A Hybrid Type III Effectiveness-Implementation Trial to Optimize Medication Safety With Oral Antitumor Therapy in Real-World: The AMBORA Competence and Consultation Center.

PURPOSE: Implementation science endeavors to facilitate the translation of evidence-based research into clinical routine. The clinical pharmacological/pharmaceutical care program evaluated in the randomized AMBORA trial on medication safety with oral antitumor therapeutics (OAT) optimizes care delivery and provides significant benefits for patients, treatment teams, and health care systems. Thus, we aimed to investigate the implementation of this care program within the AMBORA Competence and Consultation Center (AMBORA Center). METHODS: The AMBORA Center within a University Comprehensive Cancer Center offered several services (eg, patient consultations) and was evaluated according to the RE-AIM framework. This multicenter hybrid type III trial focused on implementation outcomes (eg, patient recruitment, referring units, evaluation of services) while concurrently investigating effectiveness (eg, side effects, medication errors). Quantitative and qualitative assessments were combined. RESULTS: The AMBORA Center conducted over 800 consultations with 420 patients in seven institutions. The primary end point of counseling 70% of patients treated with OAT was not reached. Patients were referred by 15 treatment units compared with 11 units in the AMBORA trial. On the basis of heterogeneous referral rates and characteristics across the institutions, barriers and facilitators of the implementation process were derived. Several survey results (eg, stakeholder interviews, online/paper-based questionnaires) reflected a high appreciation of services by patients and health care professionals. The severity of 60.1% (178 of 296) of detected side effects improved, and 86.3% (297 of 344) of medication errors were resolved. CONCLUSION: Despite not reaching the primary implementation outcome, the AMBORA Center included more treatment units and demonstrated patient benefit of the AMBORA care program by meeting all effectiveness outcomes. We outlined quantitative and qualitative implementation characteristics to enhance outreach and foster further dissemination of centers to optimize medication safety with OAT.

The Conservative and Operative Treatment of Carpal Fractures.

BACKGROUND: Carpal fractures (incidence: 30-60 per 100 000 persons per year) are one of the more commonly overlooked fracture types. They can have serious consequences, as the use of the hand is indispensable in everyday life. In the following article, we present the elements of the diagnosis and treatment of fractures of the carpal bones. METHODS: This review is based on meta-analyses and randomized controlled trials (RCTs) published from 2013 to 2023 that were retrieved by a structured literature search, supplemented by guideline recommendations and expert consensus statements. In addition, data on the administrative prevalence of carpal fractures were obtained from the German Association of Statutory Health Insurance Physicians (Kassenärztliche Vereinigung, KV) and from the German Statutory Accident Insurance (Deutsche Gesetzliche Unfallversicherung, DGUV). RESULTS: The administrative prevalence of carpal fractures in 2022 was 44 496 outpatient cases (KV, DGUV) in one year. After clinical history-taking, physical examination and x-ray have been performed, thin-slice computed tomography is recommended as part of the diagnostic evaluation. Treatment recommendations are based on evidence of levels II to IV. Multiple RCTs have been carried out on the treatment of scaphoid fractures, and a clinical guideline exists. Proximal, dislocated and unstable scaphoid fractures should be treated surgically. Non-displaced or minimally displaced fractures of the middle third of the scaphoid bone require a shorter period of immobilization with surgical treatment (2-4 weeks) than with conservative treatment (6-8 weeks). The use of plaster casts that do not hinder elbow and thumb mobility yields healing rates similar to those obtained with the immobilization of both of these joints. Failure to treat an unrecognized scaphoid fracture can lead to pseudarthrosis, avascular bony necrosis, and misalignment. Other, rarer types of carpal fractures must be managed on an individual basis, as the available evidence is limited to expert consensus. CONCLUSION: Early recognition and appropriate treatment of carpal fractures lead to healing in more than 90% of cases. Although the available evidence on their proper treatment is growing, many questions are subject to expert consensus, and decisions about treatment must be made individually.

Initiative to deprescribe high-risk drugs for older adults presenting to the emergency department after falls.

