Ferritin Cutoffs and Diagnosis of Iron Deficiency in Primary Care.

Importance: Ferritin is often measured by general practitioners, but the association of different cutoffs with the rates of iron deficiency diagnoses, particularly nonanemic iron deficiency, is unknown. Objective: To investigate the association of the ferritin cutoff choice with the incidence of nonanemic and anemic iron deficiency diagnoses in primary care. Design, Setting, and Participants: In this retrospective cohort study, patients 18 years or older with at least 1 consultation with a general practitioner participating in the Family Medicine Research Using Electronic Medical Records (FIRE) project, an electronic medical records database of Swiss primary care, from January 1, 2021, to November 30, 2023, were evaluated. Exposures: Sex, age, clinical patient characteristics, and professional general practitioner characteristics. Main Outcomes and Measures: Incidence of iron deficiency diagnoses (nonanemic and anemic) at ferritin cutoffs of 15, 30, and 45 ng/mL and ferritin testing itself. Time-dependent Cox proportional hazards regression was used to examine associations of patient and general practitioner characteristics with ferritin testing as adjusted hazard ratios (AHRs). Results: The study included 255 351 patients (median [IQR] age, 52 [36-66] years; 52.1% female). Per 1000 patient-years and at ferritin cutoffs of 15, 30, and 45 ng/mL, iron deficiency diagnoses had incidences of 10.9 (95% CI, 10.6-11.2), 29.9 (95% CI, 29.4-30.4), and 48.3 (95% CI, 47.7-48.9) cases, respectively; nonanemic iron deficiency diagnoses had incidences of 4.1 (95% CI, 3.9-4.2), 14.6 (95% CI, 14.3-15.0), and 25.8 (95% CI, 25.3-26.2) cases, respectively; and anemic iron deficiency diagnoses had incidences of 3.5 (95% CI, 3.3-3.7), 6.0 (95% CI, 5.8-6.2), and 7.5 (95% CI, 7.3-7.7) cases, respectively. Ferritin testing showed notable associations with fatigue (AHR, 2.03; 95% CI, 1.95-2.12), anemia (AHR, 1.75; 95% CI, 1.70-1.79), and iron therapy (AHR, 1.50; 95% CI, 1.46-1.54). Ferritin testing was associated with female sex in all age groups, including postmenopausal. Of the patients who received ferritin testing, 72.1% received concomitant hemoglobin testing, and 49.6% received concomitant C-reactive protein testing. Conclusions and Relevance: In this retrospective cohort study of primary care patients, ferritin cutoffs of 30 and 45 ng/mL were associated with a substantially higher incidence of iron deficiency compared with 15 ng/mL. These results provide a basis for health system-level evaluation and benchmarking of ferritin testing in high-resource settings and call for a harmonization of diagnostic criteria for iron deficiency in primary care.

Malignant Proliferating Pilar Tumor With Sarcomatous Transformation ("Carcinosarcoma"): Case Report With Molecular Profile.

ABSTRACT: Malignant proliferating pilar tumors (MPPTs) are rare, unique cutaneous adnexal tumors. Sarcomatous transformation in MPPTs is even rarer (4 previous cases reported). Here, we report an extraordinary case of a MPPT with sarcomatous transformation occurring on the scalp of a 63-year-old man with an in-depth molecular profile along with histologic, immunohistochemical, and follow-up data. Shared mutations in the epithelial and sarcomatous components included a loss-of-function TP53 mutation. An inactivating TP53 mutation was only identified in the epithelial component, and an inactivating CDKN2A mutation was only identified in the sarcomatous component. Copy number variations previously reported in MPPT were also identified, including 6p21.1 loss, 6q arm loss, and 15q21.1-q26.3 gain [epithelial], and 6p22.2-p22.3 loss [sarcoma]. Histologically, the tumor demonstrated juxtaposed areas of proliferating pilar tumor, carcinoma with clear cell change, and sarcomatous areas that did not stain for AE1/AE3, p40, CD34, S100 protein, and smooth muscle actin  by immunohistochemistry. The patient is alive at 2 years without evidence of recurrence or metastasis.

