Occupational radiation dose trends in U.S. radiologic technologists assisting with fluoroscopically-guided interventional procedures, 1980-2020.

PURPOSE: To summarize dose trends from 1980-2020 for 19,651 U.S. radiologic technologists who reported assisting with fluoroscopically-guided interventional procedures (FGIP), overall and by work history characteristics. METHODS: We summarized 762,310 annual personal dose equivalents at a 10 mm-reference depth ("doses") during 1980-2020 for 43,823 participants of the U.S. Radiologic Technologists (USRT) cohort who responded to work history questionnaires administered during 2012-2014. This population included 19,651 technologists who reported assisting with FGIP (≥1 time per month for ≥12 consecutive months) at any time during the study period. We estimated doses corresponding to assistance with FGIP by proximity to patients, monthly procedure frequency, and procedure type. We used box plots and summary statistics (e.g., median, percentiles) to describe annual doses and dose trends. RESULTS: Median annual dose corresponding to assistance with FGIP was 0.65 mSv, [interquartile range (IQR)=0.60-1.40; 95th percentile=6.80]. Higher occupational doses with wider variability were associated with close proximity to patients during assistance with FGIP (median=1.20 mSv; IQR=0.60-4.18; 95th percentile=12.66), performing ≥20 FGIP per month (median=0.75 mSv; IQR=0.60, 2.40; 95th percentile=9.44), and assisting with high-dose FGIP (median=0.70; IQR=0.60, 1.90; 95th percentile=8.30). CONCLUSION: Occupational doses corresponding to assistance with FGIP were generally low but varied with exposure frequency, procedure type, and proximity to patients. These results highlight the need for vigilant dose monitoring, radiation safety training, and proper protective equipment.

Nuclear factor kappa B-dependent persistence of Salmonella Typhi and Paratyphi in human macrophages.

Salmonella serovars Typhi and Paratyphi cause a prolonged illness known as enteric fever, whereas other serovars cause acute gastroenteritis. Mechanisms responsible for the divergent clinical manifestations of nontyphoidal and enteric fever Salmonella infections have remained elusive. Here, we show that S. Typhi and S. Paratyphi A can persist within human macrophages, whereas S. Typhimurium rapidly induces apoptotic macrophage cell death that is dependent on Salmonella pathogenicity island 2 (SPI2). S. Typhi and S. Paratyphi A lack 12 specific SPI2 effectors with pro-apoptotic functions, including nine that target nuclear factor κB (NF-κB). Pharmacologic inhibition of NF-κB or heterologous expression of the SPI2 effectors GogA or GtgA restores apoptosis of S. Typhi-infected macrophages. In addition, the absence of the SPI2 effector SarA results in deficient signal transducer and activator of transcription 1 (STAT1) activation and interleukin 12 production, leading to impaired TH1 responses in macrophages and humanized mice. The absence of specific nontyphoidal SPI2 effectors may allow S. Typhi and S. Paratyphi A to cause chronic infections. IMPORTANCE: Salmonella enterica is a common cause of gastrointestinal infections worldwide. The serovars Salmonella Typhi and Salmonella Paratyphi A cause a distinctive systemic illness called enteric fever, whose pathogenesis is incompletely understood. Here, we show that enteric fever Salmonella serovars lack 12 specific virulence factors possessed by nontyphoidal Salmonella serovars, which allow the enteric fever serovars to persist within human macrophages. We propose that this fundamental difference in the interaction of Salmonella with human macrophages is responsible for the chronicity of typhoid and paratyphoid fever, suggesting that targeting the nuclear factor κB (NF-κB) complex responsible for macrophage survival could facilitate the clearance of persistent bacterial infections.

Muscle and joint mechanics during maximum force biting following total temporomandibular joint replacement surgery.