BACKGROUND: Over 35 million falls occur in older adults annually and are associated with increased emergency department (ED) revisits and 1-year mortality. Despite associations between medications and falls, the prevalence of fall risk-increasing drugs remains high. Our objective was to implement an ED-based medication reconciliation for patients presenting after falls and determine whether an intervention targeting high-risk medications was related to decreased future falls. METHODS: This was an observational prospective cohort study at a single site in the United States. Adults 65 years and older presenting to the ED after falls had a pharmacist review their medicines. Pharmacists made recommendations to taper, stop, or discuss medications with the primary clinician. At 3, 6, and 12 months, we recorded the number of fall-related return ED visits and determined if recommended medication changes had been implemented. We compared the rate of return visits of patients who had followed the medication change recommendations and those who received recommendations but had no change in their medications using chi-square tests. RESULTS: A total of 577 patients (mean age 81 years, 63.6% female) were enrolled of 1509 potentially eligible patients. High-risk medications were identified in 310 patients (53.7%) who received medication recommendations. High-risk medications were associated with repeat fall-related visits at 12 months (risk difference 8.1% [95% confidence interval 0.97-15.0]). A total of 134 (43%) patients on high-risk medications had evidence of medication modification. At 12 months, there was no statistically significant difference in return fall visits between patients who had modifications to medications compared with those who had not implemented changes (p = 0.551). CONCLUSIONS: Our findings identified opportunities for medication optimization in over half of emergency visits for falls and demonstrated that medication counseling in the ED is feasible. However, evaluation of the effect on future falls was limited.

Point mutation in a virus-like capsid drives symmetry reduction to form tetrahedral cages.

Protein capsids are a widespread form of compartmentalization in nature. Icosahedral symmetry is ubiquitous in capsids derived from spherical viruses, as this geometry maximizes the internal volume that can be enclosed within. Despite the strong preference for icosahedral symmetry, we show that simple point mutations in a virus-like capsid can drive the assembly of unique symmetry-reduced structures. Starting with the encapsulin from Myxococcus xanthus, a 180-mer bacterial capsid that adopts the well-studied viral HK97 fold, we use mass photometry and native charge detection mass spectrometry to identify a triple histidine point mutant that forms smaller dimorphic assemblies. Using cryoelectron microscopy, we determine the structures of a precedented 60-mer icosahedral assembly and an unexpected 36-mer tetrahedron that features significant geometric rearrangements around a new interaction surface between capsid protomers. We subsequently find that the tetrahedral assembly can be generated by triple-point mutation to various amino acids and that even a single histidine point mutation is sufficient to form tetrahedra. These findings represent a unique example of tetrahedral geometry when surveying all characterized encapsulins, HK97-like capsids, or indeed any virus-derived capsids reported in the Protein Data Bank, revealing the surprising plasticity of capsid self-assembly that can be accessed through minimal changes in the protein sequence.

The macroecology of butyrate-producing bacteria via metagenomic assessment of butyrate production capacity.

Butyrate-producing bacteria are found in many outdoor ecosystems and host organisms, including humans, and are vital to ecosystem functionality and human health. These bacteria ferment organic matter, producing the short-chain fatty acid butyrate. However, the macroecological influences on their biogeographical distribution remain poorly resolved. Here we aimed to characterise their global distribution together with key explanatory climatic, geographical and physicochemical variables. We developed new normalised butyrate production capacity (BPC) indices derived from global metagenomic (n = 13,078) and Australia-wide soil 16S rRNA (n = 1331) data, using Geographic Information System (GIS) and modelling techniques to detail their ecological and biogeographical associations. The highest median BPC scores were found in anoxic and fermentative environments, including the human (BPC = 2.99) and non-human animal gut (BPC = 2.91), and in some plant-soil systems (BPC = 2.33). Within plant-soil systems, roots (BPC = 2.50) and rhizospheres (BPC = 2.34) had the highest median BPC scores. Among soil samples, geographical and climatic variables had the strongest overall effects on BPC scores (variable importance score range = 0.30-0.03), with human population density also making a notable contribution (variable importance score = 0.20). Higher BPC scores were in soils from seasonally productive sandy rangelands, temperate rural residential areas and sites with moderate-to-high soil iron concentrations. Abundances of butyrate-producing bacteria in outdoor soils followed complex ecological patterns influenced by geography, climate, soil chemistry and hydrological fluctuations. These new macroecological insights further our understanding of the ecological patterns of outdoor butyrate-producing bacteria, with implications for emerging microbially focused ecological and human health policies.

Physiological basis for atmospheric methane oxidation and methanotrophic growth on air.