The use of vasopressors to reduce post-intubation hypotension in critically ill adult patients undergoing emergent endotracheal intubation: a scoping review.

INTRODUCTION: Patients requiring emergent endotracheal intubation are at higher risk of post-intubation hypotension due to altered physiology in critical illness. Post-intubation hypotension increases mortality and hospital length of stay, however, the impact of vasopressors on its incidence and outcomes is not known. This scoping review identified studies reporting hemodynamic data in patients undergoing emergent intubation to provide a literature overview on post-intubation hypotension in cohorts that did and did not receive vasopressors. METHODS: A systematic search of CINAHL, Cochrane, EMBASE and PubMed-Medline was performed from database inception until September 28, 2023. Two independent reviewers completed the title and abstract screen, full text review and data extraction per PRISMA guidelines. Studies including patients < 18 years or intubations during cardiac arrest were excluded. Primary outcome was the presence of hypotension within 30 min of emergent intubation. Secondary outcomes included mortality at 1 h and in-hospital. RESULTS: The systematic search yielded 13,126 articles, with 61 selected for final inclusion. There were 24,547 patients with a mean age of 57.2 years and a slight male predominance (63.8%). Respiratory failure was the most common intubation indication. Across 18 studies reporting on vasopressor use prior to intubation, 1171/7085 patients received vasopressors pre-intubation. Post-intubation hypotension occurred in 22.2% of patients across all studies, and in 34.3% of patients in studies where vasopressor administration pre-intubation was specifically reported. One-hour mortality of patients across all studies and within the vasopressor use studies was 1.2% and 1.6%, respectively. In-hospital mortality across studies was 21.5%, and 13.1% in studies which reported on vasopressor use pre-intubation. CONCLUSION: Patients requiring emergent intubation have a high rate of post-intubation hypotension and in-hospital mortality. While there is an intuitive rationale for the use of vasopressors during emergent intubation, current evidence is limited to support a definitive change in clinical practice at this time.

RéSUMé: INTRODUCTION: Les patients nécessitant une intubation endotrachéale en émergence présentent un risque plus élevé d'hypotension post-intubation en raison de la physiologie altérée de la maladie grave. L'hypotension post-intubation augmente la mortalité et la durée du séjour à l'hôpital, mais on ne connaît pas l'impact des vasopresseurs sur son incidence et ses résultats. Cette revue de la portée a identifié des études qui ont rapporté des données hémodynamiques chez des patients soumis à une intubation d'urgence afin de fournir un aperçu de la littérature sur l'hypotension post-intubation dans les cohortes ayant reçu et n'ayant pas reçu des vasopresseurs. MéTHODES: Une recherche systématique de CINAHL, Cochrane, EMBASE et PubMed-Medline a été effectuée depuis la création de la base de données jusqu'au 28 septembre 2023. Deux examinateurs indépendants ont complété le titre et l'écran des résumés, la révision du texte intégral et l'extraction des données selon les lignes directrices de PRISMA. Les études incluant des patients de moins de 18 ans ou des intubations pendant un arrêt cardiaque ont été exclues. Le principal critère de jugement était la présence d'hypotension dans les 30 minutes suivant l'intubation. Les critères de jugement secondaires comprenaient la mortalité à l'heure et en milieu hospitalier. RéSULTATS: La recherche systématique a donné lieu à 13126 articles, dont 61 ont été sélectionnés pour inclusion finale. On a recensé 24547 patients avec un âge moyen de 57,2 ans et une légère prédominance masculine (63,8 %). L'insuffisance respiratoire était la plus fréquente indication d'intubation. Dans 18 études sur l'utilisation de vasopresseurs avant l'intubation, 1171/7085 patients ont reçu des vasopresseurs avant l'intubation. Une hypotension post-intubation est survenue chez 22,2 % des patients dans toutes les études et chez 34,3 % des patients dans les études où l'administration de vasopresseurs avant l'intubation a été spécifiquement signalée. La mortalité d'une heure des patients dans toutes les études et dans le cadre des études sur l'utilisation de vasopresseurs était respectivement de 1,2 % et 1,6 %. La mortalité en milieu hospitalier dans l'ensemble des études était de 21,5 %, et de 13,1 % dans les études qui ont fait état d'un recours à un vasopresseur avant intubation. CONCLUSION: Les patients nécessitant une intubation d'urgence ont un taux élevé d'hypotension post-intubation et de mortalité en milieu hospitalier. Bien qu'il existe une justification intuitive pour l'utilisation de vasopresseurs pendant l'intubation en phase émergente, les preuves actuelles sont limitées pour soutenir un changement définitif dans la pratique clinique à ce moment-ci.