Total temporomandibular joint replacement (TMJR) surgery is the established treatment for severe temporomandibular joint disorders. While TMJR surgery is known to increase mouth-opening capacity, reduce pain and improve quality of life, little is known about post-surgical jaw function during activities of daily living such as biting and chewing. The aim of this study was to use subject-specific 3D bite force measurements to evaluate the magnitude and direction of joint loading in unilateral total TMJR patients and compare these data to those in healthy control subjects. An optoelectronic tracking system was used to measure jaw kinematics while biting a rubber sample for 5 unilateral total TMJR patients and 8 controls. Finite element simulations driven by the measured kinematics were employed to calculate the resultant bite force generated when compressing the rubber between teeth during biting tasks. Subject-specific musculoskeletal models were subsequently used to calculate muscle and TMJ loading. Unilateral total TMJR patients generated a bite force of 249.6 ± 24.4 N and 164.2 ± 62.3 N when biting on the contralateral and ipsilateral molars, respectively. In contrast, controls generated a bite force of 317.1 ± 206.6 N. Unilateral total TMJR patients biting on the contralateral molars had a significantly higher lateral TMJ force direction (median difference: 63.6°, p = 0.028) and a significantly lower ratio of working TMJ force to bite force (median difference: 0.17, p = 0.049) than controls. Results of this study may guide TMJ prosthesis design and evaluation of dental implants.

[18F]FDG PET/CT-Avid Discordant Volume as a Biomarker in Patients with Gastroenteropancreatic Neuroendocrine Neoplasms: A Multicenter Study.

[18F]FDG PET/CT and [68Ga]Ga-DOTATATE PET/CT are both used to predict tumor biology in neuroendocrine neoplasms. Although the presence of discordant ([18F]FDG-avid/non-[68Ga]Ga-DOTATATE-avid) disease predicts poor prognosis, the significance of the volume of such discordant disease remains undetermined. The aim of this study is to investigate discordant tumor volume as a potential biomarker in patients with advanced gastroenteropancreatic neuroendocrine neoplasms (GEPNENs). Methods: A multicenter retrospective study in patients with advanced GEPNENs and paired [18F]FDG and [68Ga]Ga-DOTATATE PET/CT no more than 85 d apart was conducted. Patients with discordant disease were identified by the NETPET score, and discordant lesions were contoured with a flat [18F]FDG SUV cutoff of 4. The primary variable of interest was the total discordant volume (TDV), which was the sum of the volumes of discordant lesions. Patients were dichotomized into high- and low-TDV cohorts by the median value. The primary endpoint was overall survival. Results: In total, 44 patients were included (50% men; median age, 60 y), with primary cancers in the pancreas (45%), small bowel (23%), colon (20%), and other (12%). Of the patients, 5% had grade 1 disease, 48% had grade 2 disease, and 48% had grade 3 disease (24% well differentiated, 67% poorly differentiated, 10% unknown within the grade 3 cohort). The overall median survival was 14.1 mo. Overall survival was longer in the low-TDV cohort than in the high-TDV cohort (median volume, 43.7 cm3; survival time, 23.8 mo vs. 9.4 mo; hazard ratio, 0.466 [95% CI, 0.229-0.948]; P = 0.0221). Patients with no more than 2 discordant intrahepatic lesions survived longer than those with 2 or more lesions (31.8 mo vs. 10.2 mo, respectively; hazard ratio, 0.389 [95% CI, 0.194-0.779]; P = 0.0049). Conclusion: TDV is a potential prognostic biomarker in GEPNENs and should be investigated in future neuroendocrine neoplasm trials.

A practical method for assessing quantitative scanner accuracy with long-lived radionuclides: The ARTnet insert.