Atmospheric methane oxidizing bacteria (atmMOB) constitute the sole biological sink for atmospheric methane. Still, the physiological basis allowing atmMOB to grow on air is not well understood. Here we assess the ability and strategies of seven methanotrophic species to grow with air as sole energy, carbon, and nitrogen source. Four species, including three outside the canonical atmMOB group USCα, enduringly oxidized atmospheric methane, carbon monoxide, and hydrogen during 12 months of growth on air. These four species exhibited distinct substrate preferences implying the existence of multiple metabolic strategies to grow on air. The estimated energy yields of the atmMOB were substantially lower than previously assumed necessary for cellular maintenance in atmMOB and other aerobic microorganisms. Moreover, the atmMOB also covered their nitrogen requirements from air. During growth on air, the atmMOB decreased investments in biosynthesis while increasing investments in trace gas oxidation. Furthermore, we confirm that a high apparent specific affinity for methane is a key characteristic of atmMOB. Our work shows that atmMOB grow on the trace concentrations of methane, carbon monoxide, and hydrogen present in air and outlines the metabolic strategies that enable atmMOB to mitigate greenhouse gases.

Heterologous Ad26.COV2.S booster after primary BBIBP-CorV vaccination against SARS-CoV-2 infection: 1-year follow-up of a phase 1/2 open-label trial.

BACKGROUND: Inactivated whole-virus vaccination elicits immune responses to both SARS-CoV-2 nucleocapsid (N) and spike (S) proteins, like natural infections. A heterologous Ad26.COV2.S booster given at two different intervals after primary BBIBP-CorV vaccination was safe and immunogenic at days 28 and 84, with higher immune responses observed after the longer pre-boost interval. We describe booster-specific and hybrid immune responses over 1 year. METHODS: This open-label phase 1/2 study was conducted in healthy Thai adults aged ≥ 18 years who had completed primary BBIBP-CorV primary vaccination between 90-240 (Arm A1; n = 361) or 45-75 days (Arm A2; n = 104) before enrolment. All received an Ad26.COV2.S booster. We measured anti-S and anti-N IgG antibodies by Elecsys®, neutralizing antibodies by SARS-CoV-2 pseudovirus neutralization assay, and T-cell responses by quantitative interferon (IFN)-γ release assay. Immune responses were evaluated in the baseline-seronegative population (pre-booster anti-N < 1.4 U/mL; n = 241) that included the booster-effect subgroup (anti-N < 1.4 U/mL at each visit) and the hybrid-immunity subgroup (anti-N ≥ 1.4 U/mL and/or SARS-CoV-2 infection, irrespective of receiving non-study COVID-19 boosters). RESULTS: In Arm A1 of the booster-effect subgroup, anti-S GMCs were 131-fold higher than baseline at day 336; neutralizing responses against ancestral SARS-CoV-2 were 5-fold higher than baseline at day 168; 4-fold against Omicron BA.2 at day 84. IFN-γ remained approximately 4-fold higher than baseline at days 168 and 336 in 18-59-year-olds. Booster-specific responses trended lower in Arm A2. In the hybrid-immunity subgroup at day 336, anti-S GMCs in A1 were 517-fold higher than baseline; neutralizing responses against ancestral SARS-CoV-2 and Omicron BA.2 were 28- and 31-fold higher, respectively, and IFN-γ was approximately 14-fold higher in 18-59-year-olds at day 336. Durable immune responses trended lower in ≥ 60-year-olds. CONCLUSION: A heterologous Ad26.COV2.S booster after primary BBIBP-CorV vaccination induced booster-specific immune responses detectable up to 1 year that were higher in participants with hybrid immunity. CLINICAL TRIALS REGISTRATION: NCT05109559.

Sex and Age Differences in Atypical Chief Complaints for Acute Decompensated Heart Failure in Emergency Department Visits.