Spectroscopic confirmation of two luminous galaxies at a redshift of 14.

The first observations of the James Webb Space Telescope (JWST) have revolutionized our understanding of the Universe by identifying galaxies at redshift z ≈ 13 (refs. 1-3). In addition, the discovery of many luminous galaxies at Cosmic Dawn (z > 10) has suggested that galaxies developed rapidly, in apparent tension with many standard models4-8. However, most of these galaxies lack spectroscopic confirmation, so their distances and properties are uncertain. Here we present JWST Advanced Deep Extragalactic Survey-Near-Infrared Spectrograph spectroscopic confirmation of two luminous galaxies at z = 14.32 - 0.20 + 0.08 and z = 13.90 ± 0.17. The spectra reveal ultraviolet continua with prominent Lyman-α breaks but no detected emission lines. This discovery proves that luminous galaxies were already in place 300 million years after the Big Bang and are more common than what was expected before JWST. The most distant of the two galaxies is unexpectedly luminous and is spatially resolved with a radius of 260 parsecs. Considering also the very steep ultraviolet slope of the second galaxy, we conclude that both are dominated by stellar continuum emission, showing that the excess of luminous galaxies in the early Universe cannot be entirely explained by accretion onto black holes. Galaxy formation models will need to address the existence of such large and luminous galaxies so early in cosmic history.

Developing and testing a framework for coding general practitioners' free-text diagnoses in electronic medical records - a reliability study for generating training data in natural language processing.

BACKGROUND: Diagnoses entered by general practitioners into electronic medical records have great potential for research and practice, but unfortunately, diagnoses are often in uncoded format, making them of little use. Natural language processing (NLP) could assist in coding free-text diagnoses, but NLP models require local training data to unlock their potential. The aim of this study was to develop a framework of research-relevant diagnostic codes, to test the framework using free-text diagnoses from a Swiss primary care database and to generate training data for NLP modelling. METHODS: The framework of diagnostic codes was developed based on input from local stakeholders and consideration of epidemiological data. After pre-testing, the framework contained 105 diagnostic codes, which were then applied by two raters who independently coded randomly drawn lines of free text (LoFT) from diagnosis lists extracted from the electronic medical records of 3000 patients of 27 general practitioners. Coding frequency and mean occurrence rates (n and %) and inter-rater reliability (IRR) of coding were calculated using Cohen's kappa (Κ). RESULTS: The sample consisted of 26,980 LoFT and in 56.3% no code could be assigned because it was not a specific diagnosis. The most common diagnostic codes were, 'dorsopathies' (3.9%, a code covering all types of back problems, including non-specific lower back pain, scoliosis, and others) and 'other diseases of the circulatory system' (3.1%). Raters were in almost perfect agreement (Κ ≥ 0.81) for 69 of the 105 diagnostic codes, and 28 codes showed a substantial agreement (K between 0.61 and 0.80). Both high coding frequency and almost perfect agreement were found in 37 codes, including codes that are particularly difficult to identify from components of the electronic medical record, such as musculoskeletal conditions, cancer or tobacco use. CONCLUSION: The coding framework was characterised by a subset of very frequent and highly reliable diagnostic codes, which will be the most valuable targets for training NLP models for automated disease classification based on free-text diagnoses from Swiss general practice.

Novel metagenomics analysis of stony coral tissue loss disease.