Objectives: To address the problem of using large volumes of long-lived radionuclides in test phantoms to check calibration accuracy of PET and SPECT systems we have developed a test object which (a) contains less radioactivity, (b) has a low total volume, and (c) is easier to store than currently used phantoms, while still making use of readily-available "standardised" test objects. Methods: We have designed a hollow acrylic cylindrical insert compatible with the NEMA/IEC PET Body Image Quality (IQ) phantom used in NU 2 performance testing of PET systems. The insert measures 90 mm internal diameter and 70 mm internal height and so is sufficiently large to not be subject to partial volume effects in PET or SPECT imaging. The volume of the insert is approximately 500 mL. It has been designed as a replacement for the standard long cylindrical "lung insert" in the IQ phantom without needing to remove the fillable hollow spheres of the phantom. The insert been tested with 18F, 68Ga and 124I PET/CT and 99mTc, 131I and 177Lu SPECT/CT on scanners that had previously been calibrated for these radionuclides. Results: The scanners were found to produce accurate image reconstructions in the insert with  5% of the true value without any confounding uncertainty from partial volume effects when compared to NEMA NU 2-2018 Phantom measurement. Conclusions: The "ARTnet Insert" is simple to use, inexpensive, compatible with current phantoms and is suitable for both PET and SPECT systems. It does not suffer from significant partial volume losses permitting its use even with the poor spatial resolution of high-energy imaging with 131I SPECT. Furthermore, it uses less radioactivity in a smaller volume than would be required to fill the entire phantom as is usually done. Long-term storage is practical while allowing radioactive decay of the insert contents.

Treating a common comorbidity: Pain outcomes following a 3-week cognitive processing therapy-based intensive treatment for posttraumatic stress disorder address.

Posttraumatic stress disorder (PTSD) commonly co-occurs with pain and has been implicated in the maintenance of chronic pain. However, limited research has examined whether intervening for PTSD can hinder or optimize treatment outcomes for co-occurring pain and PTSD. In the present study, we examined changes in pain, PTSD, and depressive symptoms among 125 veterans completing a 3-week cognitive processing therapy (CPT)-based intensive treatment program (ITP) for PTSD. We also explored whether pretreatment pain interference predicted changes in PTSD and depressive symptom severity and whether larger changes in pain interference over the course of treatment were associated with larger changes in PTSD and depressive symptom severity. Linear mixed models revealed that participants' pain interference decreased throughout treatment, d = 0.15, p = .039. Higher levels of pretreatment pain interference were associated with higher PTSD, p = .001, and depressive symptom severity, p = .014, over time. Larger reductions in pain interference corresponded to more improvement in PTSD symptoms, ß = -.03; p < .001, but not depressive symptoms. These findings indicate that ITPs for PTSD can reduce pain interferences, albeit to a small degree, and that reductions in pain interference can contribute to reductions in PTSD symptom severity. Future studies should examine which treatment components contribute to larger changes in symptom severity for veterans with co-occurring pain and PTSD.

Outcome-Based Risk Stratification Model for the Diagnosis of Placental Maternal Vascular Malperfusion.

The Amsterdam Consensus Statement introduced the term maternal vascular malperfusion (MVM) to group a constellation of findings associated with impaired maternal-placental circulation. In isolation, these findings are relatively common in placentas from normal gestations, and there is uncertainty on how many, and which, are required. We aimed to determine the criteria essential for MVM diagnosis in correlation with obstetrical outcomes. A total of 200 placentas (100 with a reported diagnosis of MVM and 100 controls matched by maternal age and gravida-para-abortus status) were reviewed to document MVM features. Obstetrical outcomes in the current pregnancy were recorded including hypertension, pre-eclampsia with or without severe features, gestational diabetes, prematurity, fetal growth restriction, and intrauterine fetal demise. On univariate logistic regression analysis, adverse outcome was associated with low placental weight (LPW, <10% percentile for gestational age), accelerated villous maturation (AVM), decidual arteriopathy (DA), infarcts (presence and volume), distal villous hypoplasia, and excess multinucleated trophoblast in basal plate ≥2 mm (all P < .01) but not with retroplacental hemorrhage. In a multivariable model DA, infarcts and AVM were significantly associated with adverse outcomes, whereas LPW showed a trend toward significance. A receiver-operating characteristic curve including these 4 parameters showed good predictive ability (area under the curve [AUC], 0.8256). Based on the probability of an adverse outcome, we recommend consistent reporting of DA, AVM, infarcts, and LPW, summarizing them as "diagnostic of MVM" (DA or AVM plus any other feature, yielding a probability of 65%-97% for adverse obstetrical outcomes) or "suggestive of MVM" (if only 1 feature is present, or only 2 features are infarcts plus LPW, yielding a probability of up to 52%). Other features such as distal villous hypoplasia, excess (≥2 mm) multinucleated trophoblast, and retroplacental hemorrhage can also be reported, and their role in MVM diagnosis should be further studied.