Objectives: Around one million United States emergency department (ED) visits annually are due to acute decompensated heart failure (ADHF) symptoms. Characterizing ED symptom presentation of ADHF patients may improve clinical care, yet sex and age differences in ED chief complaints have not been thoroughly investigated. This paper aims to describe differences in chief complaints and comorbid conditions for ED patients with a ADHF diagnosis, stratified by sex and age. Methods: Retrospective analysis of adults presenting to North Carolina EDs in NC DETECT, a statewide syndromic surveillance system, between 2010 and 2016 with a diagnosis of ADHF. Frequencies of chief complaint categories for ED visits and comorbid conditions, stratified by sex and age, were evaluated and standardized differences computed. Results: Top chief complaints were dyspnea (19.1%), chest pain (13.5%), and other respiratory complaints (13.4%). In the 18-44 age group, females when compared to males reported more nausea/vomiting (6.7% versus 4.1%) and headache (4.2% versus 2.0%). In those 45-64 and 65+ years old, complaints were similar by sex. When stratified by age group alone, the 18-44 and 45-64 age groups had more complaints of chest pain, whereas balance issues, weakness, and confusion were more common in the 65+ age group. Conclusion: Sex and age differences in atypical ADHF symptoms were seen in in ED patients with ADHF. Characterizing variation of ADHF symptoms in ED patients can inform the identification of ED patients with ADHF and the management of ADHF-related symptoms.

Intraoperative 3D Fluoroscopy During Open Reduction for DDH: An Effective Alternative to Postoperative CT/MRI.

BACKGROUND: Computed tomography CT or magnetic resonance imaging (MRI) has been the most used imaging modality to assess hip reduction in developmental dysplasia of the hip (DDH) after open reduction (OR). In 2015, intraoperative 3D fluoroscopy (3D) was introduced at our center as an alternative to CT/MRI. 3D offers the advantage that if hip reduction is insufficient, it can be addressed at the time of surgery. The purpose of this study was to assess the efficacy of 3D in comparison to CT/MRI. METHODS: This was a single-centre, retrospective comparative study of two consecutive cohorts: those with OR and 3D between 2015 and 2017 and those with OR and CT/MRI between 2012 and 2014. Time to imaging, re-imaging, length of stay (LOS), re-operation, and redislocation or subluxation after cast removal were evaluated. RESULTS: Forty-two patients (46 hips) had 3D, and 30 patients (32 hips) had CT/MRI. Significant differences were found between groups in time to imaging, cast changes, and LOS. All 3D was intraoperative (46 hips), and only 69% (22 hips) of CT/MRI was on the day of surgery (P<0.01). In the 3D group, 1 hip (2%) had a cast change under the same anesthetic, and 4 hips (13%) from CT/MRI had cast changes in subsequent surgery (P=0.03). The mean LOS in days for 3D was 1.72 and 2.20 for CT/MRI (P=0.03). There were no statistically significant differences between groups in further imaging and subluxations or re-dislocations at cast removal. Two hips (4%) in the 3D group had MRI, but with no further intervention (P=0.51), and at cast removal, there were 3 subluxations in each group (P=0.69) and 1 redislocation in the 3D group (P=1.00). CONCLUSIONS: Intraoperative 3D improved time to imaging, allowed for cast changes at surgery and had a shorter LOS. Moreover, there were no significant differences found in adverse outcomes between those who underwent 3D versus CT/MRI. 3D should thus be considered an effective alternative to CT/MRI for assessing hip reduction during OR for DDH. LEVEL OF EVIDENCE: Diagnostic Study, level II.

New Frontiers in Wide-Awake Surgery.

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Explain the most important benefits of wide-awake surgery to patients. 2. Tumesce large parts of the body with minimal pain local anesthesia injection technique to eliminate the need for sedation for many operations. 3. Apply tourniquet-free surgery to upper and lower limb operations to avoid the sedation required to tolerate tourniquet pain. 4. Move many procedures out of the main operating room to minor procedure rooms with no increase in infection rates to decrease unnecessary cost and solid waste in surgery. SUMMARY: Three disruptive innovations are changing the landscape of surgery: (1) minimally painful injection of large-volume, low-concentration tumescent local anesthesia eliminates the need for sedation for many procedures over the entire body; (2) epinephrine vasoconstriction in tumescent local anesthesia is a good alternative to the tourniquet and proximal nerve blocks in extremity surgery (sedation for tourniquet pain is no longer required for many procedures); and (3) evidence-based sterility and the elimination of sedation enable many larger procedures to move out of the main operating room into minor procedure rooms with no increase in infection rates. This continuing medical education article explores some of the new frontiers in which these changes affect surgery all over the body.

CDK9 inhibition as an effective therapy for small cell lung cancer.

