporting concussion symptoms (mean = 3.64; ± = 0.70). There were no differences between gender, t(299) = -.78, P = .44, and previous concussion education, t(296) = 1.93, P = .06, related to concussion knowledge. Results of a hierarchical regression indicated that after entering athlete demographics, concussion knowledge, and perceived seriousness of concussions, of the 3 psychological variables in the final stage of the model, only obsessive passion was a significant predictor of athlete's attitudes to report a concussion. CONCLUSIONS: Perceived seriousness of concussion, perceived threat to long-term health, and obsessive passion were the strongest predictors of athlete's willingness to report concussions. Athletes who did not believe concussions posed a threat to their current or future health, and those that held an obsessive passion for sport were most at risk for not reporting concussions. Future research should continue to investigate the relationship between reporting behaviors and psychological factors.

Risk factors and outcomes associated with recurrent autoimmune hepatitis following liver transplantation.

BACKGROUND & AIMS: Autoimmune hepatitis can recur after liver transplantation (LT), though the impact of recurrence on patient and graft survival has not been well characterized. We evaluated a large, international, multicenter cohort to identify the probability and risk factors associated with recurrent AIH and the association between recurrent disease and patient and graft survival. METHODS: We included 736 patients (77% female, mean age 42±1 years) with AIH who underwent LT from January 1987 through June 2020, among 33 centers in North America, South America, Europe and Asia. Clinical data before and after LT, biochemical data within the first 12 months after LT, and immunosuppression after LT were analyzed to identify patients at higher risk of AIH recurrence based on histological diagnosis. RESULTS: AIH recurred in 20% of patients after 5 years and 31% after 10 years. Age at LT ≤42 years (hazard ratio [HR] 3.15; 95% CI 1.22-8.16; p = 0.02), use of mycophenolate mofetil post-LT (HR 3.06; 95% CI 1.39-6.73; p = 0.005), donor and recipient sex mismatch (HR 2.57; 95% CI 1.39-4.76; p = 0.003) and high IgG pre-LT (HR 1.04; 95% CI 1.01-1.06; p = 0.004) were associated with higher risk of AIH recurrence after adjusting for other confounders. In multivariate Cox regression, recurrent AIH (as a time-dependent covariate) was significantly associated with graft loss (HR 10.79, 95% CI 5.37-21.66, p <0.001) and death (HR 2.53, 95% CI 1.48-4.33, p = 0.001). CONCLUSION: Recurrence of AIH following transplant is frequent and is associated with younger age at LT, use of mycophenolate mofetil post-LT, sex mismatch and high IgG pre-LT. We demonstrate an association between disease recurrence and impaired graft and overall survival in patients with AIH, highlighting the importance of ongoing efforts to better characterize, prevent and treat recurrent AIH. LAY SUMMARY: Recurrent autoimmune hepatitis following liver transplant is frequent and is associated with some recipient features and the type of immunosuppressive medications use. Recurrent autoimmune hepatitis negatively affects outcomes after liver transplantation. Thus, improved measures are required to prevent and treat this condition.

In situ tomographic study of a 3D-woven SiC/SiC composite part subjected to severe thermo-mechanical loads.

A high-temperature multi-axial test is carried out to characterize the thermo-mechanical behaviour of a 3D-woven SiC/SiC composite aeronautical part under loads representative of operating conditions. The sample is L-shaped and cut out from the part. It is subjected to severe thermal gradients and a superimposed mechanical load that progressively increases up to the first damage. The sample shape and its associated microstructure, the heterogeneity of the stress field and the limited accessibility to regions susceptible to damage require non-contact imaging modalities. An in situ experiment, conducted with a dedicated testing machine at the SOLEIL synchrotron facility, provides the sample microstructure from computed micro-tomographic imaging and thermal loads from infrared thermography. Experimental constraints lead to non-ideal acquisition conditions for both measurement modalities. This article details the procedure of correcting artefacts to use the volumes for quantitative exploitation (i.e. full-field measurement, model validation and identification). After proper processing, despite its complexity, the in situ experiment provides high-quality data about a part under realistic operating conditions. The influence of the mesostructure on fracture phenomena can be inferred from the tomography in the damaged state. Experiments show that the localization of damage initiation is driven by the geometry, while the woven structure moderates the crack propagation. This study widens the scope of in situ thermo-mechanical experiments to more complex loading states, closer to in-service conditions.