Prediction of key milk biomarkers in dairy cows through milk mid-infrared spectra and international collaborations.

At the individual cow level, suboptimum fertility, mastitis, negative energy balance, and ketosis are major issues in dairy farming. These problems are widespread on dairy farms and have an important economic impact. The objectives of this study were (1) to assess the potential of milk mid-infrared (MIR) spectra to predict key biomarkers of energy deficit (citrate, isocitrate, glucose-6 phosphate [glucose-6P], free glucose), ketosis (ß-hydroxybutyrate [BHB] and acetone), mastitis (N-acetyl-ß-d-glucosaminidase activity [NAGase] and lactate dehydrogenase), and fertility (progesterone); (2) to test alternative methodologies to partial least squares (PLS) regression to better account for the specific asymmetric distribution of the biomarkers; and (3) to create robust models by merging large datasets from 5 international or national projects. Benefiting from this international collaboration, the dataset comprised a total of 9,143 milk samples from 3,758 cows located in 589 herds across 10 countries and represented 7 breeds. The samples were analyzed by reference chemistry for biomarker contents, whereas the MIR analyses were performed on 30 instruments from different models and brands, with spectra harmonized into a common format. Four quantitative methodologies were evaluated to address the strongly skewed distribution of some biomarkers. Partial least squares regression was used as the reference basis, and compared with a random modification of distribution associated with PLS (random-downsampling-PLS), an optimized modification of distribution associated with PLS (KennardStone-downsampling-PLS), and support vector machine (SVM). When the ability of MIR to predict biomarkers was too low for quantification, different qualitative methodologies were tested to discriminate low versus high values of biomarkers. For each biomarker, 20% of the herds were randomly removed within all countries to be used as the validation dataset. The remaining 80% of herds were used as the calibration dataset. In calibration, the 3 alternative methodologies outperform the PLS performances for the majority of biomarkers. However, in the external herd validation, PLS provided the best results for isocitrate, glucose-6P, free glucose, and lactate dehydrogenase (coefficient of determination in external herd validation [R2v] = 0.48, 0.58, 0.28, and 0.24, respectively). For other molecules, PLS-random-downsampling and PLS-KennardStone-downsampling outperformed PLS in the majority of cases, but the best results were provided by SVM for citrate, BHB, acetone, NAGase, and progesterone (R2v = 0.94, 0.58, 0.76, 0.68, and 0.15, respectively). Hence, PLS and SVM based on the entire dataset provided the best results for normal and skewed distributions, respectively. Complementary to the quantitative methods, the qualitative discriminant models enabled the discrimination of high and low values for BHB, acetone, and NAGase with a global accuracy around 90%, and glucose-6P with an accuracy of 83%. In conclusion, MIR spectra of milk can enable quantitative screening of citrate as a biomarker of energy deficit and discrimination of low and high values of BHB, acetone, and NAGase, as biomarkers of ketosis and mastitis. Finally, progesterone could not be predicted with sufficient accuracy from milk MIR spectra to be further considered. Consequently, MIR spectrometry can bring valuable information regarding the occurrence of energy deficit, ketosis, and mastitis in dairy cows, which in turn have major influences on their fertility and survival.

Tumor lysis syndrome in patients with acute myeloid leukemia treated with venetoclax and hypomethylating agents with or without dose ramp-up.