Stony coral tissue loss disease (SCTLD) has devastated coral reefs off the coast of Florida and continues to spread throughout the Caribbean. Although a number of bacterial taxa have consistently been associated with SCTLD, no pathogen has been definitively implicated in the etiology of SCTLD. Previous studies have predominantly focused on the prokaryotic community through 16S rRNA sequencing of healthy and affected tissues. Here, we provide a different analytical approach by applying a bioinformatics pipeline to publicly available metagenomic sequencing samples of SCTLD lesions and healthy tissues from 4 stony coral species. To compensate for the lack of coral reference genomes, we used data from apparently healthy coral samples to approximate a host genome and healthy microbiome reference. These reads were then used as a reference to which we matched and removed reads from diseased lesion tissue samples, and the remaining reads associated only with disease lesions were taxonomically classified at the DNA and protein levels. For DNA classifications, we used a pathogen identification protocol originally designed to identify pathogens in human tissue samples, and for protein classifications, we used a fast protein sequence aligner. To assess the utility of our pipeline, a species-level analysis of a candidate genus, Vibrio, was used to demonstrate the pipeline's effectiveness. Our approach revealed both complementary and unique coral microbiome members compared with a prior metagenome analysis of the same dataset.

Theory and experiment of transient two-wave mixing in Yb-doped single-frequency fiber amplifiers induced by frequency modulation.

This paper presents a theoretical and experimental characterization of an instability phenomenon observed in single-frequency fiber amplifiers when the frequency of the seed laser is modulated. The instability manifests itself as fluctuating elastic back-reflections that occur only when the frequency is decreasing with time. The theory is a generalization of a coupled-mode model developed for a single-frequency fiber amplifier back-seeded with a constant frequency shift relative to the main signal. It can explain most observed features of the experiments in a qualitative and semi-quantitative way. Open questions and directions for further developments are also discussed.

Combining DNA and protein alignments to improve genome annotation with LiftOn.

As the number and variety of assembled genomes continues to grow, the number of annotated genomes is falling behind, particularly for eukaryotes. DNA-based mapping tools help to address this challenge, but they are only able to transfer annotation between closely-related species. Here we introduce LiftOn, a homology-based software tool that integrates DNA and protein alignments to enhance the accuracy of genome-scale annotation and to allow mapping between relatively distant species. LiftOn's protein-centric algorithm considers both types of alignments, chooses optimal open reading frames, resolves overlapping gene loci, and finds additional gene copies where they exist. LiftOn can reliably transfer annotation between genomes representing members of the same species, as we demonstrate on human, mouse, honey bee, rice, and Arabidopsis thaliana. It can further map annotation effectively across species pairs as far apart as mouse and rat or Drosophila melanogaster and D. erecta.

Detection of structural lesions of the sacroiliac joints in patients with spondyloarthritis: A comparison of T1-weighted 3D spoiled gradient echo MRI and MRI-based synthetic CT versus T1-weighted turbo spin echo MRI.

OBJECTIVES: To investigate the detection of erosion, sclerosis and ankylosis using 1 mm 3D T1-weighted spoiled gradient echo (T1w-GRE) MRI and 1 mm MRI-based synthetic CT (sCT), compared with conventional 4 mm T1w-TSE. MATERIALS AND METHODS: Prospective, cross-sectional study. Semi-coronal 4 mm T1w-TSE and axial T1w-GRE with 1.6 mm slice thickness and 0.8 mm spacing between overlapping slices were performed. The T1w-GRE images were processed into sCT images using a commercial deep learning algorithm, BoneMRI. Both were reconstructed into 1 mm semi-coronal images. T1w-TSE, T1w-GRE and sCT images were assessed independently by 3 expert and 4 non-expert readers for erosion, sclerosis and ankylosis. Cohen's kappa for inter-reader agreement, exact McNemar test for lesion frequencies and Wilcoxon signed-rank test for confidence in lesion detection were used. RESULTS: Nineteen patients with axial spondyloarthritis were evaluated. T1w-GRE increased inter-reader agreement for detecting erosion (kappa 0.42 vs 0.21 in non-experts), increased detection of erosion (57 vs 43 of 152 joint quadrants) and sclerosis (26 vs 17 of 152 joint quadrants) among experts, and increased reader confidence for scoring erosion and sclerosis. sCT increased inter-reader agreement for detecting sclerosis (kappa 0.69 vs 0.37 in experts) and ankylosis (0.71 vs 0.52 in non-experts), increased detection of sclerosis (34 vs 17 of 152 joint quadrants) and ankylosis (20 vs 13 of 76 joint halves) among experts, and increased reader confidence for scoring erosion, sclerosis and ankylosis. CONCLUSION: T1w-GRE and sCT increase sensitivity and reader confidence for the detection of erosion, sclerosis and ankylosis, compared with T1w-TSE. CLINICAL RELEVANCE STATEMENT: These methods improve the detection of sacroiliac joint structural lesions and might be a useful addition to SIJ MRI protocols both in routine clinical care and as structural outcome measures in clinical trials.