Treatment-naïve small cell lung cancer (SCLC) is typically susceptible to standard-of-care chemotherapy consisting of cisplatin and etoposide recently combined with PD-L1 inhibitors. Yet, in most cases, SCLC patients develop resistance to first-line therapy and alternative therapies are urgently required to overcome this resistance. In this study, we tested the efficacy of dinaciclib, an FDA-orphan drug and inhibitor of the cyclin-dependent kinase (CDK) 9, among other CDKs, in SCLC. Furthermore, we report on a newly developed, highly specific CDK9 inhibitor, VC-1, with tumour-killing activity in SCLC. CDK9 inhibition displayed high killing potential in a panel of mouse and human SCLC cell lines. Mechanistically, CDK9 inhibition led to a reduction in MCL-1 and cFLIP anti-apoptotic proteins and killed cells, almost exclusively, by intrinsic apoptosis. While CDK9 inhibition did not synergise with chemotherapy, it displayed high efficacy in chemotherapy-resistant cells. In vivo, CDK9 inhibition effectively reduced tumour growth and improved survival in both autochthonous and syngeneic SCLC models. Together, this study shows that CDK9 inhibition is a promising therapeutic agent against SCLC and could be applied to chemo-refractory or resistant SCLC.

Association between claims-based setting of diagnosis and treatment initiation among Medicare patients with hepatitis C.

OBJECTIVE: To develop a claims-based algorithm to determine the setting of a disease diagnosis. DATA SOURCES AND STUDY SETTING: Medicare enrollment and claims data from 2014 to 2019. STUDY DESIGN: We developed a claims-based algorithm using facility indicators, revenue center codes, and place of service codes to identify settings where HCV diagnosis first appeared. When the first appearance was in a laboratory, we attempted to associate HCV diagnoses with subsequent clinical visits. Face validity was assessed by examining association of claims-based diagnostic settings with treatment initiation. DATA COLLECTION/EXTRACTION METHODS: Patients newly diagnosed with HCV and continuously enrolled in traditional Medicare Parts A, B, and D (12 months before and 6 months after index diagnosis) were included. PRINCIPAL FINDINGS: Among 104,454 patients aged 18-64 and 66,726 aged ≥65, 70.1% and 69%, respectively, were diagnosed in outpatient settings, and 20.2% and 22.7%, respectively in laboratory or unknown settings. Logistic regression revealed significantly lower odds of treatment initiation after diagnosis in emergency departments/urgent cares, hospitals, laboratories, or unclassified settings, than in outpatient visits. CONCLUSIONS: The algorithm identified the setting of HCV diagnosis in most cases, and found significant associations with treatment initiation, suggesting an approach that can be adapted for future claims-based studies.

Restoring soil biodiversity.

Soil health is crucial for all terrestrial life, supporting, among other processes, food production, water purification and carbon sequestration. Soil biodiversity - the variety of life within soils - is key to these processes and thus key to soil restoration. Human activities that degrade ecosystems threaten soil biodiversity and associated ecosystem processes. Indeed, 75% of the world's soils are affected by degradation - a figure that could rise to 90% by 2050 if deforestation, overgrazing, urbanisation and other harmful practices persist. Restoring soil biodiversity is a prerequisite for planetary health, and it comes with many challenges and opportunities. Soil directly supports around 60% of all species on Earth, and land degradation poses a major problem for this biodiversity and the ecosystem services that sustain human populations. Indeed, 98% of human calories come from soil, and earthworms alone underpin 6.5% of the world's grain production. Moreover, the total carbon in terrestrial ecosystems is around 3,170 gigatons (1 gigaton (Gt) = 1 billion metric tons), of which approximately 80% (2,500 Gt) is found in soil. Therefore, restoring soil biodiversity is not just a human need but an ecological and Earth-system imperative. It is pivotal for maintaining ecosystem resilience, sustaining agricultural productivity and mitigating climate change impacts.

Reactivation strength during cued recall is modulated by graph distance within cognitive maps.

Declarative memory retrieval is thought to involve reinstatement of neuronal activity patterns elicited and encoded during a prior learning episode. Furthermore, it is suggested that two mechanisms operate during reinstatement, dependent on task demands: individual memory items can be reactivated simultaneously as a clustered occurrence or, alternatively, replayed sequentially as temporally separate instances. In the current study, participants learned associations between images that were embedded in a directed graph network and retained this information over a brief 8 min consolidation period. During a subsequent cued recall session, participants retrieved the learned information while undergoing magnetoencephalographic recording. Using a trained stimulus decoder, we found evidence for clustered reactivation of learned material. Reactivation strength of individual items during clustered reactivation decreased as a function of increasing graph distance, an ordering present solely for successful retrieval but not for retrieval failure. In line with previous research, we found evidence that sequential replay was dependent on retrieval performance and was most evident in low performers. The results provide evidence for distinct performance-dependent retrieval mechanisms, with graded clustered reactivation emerging as a plausible mechanism to search within abstract cognitive maps.

