Diagnosing by anticipation: Coordinating patient trajectories within and across social systems.

Anticipation is a fundamental aspect of social life and, following Weber, the hallmark of social action-it means trying to take others' responses to our actions into account when acting. In this article, we propose and argue the relevance of anticipation to the sociological study of diagnosis. To that end, we introduce and elaborate on the concept of diagnosing by anticipation. To diagnose by anticipation is to consider diagnoses as cultural objects imbued with meaning, to anticipate how others will respond to their meaning in situ and to adapt the choice of diagnosis to secure a desired outcome. Unlike prognosis, which seeks to predict the development of a disease, diagnosing by anticipation entails seeking to predict the development of a case and the effect of different diagnostic categories on its trajectory. Analytically, diagnosing by anticipation therefore involves a shift in diagnostic footing, from trying to identify what the case is a case of, to trying to identify which diagnosis will yield the desired case trajectory. This shift also implies a stronger focus on the mundane organisational work of operating diagnostic systems and coordinating case trajectories within and across social systems, to the benefit of the sociology of diagnosis.

Phase 1 study of the MDM2 inhibitor AMG 232 in patients with advanced P53 wild-type solid tumors or multiple myeloma.

Background This open-label, first-in-human, phase 1 study evaluated AMG 232, an oral selective MDM2 inhibitor in patients with TP53 wild-type (P53WT), advanced solid tumors or multiple myeloma (MM). Methods In the dose escalation (n = 39), patients with P53WT refractory solid tumors enrolled to receive once-daily AMG 232 (15, 30, 60, 120, 240, 480, and 960 mg) for seven days every 3 weeks (Q3W). In the dose expansion (n = 68), patients with MDM2-amplified (well-differentiated and de-differentiated liposarcomas [WDLPS and DDLPS], glioblastoma multiforme [GBM], or other solid tumors [OST]), MDM2-overexpressing ER+ breast cancer (BC), or MM received AMG 232 at the maximum tolerated dose (MTD). Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. Results AMG 232 had acceptable safety up to up to 240 mg. Three patients had dose-limiting toxicities of thrombocytopenia (n = 2) and neutropenia (n = 1). Due to these and other delayed cytopenias, AMG 232 240 mg Q3W was determined as the highest tolerable dose assessed in the dose expansion. Adverse events were typically mild/moderate and included diarrhea, nausea, vomiting, fatigue, decreased appetite, and anemia. AMG 232 plasma concentrations increased dose proportionally. Increases in serum macrophage inhibitor cytokine-1 from baseline were generally dose dependent, indicating p53 pathway activation. Per local review, there were no responses. Stable disease (durability in months) was observed in patients with WDLPS (3.9), OST (3.3), DDLPS (2.0), GBM (1.8), and BC (1.4-2.0). Conclusions In patients with P53WT advanced solid tumors or MM, AMG 232 showed acceptable safety and dose-proportional pharmacokinetics, and stable disease was observed.

Do nurses rate diseases according to prestige? A survey study.

AIMS: To see whether nurses rate diseases according to prestige and, if so, how their ratings compare to the disease prestige hierarchy previously uncovered among physicians. DESIGN: Cross-sectional survey. METHODS: In 2014, 122 nurses in a continuing education programme for healthcare personnel in Norway rated a sample of 38 diseases according to how prestigious they see these as being among healthcare workers in general. RESULTS: The nurses were found to rank myocardial infarction, leukaemia, and brain stroke at the top of the prestige hierarchy and depressive neurosis, anxiety neurosis, and fibromyalgia at the bottom. Their rankings overlap significantly with those previously documented for physicians and suggest that nurses assess the diseases through a 'cure' rather than a 'care' perspective on health care. CONCLUSION: The nurses ordered diseases in a prestige hierarchy and their rankings are strikingly like those of physicians. The findings are of significant relevance to nursing practice and set a new course for future research into prestige and nursing culture. IMPACT: The findings should encourage nurses - individually and collectively - to reflect on whether and how notions of disease prestige influence their decision-making. By showing that nurses as well as physicians are able to rate diseases according to prestige, the study suggests new avenues for future disease prestige research.

Mycobacterium arosiense, an unexpected cause of osteomyelitis in a patient with sarcoidosis: a case report.

