Development and validation of machine-learning algorithms predicting retention, overdoses, and all-cause mortality among US military veterans treated with buprenorphine for opioid use disorder.

BACKGROUND: Buprenorphine for opioid use disorder (B-MOUD) is essential to improving patient outcomes; however, retention is essential. OBJECTIVE: To develop and validate machine-learning algorithms predicting retention, overdoses, and all-cause mortality among US military veterans initiating B-MOUD. METHODS: Veterans initiating B-MOUD from fiscal years 2006-2020 were identified. Veterans' B-MOUD episodes were randomly divided into training (80%;n = 45,238) and testing samples (20%;n = 11,309). Candidate algorithms [multiple logistic regression, least absolute shrinkage and selection operator regression, random forest (RF), gradient boosting machine (GBM), and deep neural network (DNN)] were used to build and validate classification models to predict six binary outcomes: 1) B-MOUD retention, 2) any overdose, 3) opioid-related overdose, 4) overdose death, 5) opioid overdose death, and 6) all-cause mortality. Model performance was assessed using standard classification statistics [e.g., area under the receiver operating characteristic curve (AUC-ROC)]. RESULTS: Episodes in the training sample were 93.0% male, 78.0% White, 72.3% unemployed, and 48.3% had a concurrent drug use disorder. The GBM model slightly outperformed others in predicting B-MOUD retention (AUC-ROC = 0.72). RF models outperformed others in predicting any overdose (AUC-ROC = 0.77) and opioid overdose (AUC-ROC = 0.77). RF and GBM outperformed other models for overdose death (AUC-ROC = 0.74 for both), and RF and DNN outperformed other models for opioid overdose death (RF AUC-ROC = 0.79; DNN AUC-ROC = 0.78). RF and GBM also outperformed other models for all-cause mortality (AUC-ROC = 0.76 for both). No single predictor accounted for >3% of the model's variance. CONCLUSIONS: Machine-learning algorithms can accurately predict OUD-related outcomes with moderate predictive performance; however, prediction of these outcomes is driven by many characteristics.

CUREs for high-level Galectin-3 expression.

Galectins are a large and diverse protein family defined by the presence of a carbohydrate recognition domain (CRD) that binds ß-galactosides. They play important roles in early development, tissue regeneration, immune homeostasis, pathogen recognition, and cancer. In many cases, studies that examine galectin biology and the effect of manipulating galectins are aided by, or require the ability to express and purify, specific members of the galectin family. In many cases, E. coli is employed as a heterologous expression system, and galectin expression is induced with isopropyl ß-galactoside (IPTG). Here, we show that galectin-3 recognizes IPTG with micromolar affinity and that as IPTG induces expression, newly synthesized galectin can bind and sequester cytosolic IPTG, potentially repressing further expression. To circumvent this putative inhibitory feedback loop, we utilized an autoinduction protocol that lacks IPTG, leading to significantly increased yields of galectin-3. Much of this work was done within the context of a course-based undergraduate research experience, indicating the ease and reproducibility of the resulting expression and purification protocols.

Cardiovascular, Kidney Failure, and All-Cause Mortality Events in Patients with Focal Segmental Glomerulosclerosis in a U.S. Real-World Database.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) leads to proteinuria and progressive decline in glomerular filtration rate which correlates with kidney failure and increased cardiovascular risk. The purpose of this study was to estimate the effects of proteinuria on kidney failure status/all-cause mortality and cardiovascular disease events/all-cause mortality, as well as the relationship between progression to kidney failure and occurrence of cardiovascular disease/mortality events among adult patients (≥18 years old) with FSGS. METHODS: This was an observational, retrospective cohort study utilizing Optum® de-identified Market Clarity Data and proprietary Natural Language Processing (NLP) data. The study period was from January 1, 2007 through March 31, 2021, with patients in the overall cohort being identified from July 1, 2007 through March 31, 2021. The index date was the first FSGS ICD-10 diagnosis code or FSGS-related NLP term within the identification period. RESULTS: Elevated proteinuria >1.5 g/g and ≥3.5 g/g increased risk for kidney failure/all-cause mortality (adjusted hazard ratio [95% CI]: 2.34 [1.99-2.74] and 2.44 [2.09-2.84], respectively) and cardiovascular disease/all-cause mortality (adjusted hazard ratio [95% CI]: 2.11 [1.38-3.22] and 2.27 [1.44-3.58], respectively). Progression to kidney failure was also associated with a higher risk of cardiovascular disease/all-cause mortality (adjusted hazard ratio [95% CI]: 3.04 [2.66-3.48]. CONCLUSIONS: A significant proportion of FSGS patients experience kidney failure and cardiovascular disease events. Elevated proteinuria and progression to kidney failure were associated with a higher risk of cardiovascular disease/all-cause mortality events, and, elevated pre-kidney failure proteinuria was associated with progression to kidney failure/all-cause mortality events. Treatments that meaningfully reduce proteinuria and slow the decline in glomerular filtration rate have the potential to reduce the risk of cardiovascular disease, kidney failure and early mortality in patients with FSGS.