The State of Hepatitis C Elimination from the Front Lines: A Qualitative Study of Provider-Perceived Gaps to Treatment Initiation.

BACKGROUND: Hepatitis C (HCV) is a curable chronic infection, but lack of treatment uptake contributes to ongoing morbidity and mortality. State and national strategies for HCV elimination emphasize the pressing need for people with HCV to receive treatment. OBJECTIVE: To identify provider-perceived barriers that hinder the initiation of curative HCV treatment and elimination of HCV in the USA. APPROACH: Qualitative semi-structured interviews with 36 healthcare providers who have evaluated patients with HCV in New York City, Western/Central New York, and Alabama. Interviews, conducted between 9/2021 and 9/2022, explored providers' experiences, perceptions, and approaches to HCV treatment initiation. Transcripts were analyzed using hybrid inductive and deductive thematic analysis informed by established health services and implementation frameworks. KEY RESULTS: We revealed four major themes: (1) Providers encounter professional challenges with treatment provision, including limited experience with treatment and perceptions that it is beyond their scope, but are also motivated to learn to provide treatment; (2) providers work toward building streamlined and inclusive practice settings-leveraging partnerships with experts, optimizing efficiency through increased access, adopting inclusive cultures, and advocating for integrated care; (3) although at times overwhelmed by patients facing socioeconomic adversity, increases in public awareness and improvements in treatment policies create a favorable context for providers to treat; and (4) providers are familiar with the relative advantages of improved HCV treatments, but the reputation of past treatments continues to deter elimination. CONCLUSIONS: To address the remaining barriers and facilitators providers experience in initiating HCV treatment, strategies will need to expand educational initiatives for primary care providers, further support local infrastructures and integrated care systems, promote public awareness campaigns, remove prior authorization requirements and treatment limitations, and address the negative reputation of outdated HCV treatments. Addressing these issues should be considered priorities for HCV elimination approaches at the state and national levels.

Bortezomib Inhibits Open Configurations of the 20S Proteasome.

Bortezomib, a small dipeptide-like molecule, is a proteasome inhibitor used widely in the treatment of myeloma and lymphoma. This molecule reacts with threonine side chains near the center of the 20S proteasome and disrupts proteostasis by blocking enzymatic sites that are responsible for protein degradation. In this work, we use novel mass-spectrometry-based techniques to examine the influence of bortezomib on the structures and stabilities of the 20S core particle. These studies indicate that bortezomib binding dramatically favors compact 20S structures (in which the axial gate is closed) over larger structures (in which the axial gate is open)─suppressing gate opening by factors of at least ∼400 to 1300 over the temperature range that is studied. Thus, bortezomib may also restrict degradation in the 20S proteasome by preventing substrates from entering the catalytic pore. That bortezomib influences structures at the entrance region of the pore at such a long distance (∼65 to 75 Å) from its binding sites raises a number of interesting biophysical issues.

Bioenergetic mapping of 'healthy microbiomes' via compound processing potential imprinted in gut and soil metagenomes.

Despite mounting evidence of their importance in human health and ecosystem functioning, the definition and measurement of 'healthy microbiomes' remain unclear. More advanced knowledge exists on health associations for compounds used or produced by microbes. Environmental microbiome exposures (especially via soils) also help shape, and may supplement, the functional capacity of human microbiomes. Given the synchronous interaction between microbes, their feedstocks, and micro-environments, with functional genes facilitating chemical transformations, our objective was to examine microbiomes in terms of their capacity to process compounds relevant to human health. Here we integrate functional genomics and biochemistry frameworks to derive new quantitative measures of in silico potential for human gut and environmental soil metagenomes to process a panel of major compound classes (e.g., lipids, carbohydrates) and selected biomolecules (e.g., vitamins, short-chain fatty acids) linked to human health. Metagenome functional potential profile data were translated into a universal compound mapping 'landscape' based on bioenergetic van Krevelen mapping of function-level meta-compounds and corresponding functional relative abundances, reflecting imprinted genetic capacity of microbiomes to metabolize an array of different compounds. We show that measures of 'compound processing potential' associated with human health and disease (examining atherosclerotic cardiovascular disease, colorectal cancer, type 2 diabetes and anxious-depressive behavior case studies), and displayed seemingly predictable shifts along gradients of ecological disturbance in plant-soil ecosystems (three case studies). Ecosystem quality explained 60-92 % of variation in soil metagenome compound processing potential measures in a post-mining restoration case study dataset. With growing knowledge of the varying proficiency of environmental microbiota to process human health associated compounds, we might design environmental interventions or nature prescriptions to modulate our exposures, thereby advancing microbiota-oriented approaches to human health. Compound processing potential offers a simplified, integrative approach for applying metagenomics in ongoing efforts to understand and quantify the role of microbiota in environmental- and human-health.