Venetoclax with hypomethylating agents (HMAs) is an important treatment for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. However, there is limited data on the safety of venetoclax without a dose ramp-up in patients with AML. A retrospective cohort analysis of patients with AML treated with HMA/venetoclax (HMA/Ven) with or without a dose ramp-up, or HMA alone from 6/30/2014-8/22/2022 was conducted. The primary endpoint was the incidence of laboratory and/or clinical tumor lysis syndrome (TLS) by day 10. Of 225 patients, 111 patients received HMA alone or HMA/Ven with a dose ramp-up and 114 received HMA/Ven with no dose ramp-up. The incidence of TLS was similar between the control and no dose ramp-up groups, with rates of 5.4% and 5.3% respectively (p = 0.962). TLS incidence was comparable in patients with and without a dose ramp-up, suggesting that a dose ramp-up may not be mandatory in patients with AML.

Real-world outcomes with immunosuppressive therapy for aplastic anemia in patients treated at the University of Michigan.

Aplastic anemia (AA) is a rare bone marrow failure disorder that is treated with either allogeneic stem cell transplant or immunosuppressive therapy (IST) consisting of antithymocyte globulin (ATG), cyclosporine (CSA), and eltrombopag. While outcomes are favorable in younger patients, older patients (>60) have significantly worse long-term survival. The dose of ATG is often reduced in older patients and those with multiple comorbidities given concerns for tolerability. The efficacy and safety of dose-attenuated IST in this population is largely undescribed. We performed a retrospective review of patients with AA treated with IST. Our analysis was confounded by changes in practice patterns and the introduction of eltrombopag. We identified 53 patients >60 years old, of which, 20 received dose-attenuated IST, with no statistically significant difference in overall survival between full and attenuated dose cohorts. Overall response rates in both cohorts were similar at 6 months at 71% and 68%. There were more documented infectious complications in the full dose cohort (13 vs. 3). This supports the consideration of dose-attenuated IST in older patients with concerns about tolerance of IST. Lastly, our data confirmed favorable outcomes of younger patients receiving IST, especially in combination with eltrombopag.

Excess pancreatic cancer risk due to smoking and modifying effect of quitting smoking: The Multiethnic Cohort Study.

PURPOSE: Risk factors for pancreatic cancer include racial/ethnic disparities and smoking. However, risk trajectories by smoking history and race/ethnicity are unknown. We examined the association of smoking with pancreatic cancer by race/ethnicity to generate age-specific incidence estimates by smoking history. METHODS: We modeled pancreatic cancer incidence by race/ethnicity, age, pack-years, and years-quit using an excess relative risk model for 182,011 Multiethnic Cohort participants. We tested heterogeneity of smoking variables and pancreatic cancer by race/ethnicity and predicted incidence by smoking history. RESULTS: We identified 1,831 incident pancreatic cancer cases over an average 19.3 years of follow-up. Associations of pack-years (p interaction by race/ethnicity = 0.41) and years-quit (p interaction = 0.83) with pancreatic cancer did not differ by race/ethnicity. Fifty pack-years smoked was associated with 91% increased risk (95% CI 54%, 127%) relative to never smokers in the combined sample. Every year quit corresponded to 9% decreased excess risk (95% CI 2%, 15%) from pack-years smoked. Differences in baseline pancreatic cancer risk across racial/ethnic groups (p < 0.001) translated to large differences in risk for smokers at older ages across racial/ethnic groups (65-122 cases per 100,000 at age 70). CONCLUSION: Smoking pack-years were positively associated with elevated pancreatic cancer risk. Predicted risk trajectories showed a high impact of smoking cessation at < 65 years. Although we did not identify significant heterogeneity in the association of pack-years or years quit with pancreatic cancer risk, current smoker risk varied greatly by race/ethnicity in later life due to large differences in baseline risk.

Aryl Annulation: A Powerful Simplifying Retrosynthetic Disconnection.