Rapid multiplex ultrafast nonlinear microscopy for material characterization.

We demonstrate rapid imaging based on four-wave mixing (FWM) by assessing the quality of advanced materials through measurement of their nonlinear response, exciton dephasing, and exciton lifetimes. We use a WSe2 monolayer grown by chemical vapor deposition as a canonical example to demonstrate these capabilities. By comparison, we show that extracting material parameters such as FWM intensity, dephasing times, excited state lifetimes, and distribution of dark/localized states allows for a more accurate assessment of the quality of a sample than current prevalent techniques, including white light microscopy and linear micro-reflectance spectroscopy. We further discuss future improvements of the ultrafast FWM techniques by modeling the robustness of exponential decay fits to different spacing of the sampling points. Employing ultrafast nonlinear imaging in real-time at room temperature bears the potential for rapid in-situ sample characterization of advanced materials and beyond.

Geriatric All-Terrain Vehicle Trauma: An Unhelmeted and Severely Injured Population.

BACKGROUND: All-terrain vehicle (ATV) use is widespread, however, little is known about injury patterns and outcomes in geriatric patients. We hypothesized that geriatric patients would have distinct and more severe injuries than non-geriatric adults after ATV trauma. METHODS: A retrospective cohort study was performed using the National Trauma Databank comparing non-geriatric (18-64) and geriatric adults (≥65) presenting after ATV trauma at Level 1 and 2 trauma centers from 2011 to 2015. Demographic, admission, and outcomes data were collected, including injury severity score (ISS), abbreviated injury scale (AIS) score, discharge disposition, and mortality. We performed univariate statistical tests between cohorts and multiple logistic regression models to assess for risk factors associated with severe injury (ISS>15) and mortality. RESULTS: 23,568 ATV trauma patients were identified, of whom 1,954 (8.3%) were geriatric. Geriatric patients had higher rates of severe injury(29.2 v 22.5%,p<0.0001), and thoracic (55.2 v 37.8%,p<0.0001) and spine (31.5 v 26.0%,p<0.0001) injuries, but lower rates of abdominal injuries (14.6 v 17.9%,p<0.001) as compared to non-geriatric adults. Geriatric patients had overall lower head injury rates (39.2 v 42.1%,p=0.01), but more severe head injuries (AIS>3) (36.2 vs 30.2%,p<0.001). Helmet use was significantly lower in geriatric patients (12.0 v 22.8%,p<0.0001). On multivariate analysis age increased the odds for both severe injury (OR 1.50, 95% CI 1.31-1.72, p<0.0001) and mortality (OR 5.07, 95% CI 3.42-7.50, p<0.0001). CONCLUSIONS: While severe injury and mortality after ATV trauma occurred in all adults, geriatric adults suffered distinct injury patterns and were at greater risk for severe injury and mortality.

On the Choice of Active Site Sequences for Kinase-Ligand Affinity Prediction.

Recent work showed that active site rather than full-protein-sequence information improves predictive performance in kinase-ligand binding affinity prediction. To refine the notion of an "active site", we here propose and compare multiple definitions. We report significant evidence that our novel definition is superior to previous definitions and better models of ATP-noncompetitive inhibitors. Moreover, we leverage the discontiguity of the active site sequence to motivate novel protein-sequence augmentation strategies and find that combining them further improves performance.

Imaging dynamic exciton interactions and coupling in transition metal dichalcogenides.

Transition metal dichalcogenides (TMDs) are regarded as a possible material platform for quantum information science and related device applications. In TMD monolayers, the dephasing time and inhomogeneity are crucial parameters for any quantum information application. In TMD heterostructures, coupling strength and interlayer exciton lifetimes are also parameters of interest. However, many demonstrations in TMDs can only be realized at specific spots on the sample, presenting a challenge to the scalability of these applications. Here, using multi-dimensional coherent imaging spectroscopy, we shed light on the underlying physics-including dephasing, inhomogeneity, and strain-for a MoSe2 monolayer and identify both promising and unfavorable areas for quantum information applications. We, furthermore, apply the same technique to a MoSe2/WSe2 heterostructure. Despite the notable presence of strain and dielectric environment changes, coherent and incoherent coupling and interlayer exciton lifetimes are mostly robust across the sample. This uniformity is despite a significantly inhomogeneous interlayer exciton photoluminescence distribution that suggests a bad sample for device applications. This robustness strengthens the case for TMDs as a next-generation material platform in quantum information science and beyond.