BACKGROUND: Nontuberculous mycobacteria belonging to the Mycobacterium avium complex are recognized as opportunistic pathogens to humans. Mycobacterium arosiense is one of the novel members of the Mycobacterium avium complex. The organism has only rarely been reported in human clinical cases and may be routinely misidentified. CASE PRESENTATION: An adult male with a history of a discus prolapse and sarcoidosis presented with high fever and a strong back pain with projection to the extremities. A Magnetic Resonance Imaging scan of columna revealed a tumor suspect process at thoracic vertebrae 11/12 with changes at the second lumbar vertebra, which was partly removed by laminectomy. Biopsy smears revealed acid-fast bacilli and turned out to be Mycobacterium tuberculosis complex PCR negative. The routine line probe assay INNO-LiPa v2 (INNOGENETICS NV, Gent), which differentiates 16 mycobacterial species indicated the presence of a not readily identifiable NTM species. Whereas, the GenoType Mycobacterium CM v2.0 (HAIN Lifescience GmbH) that routinely differentiates 14 clinically relevant mycobacteria revealed a Mycobacterium intracellulare species. However, additional diagnostic sequencing of the 16S rRNA gene confirmed the presence of a Mycobacterium arosiense species. CONCLUSIONS: This is the second unusual case of osteomyelitis with clinical significance ever to be reported, caused by Mycobacterium arosiense and complicated by an underlying sarcoidosis. Mycobacterium arosiense has rarely been reported clinically and the first description of the species was identified as the cause of osteomyelitis in a child with a hereditary partial interferon gamma deficiency. Symptoms attributed to sarcoidosis waned on Mycobacterium arosiense treatment and it is inconclusive whether the patient ever suffered from sarcoidosis. Mycobacterium arosiense was misidentified by the GenoType as Mycobacterium intracellulare and implicates that the diagnosis requires supplemental sequencing of the 16S rRNA gene.

Armed conflict and population displacement as drivers of the evolution and dispersal of Mycobacterium tuberculosis.

The "Beijing" Mycobacterium tuberculosis (Mtb) lineage 2 (L2) is spreading globally and has been associated with accelerated disease progression and increased antibiotic resistance. Here we performed a phylodynamic reconstruction of one of the L2 sublineages, the central Asian clade (CAC), which has recently spread to western Europe. We find that recent historical events have contributed to the evolution and dispersal of the CAC. Our timing estimates indicate that the clade was likely introduced to Afghanistan during the 1979-1989 Soviet-Afghan war and spread further after population displacement in the wake of the American invasion in 2001. We also find that drug resistance mutations accumulated on a massive scale in Mtb isolates from former Soviet republics after the fall of the Soviet Union, a pattern that was not observed in CAC isolates from Afghanistan. Our results underscore the detrimental effects of political instability and population displacement on tuberculosis control and demonstrate the power of phylodynamic methods in exploring bacterial evolution in space and time.

A Predominant Variable-Number Tandem-Repeat Cluster of Mycobacterium tuberculosis Isolates among Asylum Seekers in the Netherlands and Denmark, Deciphered by Whole-Genome Sequencing.

In many countries, Mycobacterium tuberculosis isolates are routinely subjected to variable-number tandem-repeat (VNTR) typing to investigate M. tuberculosis transmission. Unexpectedly, cross-border clusters were identified among African refugees in the Netherlands and Denmark, although transmission in those countries was unlikely. Whole-genome sequencing (WGS) was applied to analyze transmission in depth and to assess the precision of VNTR typing. WGS was applied to 40 M. tuberculosis isolates from refugees in the Netherlands and Denmark (most of whom were from the Horn of Africa) that shared the exact same VNTR profile. Cluster investigations were undertaken to identify in-country epidemiological links. Combining WGS results for the isolates (all members of the central Asian strain [CAS]/Delhi genotype), from both European countries, an average genetic distance of 80 single-nucleotide polymorphisms (SNPs) (maximum, 153 SNPs) was observed. The few pairs of isolates with confirmed epidemiological links, except for one pair, had a maximum distance of 12 SNPs. WGS divided this refugee cluster into several subclusters of patients from the same country of origin. Although the M. tuberculosis cases, mainly originating from African countries, shared the exact same VNTR profile, most were clearly distinguished by WGS. The average genetic distance in this specific VNTR cluster was 2 times greater than that in other VNTR clusters. Thus, identical VNTR profiles did not represent recent direct M. tuberculosis transmission for this group of patients. It appears that either these strains from Africa are extremely conserved genetically or there is ongoing transmission of this genotype among refugees on their long migration routes from Africa to Europe.

