The KNee OsteoArthritis Prediction (KNOAP2020) challenge: An image analysis challenge to predict incident symptomatic radiographic knee osteoarthritis from MRI and X-ray images.

OBJECTIVES: The KNee OsteoArthritis Prediction (KNOAP2020) challenge was organized to objectively compare methods for the prediction of incident symptomatic radiographic knee osteoarthritis within 78 months on a test set with blinded ground truth. DESIGN: The challenge participants were free to use any available data sources to train their models. A test set of 423 knees from the Prevention of Knee Osteoarthritis in Overweight Females (PROOF) study consisting of magnetic resonance imaging (MRI) and X-ray image data along with clinical risk factors at baseline was made available to all challenge participants. The ground truth outcomes, i.e., which knees developed incident symptomatic radiographic knee osteoarthritis (according to the combined ACR criteria) within 78 months, were not provided to the participants. To assess the performance of the submitted models, we used the area under the receiver operating characteristic curve (ROCAUC) and balanced accuracy (BACC). RESULTS: Seven teams submitted 23 entries in total. A majority of the algorithms were trained on data from the Osteoarthritis Initiative. The model with the highest ROCAUC (0.64 (95% confidence interval (CI): 0.57-0.70)) used deep learning to extract information from X-ray images combined with clinical variables. The model with the highest BACC (0.59 (95% CI: 0.52-0.65)) ensembled three different models that used automatically extracted X-ray and MRI features along with clinical variables. CONCLUSION: The KNOAP2020 challenge established a benchmark for predicting incident symptomatic radiographic knee osteoarthritis. Accurate prediction of incident symptomatic radiographic knee osteoarthritis is a complex and still unsolved problem requiring additional investigation.

Are clinical outcomes affected by laminoplasty method and K-line in patients with cervical ossification of posterior longitudinal ligament? A multicenter study.

BACKGROUND: Open-door laminoplasty (ODL) and French-door laminoplasty (FDL) are the main laminoplasty techniques used to treat cervical ossification of the posterior longitudinal ligament (C-OPLL). However, few studies have compared the outcomes of ODL and modified FDL (mFDL) for C-OPLL. We explored the differences in outcomes between ODL and mFDL for C-OPLL and analyzed the technical efficacy of each procedure in patients with K-line (+) or (-) C-OPLL. METHODS: From January 2010 to December 2015, 202 patients with K-line (+) or (-) C-OPLL were retrospectively recruited from 4 institutions. Clinical outcomes were evaluated using the Japanese Orthopaedic Association (JOA) score, JOA score recovery rate, operative time, blood loss, and complications. Univariate analysis and binary logistic regression models were adjusted for confounding factors. RESULTS: Two hundred patients (mFDL, n = 69; ODL, n = 131) with a median follow-up of 42 months (range 36-54 months) were included. The postoperative JOA score significantly improved in both groups (P < 0.05). After adjusting for confounding factors, there was a statistically significant difference in blood loss (≥ 300 mL) between the two groups (P = 0.005), but there was no significant difference in the postoperative JOA score (≥ 14) (P = 0.062), JOA score recovery rate (≥ 0.82) (P = 0.187), or operative time (≥ 90 min) (P = 0.925). C5 palsy tended to occur more often in the mFDL group, although the difference was not significant (P > 0.05). The stratified analysis of the K-line status showed more blood loss in K-line (+) patients who underwent mFDL, but there was no significant difference in the postoperative JOA score, JOA score recovery rate, or operative time between the ODL and mFDL groups. Additionally, there was no significant difference in blood loss, postoperative JOA score, JOA score recovery rate, or operative time among all patients with K-line (+) or (-) C-OPLL in both groups. CONCLUSIONS: Both ODL and mFDL are effective for patients with C-OPLL. However, more blood loss tends to occur during mFDL. This study showed no significant difference in the operative time or incidence of complications between the two techniques. The efficacy of ODL and mFDL was not affected by the K-line status (+ or -) in patients with C-OPLL.