Kidney Failure Attributed to Focal Segmental Glomerulosclerosis: A USRDS Retrospective Cohort Study of Epidemiology, Treatment Modalities, and Economic Burden.

Rationale & Objective: This study describes the epidemiology, characteristics, and clinical outcomes of patients with focal segmental glomerulosclerosis (FSGS)-attributed kidney failure in the US Renal Data System (USRDS) during 2008-2018, and health care resource utilization and costs among those with Medicare-linked data. Study Design: This was a retrospective cohort study. Setting & Population: Patients with FSGS-attributed kidney failure in the USRDS were enrolled in the study. Outcomes: The outcomes were as follows: Prevalence and incidence, clinical and demographic characteristics, time to kidney transplant or death, health care resource utilization, and direct health care costs. Analytical Approach: Patients with FSGS as the primary cause of kidney failure were followed from USRDS registration (index date) until death or data end. Prevalence and incidence were calculated per 1,000,000 US persons. Patient characteristics at index and treatment modalities during follow-up were described. Time to kidney transplant or death was assessed with Kaplan-Meier and competing risk analyses. Health care resource utilization and costs were reported among patients with 1 year Medicare Part A+B coverage postindex, including (Medicare Coverage subgroup) or excluding (1-year Medicare Coverage subgroup) those who died. Results: The FSGS cohort and Medicare Coverage and 1-year Medicare Coverage subgroups included 25,699, 6,340, and 5,575 patients, respectively. Mean annual period prevalence and incidence rates of FSGS-attributed kidney failure were 87.6 and 7.5 per 1,000,000 US persons, respectively. Initial treatment for most patients was in-center hemodialysis (72.1%), whereas 7.3% received kidney transplant. Accounting for competing risk of death, year 1 and 5 kidney transplant rates were 15% and 34%, respectively. In the Medicare Coverage and 1-year Medicare Coverage subgroups, 76.6% and 74.2% required inpatient admission, 69.9% and 67.3% visited the emergency room, and mean monthly health care costs were $6,752 and $5,575 in the year postindex, respectively. Limitations: Drug costs may be underestimated because Medicare Part D coverage was not required; kidney acquisition costs were not available. Conclusions: FSGS-attributed kidney failure is associated with substantial clinical and economic burden, prompting the need for novel therapies for FSGS to delay kidney failure.

This study of patients in the US Renal Data System observed increasing prevalence and fluctuating incidence of focal segmental glomerulosclerosis (FSGS)-attributed kidney failure from 2008 to 2018. Patients experienced a high clinical burden, including more than 3 years of treatment with dialysis, one-third receiving a kidney transplant, and one-third dying during follow-up. In the first year after US Renal Data System registration, three-quarters of patients with Medicare coverage required hospitalization, and more than two-thirds visited the emergency room. The total annual health care costs were >$68,000 per patient with FSGS-attributed kidney failure, underscoring the high economic burden of this disorder and the treatments required to sustain life. Novel therapies for FSGS are needed to delay or ideally prevent the need dialysis and transplantation after kidney failure.

Influence of particle size and origin of field peas on apparent ileal digestibility of starch and amino acids and standardized ileal digestibility of amino acids when fed to growing pigs.