A Prospective Study of the Association Between Plasma Calprotectin Levels and New-Onset CKD in the General Population.

Introduction: Systemic inflammation has been associated with chronic kidney disease (CKD). In this study, we aimed to investigate a potential association between the plasma biomarker of inflammation calprotectin and new-onset CKD in a population-based cohort study. Methods: Individuals without CKD at baseline (n = 4662) who participated in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) prospective population-based cohort study in the Netherlands were included. Baseline plasma calprotectin levels were assessed in samples that had been stored at -80 °C. Occurrence of new-onset CKD was defined as a composite outcome of an estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2, urinary albumin excretion (UAE) >30 mg/24h, or both. Results: Baseline median (interquartile range) plasma calprotectin levels were 0.49 (0.35-0.68) mg/l and baseline median eGFR was 95.9 (interquartile range: 85.0-105.7) ml/min per 1.73 m2. After median follow-up of 8.3 (7.8-8.9) years, 467 participants developed new-onset CKD. Baseline plasma calprotectin levels were significantly associated with an increased risk of new-onset CKD (hazard ratio [HR] per doubling 1.28 [95% confidence interval, CI: 1.14-1.44], P < 0.001), independent of potentially confounding factors (HR 1.14 [95% CI: 1.01-1.29], P = 0.034), except for baseline high-sensitive C-reactive protein (hs-CRP) (HR 1.05 [0.91-1.21], P = 0.494). In secondary analyses, the association between plasma calprotectin and occurrence of UAE >30 mg/24h remained significant (HR 1.17 [1.02-1.34], P = 0.027), but not significantly so for the incidence of eGFR <60 ml/min per 1.73 m2 as individual outcome (HR 1.15 [0.92-1.43], P = 0.218). Conclusion: Higher plasma calprotectin levels are associated with an increased risk of developing CKD in the general population. This association is mitigated after adjustment for hs-CRP, and more pronounced with new-onset CKD defined by UAE.

From the Randomized AMBORA Trial to Clinical Practice: Comparison of Medication Errors in Oral Antitumor Therapy.

The randomized AMBORA trial showed that medication errors are frequent in patients treated with oral antitumor therapeutics and that they can be substantially reduced by an intensified clinical pharmacological/pharmaceutical care program. While randomized controlled trials are essential to generate clinical evidence, their generalizability in real-world is not always given. The AMBORA care program was implemented in clinical routine within the AMBORA Competence and Consultation Center (AMBORA Center) at the Comprehensive Cancer Center Erlangen-EMN, allowing a thorough comparison of medication error frequencies and characteristics. Our primary analysis compared data at therapy initiation of new oral antitumor therapeutics from the AMBORA trial intervention group (n = 98) and the AMBORA Center (n = 142). Medication errors involving the oral antitumor therapeutics were twofold higher in real-world compared to the randomized controlled trial (mean 0.83 ± 0.80 per patient vs. 0.41 ± 0.53, P < 0.001). We observed more complex oral antitumor therapeutic regimens, a higher median number of medications, and a higher ECOG status in clinical routine vs. the randomized trial. A high percentage of medication errors was completely solved in both groups (85.7% vs. 88.3%, ns). Medication error characteristics within the complete medication (oral antitumor therapeutics and concomitant medication) were similar in both groups (e.g., patient-related causes, drug-drug/drug-food interactions). Taken together, medication errors were even more frequent in clinical routine than in the randomized controlled trial and a high rate was solved in clinical routine by a clinical pharmacological/pharmaceutical care program.