Retrosynthetic deconstruction of a core aromatic ring is an especially simplifying retrosynthetic step, reducing the complexity of the precursor synthetic target. Moreover, when implemented to provide a penultimate intermediate, it enables late-stage divergent aryl introductions, permitting deep-seated core aryl modifications ordinarily accessible only by independent synthesis. Herein, we highlight the use of a ketone carbonyl group as the functionality to direct such late-stage divergent aryl introductions onto a penultimate intermediate with a projected application in the total synthesis of vinblastine and its presently inaccessible analogs containing indole replacements. Although the studies highlight this presently unconventional strategy with an especially challenging target in mind, the increase in molecular complexity (intricacy) established by the synthetic implementation of the powerful retrosynthetic disconnection, the use of a ketone as the precursor enabling functionality, and with adoption of either conventional or new wave (hetero)aromatic annulations combine to define a general and powerful strategy suited for wide-spread implementation with near limitless scope in target diversification.

Genetic risk converges on regulatory networks mediating early type 2 diabetes.

Type 2 diabetes mellitus (T2D), a major cause of worldwide morbidity and mortality, is characterized by dysfunction of insulin-producing pancreatic islet ß cells1,2. T2D genome-wide association studies (GWAS) have identified hundreds of signals in non-coding and ß cell regulatory genomic regions, but deciphering their biological mechanisms remains challenging3-5. Here, to identify early disease-driving events, we performed traditional and multiplexed pancreatic tissue imaging, sorted-islet cell transcriptomics and islet functional analysis of early-stage T2D and control donors. By integrating diverse modalities, we show that early-stage T2D is characterized by ß cell-intrinsic defects that can be proportioned into gene regulatory modules with enrichment in signals of genetic risk. After identifying the ß cell hub gene and transcription factor RFX6 within one such module, we demonstrated multiple layers of genetic risk that converge on an RFX6-mediated network to reduce insulin secretion by ß cells. RFX6 perturbation in primary human islet cells alters ß cell chromatin architecture at regions enriched for T2D GWAS signals, and population-scale genetic analyses causally link genetically predicted reduced RFX6 expression with increased T2D risk. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs and individuals, and thus we anticipate that this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits using GWAS data.

Predicting suicidal ideation 3 months following intensive posttraumatic stress disorder treatment.

OBJECTIVE: This study examined whether posttraumatic stress disorder (PTSD) symptom change during a 3- and 2-week intensive treatment program (ITP)-based in cognitive processing therapy was predictive of reduced suicidal ideation (SI) following treatment. METHOD: Veterans completed either a 3-week (n = 274, Mage = 42.35, SD = 9.43, 64.23% male, 65.33% White) or 2-week (n = 177, Mage = 42.90, SD = 9.81, 57.63% male, 66.67% White) ITP and self-reported PTSD, depression, and SI symptoms prior to, during, and 3 months following treatment. RESULTS: Mixed-effects-based two-stage location scale models assessed change in both overall PTSD severity over the course of the 3- and 2-week ITPs, as well as how this change predicted 3-month follow-up SI. Veterans in both programs reported moderate reductions in SI from baseline to posttreatment (3 weeks: d = 0.49; 2 weeks: d = 0.48). Of the 210 veterans across both programs who endorsed at least some SI at baseline, two-thirds (65.24%) reported reductions in SI posttreatment; three-quarters (74.45%) of these maintained posttreatment SI at 3-month follow-up that was lower than baseline levels. CONCLUSIONS: Both baseline SI and greater individual improvement in PTSD symptom severity during the ITPs were associated with lower SI at 3-month follow-up. Overall, study findings suggest that veterans with PTSD who also endorse SI can be successfully treated using the intensive delivery format and are likely to experience a reduction in SI both during and following treatment. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Using the Personalized Advantage Index to determine which veterans may benefit from more vs. less comprehensive intensive PTSD treatment programs.