The objective was to test the hypothesis that particle size and origin of field peas influence the apparent ileal digestibility (AID) of starch, crude protein (CP), and amino acids (AA) and the standardized ileal digestibility (SID) of AA. Three sources of field peas were procured. One source was from the United States and two sources were from Canada. The U.S. source and one of the sources from Canada (i.e., Canada 1) were each divided into two batches and ground to achieve a target particle size of 250 or 450 µm, whereas the other source from Canada (i.e., Canada 2) was only ground to a target particle size of 250 µm. Each batch of field peas was included in one diet as the only source of AA. An N-free diet was used to determine the basal endogenous losses of CP and AA. Six barrows (initial weight: 50.5 kg; SD = 3.7) that had a T-cannula installed in the distal ileum were randomly allotted to a 6 × 6 Latin square design with six diets and six 7-d periods. Ileal digesta from pigs were collected for 2 d after 5 d of adaptation. Data were analyzed using a statistical model that included batch of field peas as the fixed effect and animal and period as the random effects. Contrast statements were used to analyze the effects of particle size, origin, and the interaction between particle size and origin. Results indicated that the AID of starch was increased by reducing the particle size in the U.S. source of field peas, but that was not the case for the Canada 1 source (interaction; P < 0.001). Particle size did not influence the AID of CP or AA, but the Canada 2 source of field peas had greater (P < 0.05) AID of Trp, Ala, Cys, Gly, and Tyr than the field peas from the United States. The SID of CP and AA was also not affected by the particle size of field peas. The SID of CP and Trp was greater (P < 0.05), and the SID of His, Ile, and Thr tended (P < 0.10) to be greater in the Canada 2 source compared with the U.S. source, but no differences between the two Canada sources were observed. In conclusion, a few differences in SID of AA between field peas produced in the United States and peas produced in Canada were observed, but there was no effect on SID of AA of reducing the particle size of field peas from 450 to 250 µm, whereas the AID of starch increased by reducing the particle size only in the field peas from the United States.

Increased risk of poor clinical outcome in COVID-19 patients with diabetes mellitus and in-hospital mortality predictors: A retrospective cohort from a tertiary hospital in Indonesia.

AIM: To determine association between diabetes in confirmed cases of COVID-19 and intensive care admission and in-hospital mortality, evaluate several laboratory parameters as mortality predictor and develop predictors of in-hospital mortality among diabetics with COVID-19. METHODS: This retrospective cohort recruited all cases of COVID-19 hospitalized in Fatmawati General Hospital from March to October 2020. Inclusion criterion was RT-PCR confirmed cases of COVID-19 who aged 18 years and older while exclusion criteria were incomplete medical record or cannot be found and pregnant women. RESULTS: We enrolled 506 participants to this study with median age of 51 years (IQR:22), female (56.32%), and diabetes (28.46%). Diabetes increased intensive care admission (adjusted OR: 2.57; 95% CI: 3.52-10.43) and in-hospital mortality (adjusted OR: 2.50; 95% CI: 1.61-3.89). In predicting in-hospital mortality, ferritin and lactate dehydrogenase offered an acceptable discrimination, AUC: 0.71 (95% CI: 0.62-0.79) and AUC: 0.70 (95% CI: 0.61-0.78), respectively. The optimal cut-off of predicting mortality for ferritin was 786 g/mL and for LDH was 514.94 u/L. Factors include age above 70 years old, RBGs level on admission above 250 mg/dL or below 140 mg/dL, ferritin level above 786 ng/mL and presence of ARDS increased the odds of mortality among individuals with diabetes. CONCLUSIONS: Diabetes increases risk intensive care admission and in hospital mortality in COVID-19. Multivariate analysis showed that older age, RBG on admission, high ferritin level, presence of ARDS increased the odds of mortality among individuals with diabetes.

Viruses of the Turriviridae: an emerging model system for studying archaeal virus-host interactions.