A phase 1, first-in-human study of AMG 900, an orally administered pan-Aurora kinase inhibitor, in adult patients with advanced solid tumors.

Background Aurora kinase overexpression or amplifications are associated with high proliferation, poor prognosis, and therapeutic resistance in human tumors. AMG 900 is an investigational, oral, selective pan-Aurora kinase inhibitor. Methods This first-in-human trial included dose-escalation and dose-expansion phases ( ClinicalTrials.gov : NCT00858377). Dose escalation evaluated the safety, tolerability, and pharmacokinetics of AMG 900 in advanced solid tumors and determined the maximum tolerated dose (MTD) with/without granulocyte colony-stimulating factor (G-CSF) prophylaxis. Dose expansion evaluated clinical activity in three tumor types: taxane- and platinum-resistant ovarian cancer, taxane-resistant triple-negative breast cancer (TNBC), and castration-resistant and taxane- or cisplatin/etoposide-resistant prostate cancer (CRPC). AMG 900 was administered 4 days on/10 days off at 1-50 mg/day during escalation and at the MTD with G-CSF during expansion. Results AMG 900 showed rapid absorption with fast clearance, supporting once-daily dosing. The MTD was 25 mg/day, increasing to 40 mg/day with G-CSF. Grade ≥ 3 treatment-related adverse events included neutropenia (37%), anemia (23%), leukopenia (14%), and thrombocytopenia (12%). During dose expansion, 3/29 (10.3%, 95% CI: 2.0%-28.0%) evaluable patients with ovarian cancer experienced partial response by central imaging per RECIST 1.1; median duration of response was 24.1 weeks (95% CI: 16.1-34.1). Seven patients (24.1%, 95% CI: 10.3%-43.5%) experienced partial response per Gynecologic Cancer InterGroup criteria; 5/9 patients positive for p53 expression responded to treatment. No objective responses were observed in patients with TNBC or CRPC per RECIST 1.1. Conclusions AMG 900 40 mg/day with G-CSF had manageable toxicity and demonstrated single-agent activity in patients with heavily pretreated, chemotherapy-resistant ovarian cancer.

How general practitioners understand and handle medically unexplained symptoms: a focus group study.

BACKGROUND: Medically unexplained symptoms (MUS) are a common yet challenging encounter in primary care. The aim of this study was to explore how general practitioners (GPs) understand and handle MUS. METHODS: Three focus group interviews were conducted with a total of 23 GPs. Participants with varied clinical experience were purposively recruited. The data were analysed thematically, using the concept of framing as an analytical lens. RESULTS: The GPs alternated between a biomedical frame, centred on disease, and a biopsychosocial frame, centred on the sick person. Each frame shaped the GPs' understanding and handling of MUS. The biomedical frame emphasised the lack of objective evidence, problematized subjective patient testimony, and manifested feelings of uncertainty, doubt and powerlessness. This in turn complicated patient handling. In contrast, the biopsychosocial frame emphasised clinical experience, turned patient testimony into a valuable source of information, and manifested feelings of confidence and competence. This in turn made them feel empowered. The GPs with the least experience relied more on the biomedical frame, whereas their more seasoned seniors relied mostly on the biopsychosocial frame. CONCLUSION: The biopsychosocial frame helps GPs to understand and handle MUS better than the biomedical frame does. Medical students should spend more time learning biopsychosocial medicine, and to integrate the clinical knowledge of their peers with their own.

Genomic Epidemiology of a Major Mycobacterium tuberculosis Outbreak: Retrospective Cohort Study in a Low-Incidence Setting Using Sparse Time-Series Sampling.