KdpD is a tandem serine histidine kinase that controls K+ pump KdpFABC transcriptionally and post-translationally.

Two-component systems, consisting of a histidine kinase and a response regulator, serve signal transduction in bacteria, often regulating transcription in response to environmental stimuli. Here, we identify a tandem serine histidine kinase function for KdpD, previously described as a histidine kinase of the KdpDE two-component system, which controls production of the potassium pump KdpFABC. We show that KdpD additionally mediates an inhibitory serine phosphorylation of KdpFABC at high potassium levels, using not its C-terminal histidine kinase domain but an N-terminal atypical serine kinase domain. Sequence analysis of KdpDs from different species highlights that some KdpDs are much shorter than others. We show that, while Escherichia coli KdpD's atypical serine kinase domain responds directly to potassium levels, a shorter version from Deinococcus geothermalis is controlled by second messenger cyclic di-AMP. Our findings add to the growing functional diversity of sensor kinases while simultaneously expanding the framework for regulatory mechanisms in bacterial potassium homeostasis.

Discontinuation of psychotropic medication: a synthesis of evidence across medication classes.

Pharmacotherapy is an effective treatment modality across psychiatric disorders. Nevertheless, many patients discontinue their medication at some point. Evidence-based guidance for patients, clinicians, and policymakers on rational discontinuation strategies is vital to enable the best, personalized treatment for any given patient. Nonetheless, there is a scarcity of guidelines on discontinuation strategies. In this perspective, we therefore summarize and critically appraise the evidence on discontinuation of six major psychotropic medication classes: antidepressants, antipsychotics, benzodiazepines, mood stabilizers, opioids, and stimulants. For each medication class, a wide range of topics pertaining to each of the following questions are discussed: (1) Who can discontinue (e.g., what are risk factors for relapse?); (2) When to discontinue (e.g., after 1 year or several years of antidepressant use?); and (3) How to discontinue (e.g., what's the efficacy of dose reduction compared to full cessation and interventions to mitigate relapse risk?). We thus highlight how comparing the evidence across medication classes can identify knowledge gaps, which may pave the way for more integrated research on discontinuation.

Hemiplegic migraine.

Hemiplegic migraine (HM) is a rare subtype of migraine with aura in which the aura phase includes transient motor weakness. Diagnosis is based on the International Classification of Headache Disorders criteria (ICHD-3). The most important diagnostic tools remain a patient interview, neurological examination during attacks, and exclusion of other disorders, such as epilepsy, stroke, encephalitis and secondary headache syndromes. Hemiplegic migraine can occur either familial or sporadic. Three genes, CACNA1A, ATP1A2, and SCN1A have been identified. Taken together, mutations in these three genes predict increased neurotransmitter and potassium ion levels at the synaptic cleft, which facilitates cortical spreading depolarization, the phenomenon underlying the migraine aura. The presence of several symptoms, including extensive weakness and brainstem manifestations increase the likelihood of finding a monogenic cause. While the diagnosis can be confirmed by genetic testing, it cannot be excluded if one of the known (F)HM genes is not implicated. Most patients with hemiplegic migraine without a mutation in CACNA1A, ATP1A2, or SCN1A display a mild phenotype that is more akin to that of common (nonhemiplegic) migraine. Additional diagnostics such as brain imaging, cerebrospinal fluid analysis or an electroencephalography are mainly performed to exclude other causes of focal neurologic symptoms associated with hemiparesis and headache. Due to the rarity of the disorder, current treatment recommendations are based on small, unblinded studies and empirical data.