Viruses have played a central role in the evolution and ecology of cellular life since it first arose. Investigations into viral molecular biology and ecological dynamics have propelled abundant progress in our understanding of living systems, including genetic inheritance, cellular signaling and trafficking, and organismal development. As well, the discovery of viral lineages that infect members of all three domains suggest that these lineages originated at the earliest stages of biological evolution. Research into these viruses is helping to elucidate the conditions under which life arose, and the dynamics that directed its early development. Archaeal viruses have only recently become a subject of intense study, but investigations have already produced intriguing and exciting results. STIV was originally discovered in Yellowstone National Park and has been the focus of concentrated research. Through this research, a viral genetic system was created, a novel lysis mechanism was discovered, and the interaction of the virus with cellular ESCRT machinery was revealed. This review will summarize the discoveries within this group of viruses and will also discuss future work.

Computational engineering of previously crystallized pyruvate formate-lyase activating enzyme reveals insights into SAM binding and reductive cleavage.

Radical S-adenosyl-l-methionine (SAM) enzymes are ubiquitous in nature and carry out a broad variety of difficult chemical transformations initiated by hydrogen atom abstraction. Although numerous radical SAM (RS) enzymes have been structurally characterized, many prove recalcitrant to crystallization needed for atomic-level structure determination using X-ray crystallography, and even those that have been crystallized for an initial study can be difficult to recrystallize for further structural work. We present here a method for computationally engineering previously observed crystallographic contacts and employ it to obtain more reproducible crystallization of the RS enzyme pyruvate formate-lyase activating enzyme (PFL-AE). We show that the computationally engineered variant binds a typical RS [4Fe-4S]2+/+ cluster that binds SAM, with electron paramagnetic resonance properties indistinguishable from the native PFL-AE. The variant also retains the typical PFL-AE catalytic activity, as evidenced by the characteristic glycyl radical electron paramagnetic resonance signal observed upon incubation of the PFL-AE variant with reducing agent, SAM, and PFL. The PFL-AE variant was also crystallized in the [4Fe-4S]2+ state with SAM bound, providing a new high-resolution structure of the SAM complex in the absence of substrate. Finally, by incubating such a crystal in a solution of sodium dithionite, the reductive cleavage of SAM is triggered, providing us with a structure in which the SAM cleavage products 5'-deoxyadenosine and methionine are bound in the active site. We propose that the methods described herein may be useful in the structural characterization of other difficult-to-resolve proteins.

The Open Virtual Mirror Framework for enfacement illusions : Enhancing the sense of agency with avatars that imitate facial expressions.

Enfacement illusions are traditionally elicited by visuo-tactile stimulation, but more active paradigms become possible through the usage of virtual reality techniques. For instance, virtual mirrors have been recently proposed to induce enfacement by visuo-motor stimulation. In a virtual mirror experiment, participants interact with an avatar that imitates their facial movements. The active control over the avatar greatly enhances the sense of agency, which is an important ingredient for successful enfacement illusion induction. Due to technological challenges, most virtual mirrors so far were limited to the imitation of the participant's head pose, i.e., its location and rotation. However, stronger experiences of agency can be expected by an increase in the avatar's mimicking abilities. We here present a new open-source framework for virtual mirror experiments, which we call the Open Virtual Mirror Framework (OVMF). The OVMF can track and imitate a large range of facial movements, including pose and expressions. It has been designed to run on standard computer hardware and easily interfaces with existing toolboxes for psychological experimentation, while satisfying the requirement of a tightly controlled experimental setup. Further, it is designed to enable convenient extension of its core functionality such that it can be flexibly adjusted to many different experimental paradigms. We demonstrate the usage of the OVMF and experimentally validate its ability to elicit experiences of agency over an avatar, concluding that the OVMF can serve as a reference for future experiments and that it provides high potential to stimulate new directions in enfacement research and beyond.

Design and validation of a medical robotic device system to control two collaborative robots for ultrasound-guided needle insertions.