Genetic and phenotypic characteristics of Clostridium (Clostridioides) difficile from canine, bovine, and pediatric populations.

OBJECTIVES: Carriage of Clostridioides difficile by different species of animals has led to speculation that animals could represent a reservoir of this pathogen for human infections. The objective of this study was to compare C. difficile isolates from humans, dogs, and cattle from a restricted geographic area. METHODS: C. difficile isolates from 36 dogs and 15 dairy calves underwent whole genome sequencing, and phenotypic assays assessing growth and virulence were performed. Genomes of animal-derived isolates were compared to 29 genomes of isolates from a pediatric population as well as 44 reference genomes. RESULTS: Growth rates and relative cytotoxicity of isolates were significantly higher and lower, respectively, in bovine-derived isolates compared to pediatric- and canine-derived isolates. Analysis of core genes showed clustering by host species, though in a few cases, human strains co-clustered with canine or bovine strains, suggesting possible interspecies transmission. Geographic differences (e.g., farm, litter) were small compared to differences between species. In an analysis of accessory genes, the total number of genes in each genome varied between host species, with 6.7% of functional orthologs differentially present/absent between host species and bovine-derived strains having the lowest number of genes. Canine-derived isolates were most likely to be non-toxigenic and more likely to carry phages. A targeted study of episomes identified in local pediatric strains showed sharing of a methicillin-resistance plasmid with dogs, and historic sharing of a wide range of episomes across hosts. Bovine-derived isolates harbored the widest variety of antibiotic-resistance genes, followed by canine CONCLUSIONS: While C. difficile isolates mostly clustered by host species, occasional co-clustering of canine and pediatric-derived isolates suggests the possibility of interspecies transmission. The presence of a pool of resistance genes in animal-derived isolates with the potential to appear in humans given sufficient pressure from antibiotic use warrants concern.

Distinct tumor-infiltrating lymphocyte landscapes are associated with clinical outcomes in localized non-small-cell lung cancer.

BACKGROUND: Despite the importance of tumor-infiltrating T lymphocytes (TILs) in cancer biology, the relationship between TIL phenotypes and their prognostic relevance for localized non-small-cell lung cancer (NSCLC) has not been well established. PATIENTS AND METHODS: Fresh tumor and normal adjacent tissue was prospectively collected from 150 patients with localized NSCLC. Tissue was comprehensively characterized by high-dimensional flow cytometry of TILs integrated with immunogenomic data from multiplex immunofluorescence, T-cell receptor sequencing, exome sequencing, RNA sequencing, targeted proteomics, and clinicopathologic features. RESULTS: While neither the magnitude of TIL infiltration nor specific TIL subsets were significantly prognostic alone, the integration of high-dimensional flow cytometry data identified two major immunotypes (IM1 and IM2) that were predictive of recurrence-free survival independent of clinical characteristics. IM2 was associated with poor prognosis and characterized by the presence of proliferating TILs expressing cluster of differentiation 103, programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing protein 3, and inducible T-cell costimulator. Conversely, IM1 was associated with good prognosis and differentiated by an abundance of CD8+ T cells expressing cytolytic enzymes, CD4+ T cells lacking the expression of inhibitory receptors, and increased levels of B-cell infiltrates and tertiary lymphoid structures. While increased B-cell infiltration was associated with good prognosis, the best prognosis was observed in patients with tumors exhibiting high levels of both B cells and T cells. These findings were validated in patient tumors from The Cancer Genome Atlas. CONCLUSIONS: Our study suggests that although the number of infiltrating T cells is not associated with patient survival, the nature of the infiltrating T cells, resolved in distinct TIL immunotypes, is prognostically relevant in NSCLC and may inform therapeutic approaches to clinical care.

Efflux pump gene expression study using RNA-seq in multidrug-resistant TB.