Since 1992, Denmark has documented the largest outbreak of tuberculosis in Scandinavia ascribed to a single genotype, termed C2/1112-15. As of spring 2017, the International Reference Laboratory of Mycobacteriology in Copenhagen has collected and identified isolates from more than a thousand cases belonging to this outbreak via routine mycobacterial interspersed repetitive units-variable number of tandem repeats typing. Here, we present a retrospective analysis of the C2/1112-15 dataset, based on whole-genome data from a sparse time series consisting of 5 randomly selected isolates from 23 years of sampling. Even if these data are derived from only 12% of the collected isolates, we have been able to extract important key information, such as mutation rate and conserved single-nucleotide polymorphisms to identify discrete transmission chains, as well as the possible historical origins of the outbreak.

Mycobacterium chimaera in Heater-Cooler Units in Denmark Related to Isolates from the United States and United Kingdom.

Mycobacterium chimaera was present at high rates (>80%) in heater-cooler units (HCUs) from all 5 thoracic surgery departments in Denmark. Isolates were clonal to HCU-associated isolates from the United States (including some from patients) and United Kingdom. However, M. chimaera from 2 brands of HCU were genetically distinct.

Intrahepatic Transcriptional Signature Associated with Response to Interferon-α Treatment in the Woodchuck Model of Chronic Hepatitis B.

Recombinant interferon-alpha (IFN-α) is an approved therapy for chronic hepatitis B (CHB), but the molecular basis of treatment response remains to be determined. The woodchuck model of chronic hepatitis B virus (HBV) infection displays many characteristics of human disease and has been extensively used to evaluate antiviral therapeutics. In this study, woodchucks with chronic woodchuck hepatitis virus (WHV) infection were treated with recombinant woodchuck IFN-α (wIFN-α) or placebo (n = 12/group) for 15 weeks. Treatment with wIFN-α strongly reduced viral markers in the serum and liver in a subset of animals, with viral rebound typically being observed following cessation of treatment. To define the intrahepatic cellular and molecular characteristics of the antiviral response to wIFN-α, we characterized the transcriptional profiles of liver biopsies taken from animals (n = 8-12/group) at various times during the study. Unexpectedly, this revealed that the antiviral response to treatment did not correlate with intrahepatic induction of the majority of IFN-stimulated genes (ISGs) by wIFN-α. Instead, treatment response was associated with the induction of an NK/T cell signature in the liver, as well as an intrahepatic IFN-γ transcriptional response and elevation of liver injury biomarkers. Collectively, these data suggest that NK/T cell cytolytic and non-cytolytic mechanisms mediate the antiviral response to wIFN-α treatment. In summary, by studying recombinant IFN-α in a fully immunocompetent animal model of CHB, we determined that the immunomodulatory effects, but not the direct antiviral activity, of this pleiotropic cytokine are most closely correlated with treatment response. This has important implications for the rational design of new therapeutics for the treatment of CHB.

A phase 1 study of AMG 900, an orally administered pan-aurora kinase inhibitor, in adult patients with acute myeloid leukemia.

Aurora kinases are involved in the pathophysiology of several cancers including acute myeloid leukemia (AML). In this phase 1 study, we investigated the safety and efficacy of AMG 900, an orally administered, highly potent, selective, small-molecule inhibitor of both Aurora kinase A and B, in patients with AML . Patients with pathologically documented AML who either declined standard treatments or had relapsed from or were refractory to previous therapies were enrolled. Two every-2-week dose-escalation schedules using a modified 3 + 3 + 3 design were evaluated AMG 900 given daily for 4 days with 10 days off (4/10 schedule), and AMG 900 given daily for 7 days with 7 days off (7/7 schedule). Thirty-five patients were enrolled at 9 different dose levels: 22 patients on the 4/10 schedule (doses from 15 to 100 mg daily), and 13 patients on the 7/7 schedule (doses from 30 to 50 mg daily). Both schedules were tolerated; nausea (31%), diarrhea (29%), febrile neutropenia (29%), and fatigue (23%) were the most common treatment-related adverse events. Three patients (9%) achieved complete response with incomplete count recovery. Patients with higher baseline expression of a set of specific pathway-related genes (BIRC5, AURKA, TTK, CDC2, and CCNB1) were more likely to respond in an exploratory biomarker analysis. AMG 900 was tolerated in a general AML population, and pathway-specific biomarkers identified a potential target population. Future research efforts will be directed toward further exploration of biomarkers of response and combination of AMG 900 with other anticancer agents.