The percutaneous biopsy is a critical intervention for diagnosis and staging in cancer therapy. Robotic systems can improve the efficiency and outcome of such procedures while alleviating stress for physicians and patients. However, the high complexity of operation and the limited possibilities for robotic integration in the operating room (OR) decrease user acceptance and the number of deployed robots. Collaborative systems and standardized device communication may provide approaches to overcome named problems. Derived from the IEEE 11073 SDC standard terminology of medical device systems, we designed and validated a medical robotic device system (MERODES) to access and control a collaborative setup of two KUKA robots for ultrasound-guided needle insertions. The system is based on a novel standard for service-oriented device connectivity and utilizes collaborative principles to enhance user experience. Implementing separated workflow applications allows for a flexible system setup and configuration. The system was validated in three separate test scenarios to measure accuracies for 1) co-registration, 2) needle target planning in a water bath and 3) in an abdominal phantom. The co-registration accuracy averaged 0.94 ± 0.42 mm. The positioning errors ranged from 0.86 ± 0.42 to 1.19 ± 0.70 mm in the water bath setup and from 1.69 ± 0.92 to 1.96 ± 0.86 mm in the phantom. The presented results serve as a proof-of-concept and add to the current state of the art to alleviate system deployment and fast configuration for percutaneous robotic interventions.

Postreperfusion Syndrome in Liver Transplant: A Risk Factor for Acute Kidney Failure: A Retrospective Analysis.

The maximum expression of hemodynamic instability during liver transplant is the so-called postreperfusion syndrome (PRS) that increases both overall mortality and postoperative complications. It was first defined by Aggarwal et al in 1987, but the results are still conflicting when establishing the relationship between PRS and acute kidney failure (AKF). We conducted a retrospective observational study of transplant recipients with deceased-donor liver grafts between January 2002 and December 2018. We analyzed the incidence of PRS and its potential negative impact over kidney function. A total of 551 transplants were analyzed. PRS was recorded in 130 patients (23.6%). The incidence of AKF was 61.5%. A total of 111 patients required kidney replacement therapy (32.7%). Regarding the severity of AKF, 128 patients were classified as acute kidney injury (AKI) 1 (23.2%), 76 as AKI 2 (13.8%), and 135 as AKI 3 (24.5%). In the group with PRS, 75.4% (n = 98) developed AKF vs 57.2% (n = 241) in the group without PRS. In the multivariate analysis we found a relationship between PRS and AKF with an odds ratio of 2.18 (95% CI, 1.30-3.64; P = .003), once adjusted by the length of the anhepatic phase, donor age, Model for End-Stage Liver Disease score, history of ascites, and need for early surgical reintervention. The incidence of AKF decreased (44.5%) ever since the implementation of delayed calcineurin inhibitors therapy and piggyback surgical technique, but a clear influence of the occurrence of PRS on the development of AKF is still observed, with an OR of 3.78 (95% CI, 1.92-7.43; P < .001), once adjusted by albumin and hemoglobin levels, Model for End-Stage Liver Disease score, and Child classification.

Water-Based Dynamic Depsipeptide Chemistry: Building Block Recycling and Oligomer Distribution Control Using Hydration-Dehydration Cycles.

The high kinetic barrier to amide bond formation has historically placed narrow constraints on its utility in reversible chemistry applications. Slow kinetics has limited the use of amides for the generation of diverse combinatorial libraries and selection of target molecules. Current strategies for peptide-based dynamic chemistries require the use of nonpolar co-solvents or catalysts or the incorporation of functional groups that facilitate dynamic chemistry between peptides. In light of these limitations, we explored the use of depsipeptides: biorelevant copolymers of amino and hydroxy acids that would circumvent the challenges associated with dynamic peptide chemistry. Here, we describe a model system of N-(α-hydroxyacyl)-amino acid building blocks that reversibly polymerize to form depsipeptides when subjected to two-step evaporation-rehydration cycling under moderate conditions. The hydroxyl groups of these units allow for dynamic ester chemistry between short peptide segments through unmodified carboxyl termini. Selective recycling of building blocks is achieved by exploiting the differential hydrolytic lifetimes of depsipeptide amide and ester bonds, which we show are controllable by adjusting the solution pH, temperature, and time as well as the building blocks' side chains. We demonstrate that the polymerization and breakdown of the depsipeptides are facilitated by cyclic morpholinedione intermediates, and further show how structural properties dictate half-lives and product oligomer distributions using multifunctional building blocks. These results establish a cyclic mode of ester-based reversible depsipeptide formation that temporally separates the polymerization and depolymerization steps for the building blocks and may have implications for prebiotic polymer chemical evolution.