Background: Intensive PTSD treatment programs (ITPs) are highly effective but tend to differ greatly in length and the number of adjunctive services that are provided in conjunction with evidence-based PTSD treatments. Individuals' treatment response to more or less comprehensive ITPs is poorly understood.Objective: To apply a machine learning-based decision-making model (the Personalized Advantage Index (PAI)), using clinical and demographic factors to predict response to more or less comprehensive ITPs.Methods: The PAI was developed and tested on a sample of 747 veterans with PTSD who completed a 3-week (more comprehensive; n = 360) or 2-week (less comprehensive; n = 387) ITP.Results: Approximately 12.32% of the sample had a PAI value that suggests that individuals would have experienced greater PTSD symptom change (5 points) on the PTSD Checklist for DSM-5 in either a more- or less comprehensive ITP. For individuals with the highest 25% of PAI values, effect sizes for the amount of PTSD symptom change between those in their optimal vs. non-optimal programs was d = 0.35.Conclusions: Although a minority was predicted to have benefited more from a program, there generally was not a substantial difference in predicted outcomes. Less comprehensive and thus more financially sustainable ITPs appear to work well for most individuals with PTSD.

A Personalized Advantage Index (PAI) was developed for a 3-week (more comprehensive) and a 2-week (less comprehensive) intensive PTSD treatment program to predict treatment responses.Using the PAI, approximately 12% of the sample was predicted to have experienced meaningfully greater in another program than the one in which they participated.Findings suggest a less comprehensive and more financially sustainable 2-week intensive PTSD treatment program would work well for most veterans in the present study.

Linkage Transformations in a Three-Dimensional Covalent Organic Framework for High-Capacity Adsorption of Perfluoroalkyl Substances.

Despite their many advantages, covalent organic frameworks (COFs) built from three-dimensional monomers are synthetically difficult to functionalize. Herein, we provide a new synthetic approach to the functionalization of a three-dimensional covalent organic framework (COF-300) by using a series of solid-state linkage transformations. By reducing the imine linkages of the framework to amine linkages, we produced a more hydrolytically stable material and liberated a nucleophilic amino group, poised for further functionalization. We then treated the amine-linked COF with diverse electrophiles to generate a library of functionalized materials, which we tested for their ability to adsorb perfluoroalkyl substances (PFAS) from water. The framework functionalized with dimethylammonium groups, COF-300-dimethyl, adsorbed more than 250 mg of perfluorooctanoic acid (PFOA) per 1 g of COF, which represents an approximately 14,500-fold improvement over that of COF-300 and underscores the importance of electrostatic interactions to PFAS adsorption performance. This work provides a conceptually new approach to the design and synthesis of functional three-dimensional COFs.

Aspacytarabine for the treatment of patients with AML unfit for intensive chemotherapy: a phase 2 study.

High-dose cytarabine is associated with gastrointestinal and cerebellar toxicity, precluding its use for older or unfit patients with acute myeloid leukemia (AML). Aspacytarabine, an inactive prodrug of cytarabine, was evaluated as monotherapy in a phase 2b study of patients unfit for intensive chemotherapy (NCT03435848). Sixty-five patients with AML were treated with aspacytarabine 4.5 g/m2 per day (equimolar to 3 g/m2 per day cytarabine) for 6 doses per treatment. The median age was 75 years; 60.6% of patients had de novo AML, 28.8% had AML secondary to myelodysplastic syndrome, and 10.6% had therapy-related AML. Overall, 36.9% achieved complete remission (CR) with full count recovery. CR rates in patients with secondary AML, patients with prior treatment with hypomethylating agents, and patients with TP53 mutation were 26.7%, 25%, and 36%, respectively. Median overall survival was 9 months (range, 6-15.9) and was not reached among responders. Hematologic recovery was observed in all responding patients by day 26 without prolonged cytopenias. Adverse events typically precluding the use of high-dose cytarabine in older or unfit patients were not observed. These data suggest that aspacytarabine may be an effective regimen with a reduction in the attendant toxicities associated with high-dose cytarabine, an important consideration when treating AML and other hematologic disorders that use high-dose cytarabine. This trial was registered at www.clinicaltrials.gov as #NCT03435848.