Balancing medical accuracy and diagnostic consequences: diagnosing medically unexplained symptoms in primary care.

Focusing on the case of medically unexplained symptoms (MUS), this article explores diagnostic classification in the absence of biomedical evidence or other strong medical warrants for diagnosis. The data are from three focus group interviews with Norwegian general practitioners (GPs) conducted in 2015, that centred on the issue of what diagnoses to use (or not) for MUS. The qualitative analysis reconstructs the logic underlying GPs' diagnostic accounts, which centred on the meaning of diagnostic categories and on anticipating how 'generalised others' would respond to those meanings (called 'diagnosing by anticipation'). The analysis suggests that GPs confer diagnoses by balancing unwarranted medical accuracy and anticipated harmful diagnostic consequences; the goal of diagnosis was finding categories in the International Classification of Primary Care that would yield acceptable results, without making a liar of the GP in the process. Drawing on the distinction between diagnosis as colligation and classification, the findings and their relevance for medical sociology are discussed. Counter to frequent descriptions as 'illness that cannot be diagnosed', the analysis shows how GPs can diagnose MUS in the bureaucratic sense of diagnosis as classification - a sense that has been missing from sociological view.

Substantial molecular evolution and mutation rates in prolonged latent Mycobacterium tuberculosis infection in humans.

The genome of Mycobacterium tuberculosis (Mtb) of latently infected individuals may hold the key to understanding the processes that lead to reactivation and progression to clinical disease. We report here analysis of pairs of Mtb isolates from putative prolonged latent TB cases. We identified two confirmed cases, and used whole genome sequencing to investigate the mutational processes that occur over decades in latent Mtb. We found an estimated mutation rate between 0.2 and 0.3 over 33 years, suggesting that latent Mtb accumulates mutations at rates similar to observations from cases of active disease.

Differential influence of nutrient-starved Mycobacterium tuberculosis on adaptive immunity results in progressive tuberculosis disease and pathology.

When infected with Mycobacterium tuberculosis, most individuals will remain clinically healthy but latently infected. Latent infection has been proposed to partially involve M. tuberculosis in a nonreplicating stage, which therefore represents an M. tuberculosis phenotype that the immune system most likely will encounter during latency. It is therefore relevant to examine how this particular nonreplicating form of M. tuberculosis interacts with the host immune system. To study this, we first induced a state of nonreplication through prolonged nutrient starvation of M. tuberculosis in vitro. This resulted in nonreplicating persistence even after prolonged culture in phosphate-buffered saline. Infection with either exponentially growing M. tuberculosis or nutrient-starved M. tuberculosis resulted in similar lung CFU levels in the first phase of the infection. However, between week 3 and 6 postinfection, there was a very pronounced increase in bacterial levels and associated lung pathology in nutrient-starved-M. tuberculosis-infected mice. This was associated with a shift from CD4 T cells that coexpressed gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) or IFN-γ, TNF-α, and interleukin-2 to T cells that only expressed IFN-γ. Thus, nonreplicating M. tuberculosis induced through nutrient starvation promotes a bacterial form that is genetically identical to exponentially growing M. tuberculosis yet characterized by a differential impact on the immune system that may be involved in undermining host antimycobacterial immunity and facilitate increased pathology and transmission.

Pharmacokinetic drug-drug interaction study of the angiopoietin-1/angiopoietin-2-inhibiting peptibody trebananib (AMG 386) and paclitaxel in patients with advanced solid tumors.