Bull horn vascular injuries in popular celebrations: A 40-year retrospective analysis.

OBJECTIVE: The aim of the present study was to analyze and report the clinical presentation and treatment at a single center of bull horn vascular injuries (BHVIs) that had occurred during popular celebrations in the past four decades. Thus, we investigated BHVIs in a high-volume academic center in Spain. METHODS: All the patients with a BHVI admitted between January 1980 and January 2021 were retrospectively enrolled in the present study. Data collection included demographics, injury profile, and outcomes. The primary outcome was in-hospital mortality. The hospital and intensive care unit lengths of stay, rates of reintervention, postoperative complications, and mortality were also analyzed. Data were collected from the electronic and/or digitized medical history records. RESULTS: A total of 296 patients were included in the present analysis. The mean patient age was 33.4 years (range, 17-91 years), and 93.9% were men. Of the 296 patients, 126 (42.6%) had experienced a complication, and 57 (19.3%) had required reoperation. The overall in-hospital mortality was 5.1%. The risk factors for mortality were arterial injury (odds ratio [OR], 5.11; 95% confidence interval [CI], 1.45-23.3; P = .009), injury to the abdominal region (OR, 3.45; 95% CI, 1.11-14.54; P = .038), American Society of Anesthesiologists classification IV (OR, 3.27; 95% CI, 1.87-17.83; P = .004), and age >65 years (OR, 3.13; 95% CI, 1.38-10.04; P = .001). Statistically significant differences were found between bull horn arterial injuries and arterial plus concomitant venous injuries in the intensive care unit length of stay (4.9 ± 13.3 days vs 3.1 ± 12.6 days; P = .024), hospital length of stay (12.0 ± 8.2 days vs 10.1 ± 6.3 days; P = .007), postoperative complications (45.2% vs 30.6%; P = .002), and mortality (3.4% vs 1.9%; P = .001). CONCLUSIONS: The morbidity and mortality from BHVIs have remained high for the past 40 years. Popular celebrations with bulls constitute an etiology of vascular trauma that can have dire consequences.

Cyclic Tetra-Adenylate (cA4) Recognition by Csa3; Implications for an Integrated Class 1 CRISPR-Cas Immune Response in Saccharolobus solfataricus.

Csa3 family transcription factors are ancillary CRISPR-associated proteins composed of N-terminal CARF domains and C-terminal winged helix-turn-helix domains. The activity of Csa3 transcription factors is thought to be controlled by cyclic oligoadenyate (cOA) second messengers produced by type III CRISPR-Cas surveillance complexes. Here we show that Saccharolobus solfataricus Csa3a recognizes cyclic tetra-adenylate (cA4) and that Csa3a lacks self-regulating "ring nuclease" activity present in some other CARF domain proteins. The crystal structure of the Csa3a/cA4 complex was also determined and the structural and thermodynamic basis for cA4 recognition are described, as are conformational changes in Csa3a associated with cA4 binding. We also characterized the effect of cA4 on recognition of putative DNA binding sites. Csa3a binds to putative promoter sequences in a nonspecific, cooperative and cA4-independent manner, suggesting a more complex mode of transcriptional regulation. We conclude the Csa3a/cA4 interaction represents a nexus between the type I and type III CRISPR-Cas systems present in S. solfataricus, and discuss the role of the Csa3/cA4 interaction in coordinating different arms of this integrated class 1 immune system to mount a synergistic, highly orchestrated immune response.

A Quality Improvement Project to Reduce Antibiotic Utilization and Ancillary Laboratory Tests in the Appraisal of Early-Onset Sepsis in the NICU.