UHRF1 ubiquitin ligase activity supports the maintenance of low-density CpG methylation.

The RING E3 ubiquitin ligase UHRF1 is an established cofactor for DNA methylation inheritance. Nucleosomal engagement through histone and DNA interactions directs UHRF1 ubiquitin ligase activity toward lysines on histone H3 tails, creating binding sites for DNMT1 through ubiquitin interacting motifs (UIM1 and UIM2). Here, we profile contributions of UHRF1 and DNMT1 to genome-wide DNA methylation inheritance and dissect specific roles for ubiquitin signaling in this process. We reveal DNA methylation maintenance at low-density CpGs is vulnerable to disruption of UHRF1 ubiquitin ligase activity and DNMT1 ubiquitin reading activity through UIM1. Hypomethylation of low-density CpGs in this manner induces formation of partially methylated domains (PMD), a methylation signature observed across human cancers. Furthermore, disrupting DNMT1 UIM2 function abolishes DNA methylation maintenance. Collectively, we show DNMT1-dependent DNA methylation inheritance is a ubiquitin-regulated process and suggest a disrupted UHRF1-DNMT1 ubiquitin signaling axis contributes to the development of PMDs in human cancers.

A small and vigorous black hole in the early Universe.

Several theories have been proposed to describe the formation of black hole seeds in the early Universe and to explain the emergence of very massive black holes observed in the first thousand million years after the Big Bang1-3. Models consider different seeding and accretion scenarios4-7, which require the detection and characterization of black holes in the first few hundred million years after the Big Bang to be validated. Here we present an extensive analysis of the JWST-NIRSpec spectrum of GN-z11, an exceptionally luminous galaxy at z = 10.6, revealing the detection of the [NeIV]λ2423 and CII*λ1335 transitions (typical of active galactic nuclei), as well as semi-forbidden nebular lines tracing gas densities higher than 109 cm-3, typical of the broad line region of active galactic nuclei. These spectral features indicate that GN-z11 hosts an accreting black hole. The spectrum also reveals a deep and blueshifted CIVλ1549 absorption trough, tracing an outflow with velocity 800-1,000 km s-1, probably driven by the active galactic nucleus. Assuming local virial relations, we derive a black hole mass of log ( M BH / M ⊙ ) = 6.2 ± 0.3 , accreting at about five times the Eddington rate. These properties are consistent with both heavy seeds scenarios and scenarios considering intermediate and light seeds experiencing episodic super-Eddington phases. Our finding explains the high luminosity of GN-z11 and can also provide an explanation for its exceptionally high nitrogen abundance.

Update on Thrombosis Risk in Patients with Cancer: Focus on Novel Anticancer Immunotherapies.

Thromboembolic complications, including venous thromboembolism (VTE) and arterial thromboembolism (ATE), increase mortality and morbidity, and delay treatment in patients with cancer. Therefore, an increased understanding of underlying risk profiles, the identification of risk factors and predictive biomarkers, and ultimately the development of specific cardiovascular prevention strategies in patients with cancer is needed. Medical anticancer therapies have undergone a remarkable development in recent years with the advent of targeted and immunotherapeutic treatment options, including immune checkpoint inhibitors (ICI), chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engagers (BiTEs). These developments have important implications for the accompanied risk of thromboembolic events in patients with cancer. First, the increased use of these highly effective therapies renders a growing proportion of patients with cancer at risk of thromboembolic events for a prolonged risk period due to an increase in patient survival despite advanced cancer stages. Second, potential direct cardiovascular toxicity and prothrombotic effect of novel anticancer immunotherapies are a matter of ongoing debate, with emerging reports suggesting a relevant risk of VTE and ATE associated with ICI, and relevant dysregulations of hemostasis in the frequently observed cytokine-release syndrome associated with BiTEs and CAR T-cell therapy. The aim of the present narrative review is to summarize the implications of the emerging use of anticancer immunotherapy for thromboembolic events in patients with cancer, and to provide an overview of available data on the rates and risk factors for VTE and ATE associated with ICI, CAR T-cell therapy, and BiTEs.