BACKGROUND: Trebananib is an anti-angiogenic peptibody under investigation in patients with advanced cancer. This study evaluated the pharmacokinetic (PK) drug-drug interaction of paclitaxel and trebananib. PATIENTS AND METHODS: Patients with advanced solid tumors received weekly 80 mg/m(2) intravenous (IV) paclitaxel (3 weeks on/1 week off) with weekly 15 mg/kg IV trebananib starting at Week 2. Blood samples for PK analysis were collected at Week 1 (paclitaxel alone), Week 6 (paclitaxel and trebananib), and Week 8 (trebananib alone). An absence of interaction was to be concluded if the 90 % confidence intervals (CI) for the differences in paclitaxel exposure fell within the 0.80-1.25 interval. RESULTS: The primary study was conducted between 7/2012 and 10/2013. Thirty-five patients were enrolled and 34 received both treatments. Most patients were white (91 %) and female (59 %); mean age was 61 years. The most common tumor types were ovarian (32 %) and bladder (27 %), 71 % of patients had stage IV disease, and all had Eastern Cooperative Oncology Group (ECOG) scores of 0 or 1. PK parameter analysis was done on patients with evaluable PK data at both assessments (with and without concomitant therapy; n = 28). The geometric least squares mean (GLSM) ratio (90 % CI) of paclitaxel AUCinf with and without trebananib was 1.17 (1.10, 1.25). The GLSM ratio (90 % CI) of trebananib AUCtau,ss with and without paclitaxel was 0.92 (0.87, 0.97). The most common adverse events were fatigue, local edema, peripheral edema, and nausea. CONCLUSIONS: This study showed no evidence of clinically meaningful PK interaction between paclitaxel and trebananib.

Reduction of HBV replication prolongs the early immunological response to IFNα therapy.

BACKGROUND & AIMS: The interaction between HBV replication and immune modulatory effects mediated by IFNα therapy is not well understood. We characterized the impact of HBV DNA replication on the early IFNα-induced immunomodulatory mechanisms. METHODS: We interrogated the transcriptional, serum cytokine/chemokine and cellular immune profiles of 28 patients with HBeAg+ chronic HBV infection (CHB) randomly assigned to one of 4 treatment cohorts (untreated n=5, weekly dosing of 360 µg Pegasys [PegIFNα] n=11, daily dose of 300 mg Viread [tenofovir disoproxil fumarate, TDF] n=6, or a combination of both n=6). Samples were characterized at multiple early time points through day 14 of therapy, after which all patients were given standard of care (180 µg Pegasys injected subcutaneously, weekly). RESULTS: PegIFNα induced a distinct and rapid up-regulation of IFN signaling pathway that coincided with increase detection of distinct serum cytokines/chemokines (IL-15, IL-6, and CXCL-10) and the up-regulation of the frequency of proliferating NK and activated total CD8+ T cells. IFNα treatment alone did not result in rapid decay of HBV replication and was not able to restore the defective HBV-specific T cell response present in CHB patients. In addition, the IFNα immune-stimulatory effects diminished after the first dose, but this refractory effect was reduced in patients where HBV replication was simultaneously inhibited with TDF. CONCLUSIONS: We present here the first comprehensive description of the early effects of IFNα treatment on immune and viral biomarkers in HBeAg+ CHB patients. Our results show that PegIFNα-induced innate immune activation directly benefits from the suppression of HBV replication.

Single-cell m6A mapping in vivo using picoMeRIP-seq.

Current N6-methyladenosine (m6A) mapping methods need large amounts of RNA or are limited to cultured cells. Through optimized sample recovery and signal-to-noise ratio, we developed picogram-scale m6A RNA immunoprecipitation and sequencing (picoMeRIP-seq) for studying m6A in vivo in single cells and scarce cell types using standard laboratory equipment. We benchmark m6A mapping on titrations of poly(A) RNA and embryonic stem cells and in single zebrafish zygotes, mouse oocytes and embryos.

Can molecular methods detect 1% isoniazid resistance in Mycobacterium tuberculosis?

Patients may harbor both drug-susceptible and -resistant bacteria, representing heteroresistance. We studied mixtures of isoniazid-resistant and -susceptible Mycobacterium tuberculosis strains. Conventional drug susceptibility testing was the most sensitive method of detection, whereas the line probe assay and sequencing were not able to detect the clinically relevant 1% proportion of resistant bacteria.

Rifampin heteroresistance in Mycobacterium tuberculosis cultures as detected by phenotypic and genotypic drug susceptibility test methods.

Tuberculosis patients may harbor both drug-susceptible and -resistant bacteria, i.e., heteroresistance. We used mixtures of rifampin-resistant and -susceptible Mycobacterium tuberculosis strains to simulate heteroresistance in patient samples. Molecular tests can be used for earlier discovery of multidrug resistance (MDR), but the sensitivity to detect heteroresistance is unknown. Conventional phenotypic drug susceptibility testing was the most sensitive, whereas two line probe assays and sequencing were unable to detect the clinically important 1% resistant bacteria.