Lock-in detector for accelerated nonlinear imaging.

We show that accelerated nonlinear imaging, such as stimulated Raman scattering and pump-probe imaging, is enabled by an order of magnitude reduction of data acquisition time when replacing the exponentially-weighted-moving-average low-pass filter in a lock-in amplifier with a simple-moving-average filter. We show that this simple-moving-average (box) lock-in yields a superior signal-to-noise ratio and suppression of extraneous modulations with short pixel dwell times, if one condition for the relation between the lock-in time constant and modulation frequencies is met. Our results, both theoretical and experimental, indicate that for nonlinear imaging applications, the box lock-in significantly outperforms conventional lock-in detection. These results facilitate the application of ultrafast and nonlinear imaging as a new standard for material characterization.

Geriatric Snowmobile Trauma: Longer Courses After Similar Injuries.

BACKGROUND: Snowmobiling is a popular activity that leads to geriatric trauma admissions; however, this unique trauma population is not well characterized. We aimed to compare the injury burden and outcomes for geriatric versus nongeriatric adults injured riding snowmobiles. MATERIALS AND METHODS: A retrospective cohort study was performed using the National Trauma Databank comparing nongeriatric (18-64) and geriatric adults (≥65) presenting after snowmobile-related trauma at level 1 and 2 trauma centers from 2011 to 2015. Demographic, admission, injury, and outcome data were collected and compared. A multivariate logistic regression model assessed for risk factors associated with severe injury (Injury Severity Score >15). Analysis was also performed using chi square, analysis of variance, and Kruskal-Wallis testing. RESULTS: A total of 2471 adult patients with snowmobile trauma were identified; 122 (4.9%) were geriatric. Rates of severe injury (Injury Severity Score >15) were similar between groups, 27.5% in geriatric patients and 22.5% in nongeriatric adults (P = 0.2). Geriatric patients experienced higher rates of lower extremity injury (50.4 versus 40.3%, P = 0.03), neck injury (4.1 versus 1.4%, P = 0.02), and severe spine injury (20.6 versus 7.0%, P = 0.004). Geriatric patients had longer hospitalizations (5 versus 3 d, P < 0.0001), rates of discharge to a facility (36.8% versus 12%, P < 0.0001), and higher mortality (4.1 versus 0.6%, P < 0.0001). Geriatric age did not independently increase the risk for severe injury. CONCLUSIONS: Geriatric age was not a significant predictor of severe injury after snowmobile trauma; however, geriatric patients suffered unique injuries, had longer hospitalizations, had higher rates of discharge to a facility, and had higher mortality. Tailored geriatric care may improve outcomes in this unique sport-related trauma population.

Geriatric Skiers: Active But Still at Risk, a National Trauma Data Bank Study.