Tetrachlorovancomycin: Total Synthesis of a Designed Glycopeptide Antibiotic of Reduced Synthetic Complexity.

A technically straightforward total synthesis of a new class of vancomycin analogues of reduced synthetic complexity was developed that provided tetrachlorovancomycin (1, LLS = 15 steps, 15% overall yield) and its precursor aglycon 29 (nearly 20% overall yield). The class retains all the intricate vancomycin structural features that contribute to its target binding affinity and selectivity, maintains the antimicrobial activity of vancomycin, and achieves the simplification by an unusual addition, not removal, of benign substituents to the core structure. The modification, accomplished by addition of two aryl chloride substituents to provide 1, permitted a streamlined total synthesis of the new glycopeptide antibiotic class by removing the challenges associated with CD and DE ring system atropisomer stereochemical control. This also enabled their simultaneous and further-activated SNAr macrocyclizations that establish the tricyclic skeleton of 1. Key elements of the approach include catalyst-controlled diastereoselective formation of the AB biaryl axis of chirality (>30:1 dr), an essentially instantaneous macrolactamization of the AB ring system free of competitive epimerization (>30:1 dr), racemization free coupling of the E ring tetrapeptide, room temperature simultaneous CD and DE ring system cyclizations, a highly refined 4-step conversion of the cyclization product to the aglycon, and a protecting-group-free one-pot enzymatic glycosylation for disaccharide introduction. In addition to the antimicrobial evaluation of tetrachlorovancomycin (1), the preparation of key peripherally modified derivatives, which introduce independent and synergistic mechanisms of action, revealed their exceptional antimicrobial potency and provide the foundation for future use of this new class of synthetic glycopeptide analogues.

The Influence of Glenoid Bone Loss and Graft Positioning on Graft and Cartilage Contact Pressures After the Latarjet Procedure.

BACKGROUND: Glenohumeral joint contact loading before and after glenoid bone grafting for recurrent anterior instability remains poorly understood. PURPOSE: To develop a computational model to evaluate the influence of glenoid bone loss and graft positioning on graft and cartilage contact pressures after the Latarjet procedure. STUDY DESIGN: Controlled laboratory study. METHODS: A finite element model of the shoulder was developed using kinematics, muscle and glenohumeral joint loading of 6 male participants. Muscle and joint forces at 90° of abduction and external rotation were calculated and employed in simulations of the native shoulder, as well as the shoulder with a Bankart lesion, 10% and 25% glenoid bone loss, and after the Latarjet procedure. RESULTS: A Bankart lesion as well as glenoid bone loss of 10% and 25% significantly increased glenoid and humeral cartilage contact pressures compared with the native shoulder (P < .05). The Latarjet procedure did not significantly increase glenoid cartilage contact pressure. With 25% glenoid bone loss, the Latarjet procedure with a graft flush with the glenoid and the humerus positioned at the glenoid half-width resulted in significantly increased humeral cartilage contact pressure compared with that preoperatively (P = .023). Under the same condition, medializing the graft by 1 mm resulted in humeral cartilage contact pressure comparable with that preoperatively (P = .097). Graft lateralization by 1 mm resulted in significantly increased humeral cartilage contact pressure in both glenoid bone loss conditions (P < .05). CONCLUSION: This modeling study showed that labral damage and greater glenoid bone loss significantly increased glenoid and humeral cartilage contact pressures in the shoulder. The Latarjet procedure may mitigate this to an extent, although glenoid and humeral contact loading was sensitive to graft placement. CLINICAL RELEVANCE: The Latarjet procedure with a correctly positioned graft should not lead to increased glenohumeral joint contact loading. The present study suggests that lateral graft overhang should be avoided, and in the situation of large glenoid bone defects, slight medialization (ie, 1 mm) of the graft may help to mitigate glenohumeral joint contact overloading.