Novel metagenomics analysis of stony coral tissue loss disease.

Stony coral tissue loss disease (SCTLD) has devastated coral reefs off the coast of Florida and continues to spread throughout the Caribbean. Although a number of bacterial taxa have consistently been associated with SCTLD, no pathogen has been definitively implicated in the etiology of SCTLD. Previous studies have predominantly focused on the prokaryotic community through 16S rRNA sequencing of healthy and affected tissues. Here, we provide a different analytical approach by applying a bioinformatics pipeline to publicly available metagenomic sequencing samples of SCTLD lesions and healthy tissues from four stony coral species. To compensate for the lack of coral reference genomes, we used data from apparently healthy coral samples to approximate a host genome and healthy microbiome reference. These reads were then used as a reference to which we matched and removed reads from diseased lesion tissue samples, and the remaining reads associated only with disease lesions were taxonomically classified at the DNA and protein levels. For DNA classifications, we used a pathogen identification protocol originally designed to identify pathogens in human tissue samples, and for protein classifications, we used a fast protein sequence aligner. To assess the utility of our pipeline, a species-level analysis of a candidate genus, Vibrio, was used to demonstrate the pipeline's effectiveness. Our approach revealed both complementary and unique coral microbiome members compared to a prior metagenome analysis of the same dataset.

Development and internal validation of a prediction model for long-term opioid use-an analysis of insurance claims data.

ABSTRACT: In the United States, a public-health crisis of opioid overuse has been observed, and in Europe, prescriptions of opioids are strongly increasing over time. The objective was to develop and validate a multivariable prognostic model to be used at the beginning of an opioid prescription episode, aiming to identify individual patients at high risk for long-term opioid use based on routinely collected data. Predictors including demographics, comorbid diseases, comedication, morphine dose at episode initiation, and prescription practice were collected. The primary outcome was long-term opioid use, defined as opioid use of either >90 days duration and ≥10 claims or >120 days, independent of the number of claims. Traditional generalized linear statistical regression models and machine learning approaches were applied. The area under the curve, calibration plots, and the scaled Brier score assessed model performance. More than four hundred thousand opioid episodes were included. The final risk prediction model had an area under the curve of 0.927 (95% confidence interval 0.924-0.931) in the validation set, and this model had a scaled Brier score of 48.5%. Using a threshold of 10% predicted probability to identify patients at high risk, the overall accuracy of this risk prediction model was 81.6% (95% confidence interval 81.2% to 82.0%). Our study demonstrated that long-term opioid use can be predicted at the initiation of an opioid prescription episode, with satisfactory accuracy using data routinely collected at a large health insurance company. Traditional statistical methods resulted in higher discriminative ability and similarly good calibration as compared with machine learning approaches.

Molecular diagnostics tailoring personalized cancer therapy-an oncologist's view.

Medical oncology is rapidly evolving with the implementation of personalized, targeted therapies. Advances in molecular diagnostics and the biologic understanding of cancer pathophysiology led to the identification of specific genetic alterations as drivers of cancer progression. Further, improvements in drug development enable the direct interference with these pathways, which allow tailoring personalized treatments based on a distinct molecular characterization of tumors. Thereby, we are currently experiencing a paradigm-shift in the treatment of cancers towards cancer-type agnostic, molecularly targeted, personalized therapies. However, this concept has several important hurdles and limitations to overcome to ultimately increase the proportion of patients benefitting from the precision oncology approach. These include the assessment of clinical relevancy of identified alterations, capturing and interpreting levels of heterogeneity based on intra-tumoral or time-dependent molecular evolution, and challenges in the practical implementation of precision oncology in routine clinical care. In the present review, we summarize the current state of cancer-agnostic precision oncology, discuss the concept of molecular tumor boards, and consider current limitations of personalized cancer therapy. Further, we provide an outlook towards potential future developments including the implementation of functionality assessments of identified genetic alterations and the broader use of liquid biopsies in order to obtain more comprehensive and longitudinal genetic information that might guide personalized cancer therapy in the future.