BACKGROUND: Diagnosis and treatment of early-onset sepsis (EOS) of the newborn remains a controversial issue among providers due to the non-infectious symptomology which exists in the newborn period. METHODS: Pre/post interventional quality improvement project in a level III NICU to reduce antibiotic utilization and ancillary laboratory tests with the introduction of an evidence-based guideline for the evaluation of EOS in the NICU. RESULTS: Primary outcome measures include mean number of empiric antibiotic treatment days and utilization rate (AUR), number of laboratory tests ordered, and incidence of unwarranted antibiotic therapy beyond the 48-h rule out period. Mean empiric antibiotic treatment days decreased from 2.94 to 1.58 days and overall antibiotic use decreased from 73.7% to 57.1%. Likewise, the mean AUR decreased from 212.5 to 147.6 days of therapy per 1000 patient days. There was an 86% decline in the number of ancillary tests and unwarranted antibiotic use beyond 48- h was reduced by 74%. DISCUSSION: Guidelines for EOS of the newborn should include a thorough baseline evaluation of the drivers of antibiotic use to create an evidence-based foundation. Reducing unnecessary antibiotic use and EOS evaluations in a safe and effective manner have the potential to lower consumer and healthcare expenditures while improving the long-term health of the newborn in the NICU. CONCLUSIONS: These findings emphasize the importance of implementing an evidence-based protocol for antibiotic stewardship in the NICU. With further research there is the potential to improve the healthcare of newborns while reducing expenditures in a safe, effective evaluation of EOS in the newborn population.

A model based on the quantification of complement C4c, CYFRA 21-1 and CRP exhibits high specificity for the early diagnosis of lung cancer.

Lung cancer screening detects early-stage cancers, but also a large number of benign nodules. Molecular markers can help in the lung cancer screening process by refining inclusion criteria or guiding the management of indeterminate pulmonary nodules. In this study, we developed a diagnostic model based on the quantification in plasma of complement-derived fragment C4c, cytokeratin fragment 21-1 (CYFRA 21-1) and C-reactive protein (CRP). The model was first validated in two independent cohorts, and showed a good diagnostic performance across a range of lung tumor types, emphasizing its high specificity and positive predictive value. We next tested its utility in two clinically relevant contexts: assessment of lung cancer risk and nodule malignancy. The scores derived from the model were associated with a significantly higher risk of having lung cancer in asymptomatic individuals enrolled in a computed tomography (CT)-screening program (OR = 1.89; 95% CI = 1.20-2.97). Our model also served to discriminate between benign and malignant pulmonary nodules (AUC: 0.86; 95% CI = 0.80-0.92) with very good specificity (92%). Moreover, the model performed better in combination with clinical factors, and may be used to reclassify patients with intermediate-risk indeterminate pulmonary nodules into patients who require a more aggressive work-up. In conclusion, we propose a new diagnostic biomarker panel that may dictate which incidental or screening-detected pulmonary nodules require a more active work-up.

Practical setting and potential applications of interventions guided by PET/MRI.

Multimodality imaging has emerged from a vision thirty years ago to routine clinical use today. Positron emission tomography (PET)/magnetic resonance imaging (MRI) is still relatively new in this arena and particularly suitable for clinical research and technical development. PET/MRI-guidance for interventions opens up opportunities for novel treatments but at the same time demands certain technical and organizational requirements to be fulfilled. In this work, we aimed to demonstrate a practical setting and potential application of PET/MRI guidance of interventional procedures. The superior quantitative physiologic information of PET, the various unique imaging characteristics of MRI, and the reduced radiation exposure are the most relevant advantages of this technique. As a noninvasive interventional tool, focused ultrasound (FUS) ablation of tumor cells would benefit from PET/MRI for diagnostics, treatment planning and intervention. Yet, technical limitations might impeed preclinical research, given that PET/MRI sites are per se not designed as interventional suites. Nonetheless, several approaches have been offered in the past years to upgrade MRI suites for interventional purposes. Taking advantage of state of the art and easy-to-use technology it is possible to create a supporting infrastructure that is suitable for broad preclinical adaption. Several aspects are to be addressed, including remote control of the imaging system, display of the imaging results, communication technology, and implementation of additional devices such as a FUS platform and an MR-compatible robotic system for positioning of the FUS equipment. Feasibility could be demostrated with an examplary experimental setup for interventional PET/MRI. Most PET/MRI sites could allow for interventions with just a few add-ons and modifications, such as comunication, in room image display and sytems control. By unlocking this feature, and driving preclinical research in interventional PET/MRI, translation of the protocol and methodology into clinical settings seems feasible.