BACKGROUND: Downhill skiing accounts for a large portion of geriatric sport-related trauma. We assessed the national burden of geriatric versus nongeriatric ski trauma. MATERIALS AND METHODS: Adults presenting to level 1/2 trauma centers after ski-associated injuries from 2011 to 2015 were identified from the National Trauma Data Bank by ICD-9 code. We compared demographics, injury patterns, and outcomes between geriatric (age ≥65 y) and nongeriatric adult skiers (age 18-64 y). A multiple regression analysis assessed for risk factors associated with severe injury (Injury Severity Score >15). RESULTS: We identified 3255 adult ski trauma patients, and 16.7% (543) were geriatric. Mean ages for nongeriatric versus geriatric skiers were 40.8 and 72.1 y, respectively. Geriatric skiers more often suffered head (36.7 versus 24.3%, P < 0.0001), severe head (abbreviated injury scale score >3, 49.0 versus 31.5%, P < 0.0001) and thorax injuries (22.2 versus 18.1%, P = 0.03) as compared with nongeriatric skiers. Geriatric skiers were also more often admitted to the ICU (26.5 versus 14.9%, P < 0.0001), discharged to a facility (26.7 versus 11.6%, P < 0.0001), and suffered higher mortality rates (1.3 versus 0.4%, P = 0.004). Independent risk factors for severe injury included being male (OR: 1.68, CI: 1.22-2.31), helmeted (OR: 1.41, CI: 1.07-1.85), and having comorbidities (OR: 1.37, CI: 1.05-1.80). Geriatric age was not independently associated with severe injury. CONCLUSIONS: At level 1/2 trauma centers, geriatric age in ski trauma victims was associated with unique injury patterns, higher acuity, increased rates of facility care at discharge, and higher mortality as compared with nongeriatric skiers. Our findings indicate the need for specialized care after high impact geriatric ski trauma.

When is it safe to perform abdominal transplantation in patients with prior SARS-CoV-2 infection: A case series.

BACKGROUND: The Coronavirus disease 2019(COVID-19) pandemic has negatively impacted worldwide organ transplantation. However, there is limited information on recipients transplanted after SARS-CoV-2 infection. A full understanding of this scenario is required, as transplantation is a life-saving procedure and COVID-19 remains an ongoing threat. METHODS: Abdominal organ transplant recipients diagnosed with COVID-19 prior to transplantation were identified by chart review and clinical data were collected. The primary outcome was the transplant outcome including graft loss, rejection and death, and reactivation of infection post-transplant. RESULTS: We identified 14 patients who received abdominal organ transplants after symptomatic PCR confirmed SARS-CoV-2 infection; four patients had a positive PCR at the time of admission for transplantation. The median time of follow-up was 79 (22-190) days. One recipient with negative PCR before transplant tested positive 9 days after transplant. One of 14 transplanted patients developed disseminated mold infection and died 86 days after transplant. During the follow-up, only one patient developed rejection; thirteen patients had favorable graft outcomes. CONCLUSIONS: We were able to perform abdominal transplantation for patients with COVID-19 before transplant, even with positive PCR at the time of transplant. Larger studies are needed to determine the time to safe transplant after SARS-CoV-2 infection.

Collaborative Profile-QSAR: A Natural Platform for Building Collaborative Models among Competing Companies.

Massively multitask bioactivity models that transfer learning between thousands of assays have been shown to work dramatically better than separate models trained on each individual assay. In particular, the applicability domain for a given model can expand from compounds similar to those tested in that specific assay to those tested across the full complement of contributing assays. If many large companies would share their assay data and train models on the superset, predictions should be better than what each company can do alone. However, a company's compounds, targets, and activities are among their most guarded trade secrets. Strategies have been proposed to share just the individual collaborators' models, without exposing any of the training data. Profile-QSAR (pQSAR) is a two-level, multitask, stacked model. It uses profiles of level-1 predictions from single-task models for thousands of assays as compound descriptors for level-2 models. This work describes its simple and natural adaptation to safe collaboration by model sharing. Broad model sharing has not yet been implemented across multiple large companies, so there are numerous unanswered questions. Novartis was formed from several mergers and acquisitions. In principle, this should allow an internal simulation of model sharing. In practice, the lack of metadata about the origins of compounds and assays made this difficult. Nevertheless, we have attempted to simulate this process and propose some findings: multitask pQSAR is always an improvement over single-task models; collaborative multitask modeling did not improve predictions on internal compounds; collaboration did improve predictions for external compounds but far less than the purely internal multitask modeling for internal compounds; collaborative models for external compounds increasingly improve as overlap between compound collections increases; combining profiles from inside and outside the company is not best, with internal predictions better using only the inside profile and external using only the outside profile, but a consensus of models using all three profiles is best on external compounds and a good compromise on internal compounds. We anticipate similar results from other model-sharing approaches. Indeed, since collaborative pQSAR through model sharing is mathematically identical to pQSAR using actual shared data, we believe our conclusions should apply to collaborative modeling by any current method even including the unlikely scenario of directly sharing all chemical structures and assay data.