BACKGROUND: The mechanism underlying kanamycin (KM) resistance in Mycobacterium tuberculosis is not well understood, although efflux pump proteins are thought to play a role. This study used RNA-seq data to investigate changes in the expression levels of efflux pump genes following exposure to KM.METHODS: RNA expression of efflux pump and regulatory genes following exposure to different concentrations of KM (minimum inhibitory concentration MIC 25 and MIC50) in rrs wild-type strain and rrs A1401G mutated strain were compared with the control group.RESULTS: The selected strains had differential RNA expression patterns. Among the 71 putative efflux pump and regulatory genes, 46 had significant fold changes, and 12 genes (Rv0842, Rv1146, Rv1258c, Rv1473, Rv1686c, Rv1687c, Rv1877, Rv2038c, Rv3065, Rv3197a, Rv3728 and Rv3789) that were overexpressed following exposure to KM were thought to contribute to drug resistance. Rv3197A (whiB7) showed a distinct fold change based on the concentration of KM.CONCLUSION: The significant changes in the expression of the efflux pump and regulatory genes following exposure to KM may provide insights into the identification of a new resistance mechanism.

Locoregional therapy in hepatocellular carcinoma: when to start and when to stop and when to revisit.

With increasing therapeutic options available for advanced hepatocellular carcinoma (HCC), the timing and sequencing of locoregional and systemic therapy need to be re-examined. This is especially so for patients with intermediate HCC, so as to optimize responses while preserving liver reserves, and in so allowing our patients to achieve the best survival outcomes possible.

The value of interventional radiology in clinical trial teams: experience from the BATTLE lung cancer trials.

AIM: To report on the multidisciplinary approach, focusing specifically on the role of the interventional radiologist (IR), used to support the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) and BATTLE-2 trials. MATERIALS AND METHODS: Patients who underwent percutaneous image-guided biopsy for the BATTLE and BATTLE-2 trials were reviewed. A radiology-based, three-point, lesion-scoring system was developed and used by two IRs. Lesions were given a score of 3 (most likely to yield sufficient material for biomarker analysis) if they met the following criteria: size >2 cm, solid mass, demonstrated imaging evidence of viability, and were technically easy to sample. Lesions not meeting all four criteria were scored 2 with the missing criteria noted as negative factors. Lesions considered to have risks that outweighed potential benefits receive a score of 1 and were not biopsied. Univariate and multivariate analyses were performed to evaluate the score's ability to predict successful yield for biomarker adequacy. RESULTS: A total of 555 biopsies were performed. The overall yield for analysis of the required biomarkers was 86.1% (478/555), and 84% (268/319) and 88.9% (210/236) for BATTLE and BATTLE-2, respectively (p=0.09). Lesions receiving a score of 3 were adequate for biomarker analysis in 89% of cases. Lesions receiving a score of 2 with more than two negative factors were adequate for molecular analysis in 69.2% (IR1, p=0.03) and 74% (IR2, p=0.04) of cases. The two IRs scored 78.4% of the lesions the same indicating moderate agreement (kappa=0.55; 95% confidence interval [CI]: 0.48, 0.61). CONCLUSIONS: IRs add value to clinical trial teams by optimising lesions selected for biopsy and biomarker analysis.

Parity and the risk of incident dementia: a COSMIC study.

AIMS: To investigate the association between parity and the risk of incident dementia in women. METHODS: We pooled baseline and follow-up data for community-dwelling women aged 60 or older from six population-based, prospective cohort studies from four European and two Asian countries. We investigated the association between parity and incident dementia using Cox proportional hazards regression models adjusted for age, educational level, hypertension, diabetes mellitus and cohort, with additional analysis by dementia subtype (Alzheimer dementia (AD) and non-Alzheimer dementia (NAD)). RESULTS: Of 9756 women dementia-free at baseline, 7010 completed one or more follow-up assessments. The mean follow-up duration was 5.4 ± 3.1 years and dementia developed in 550 participants. The number of parities was associated with the risk of incident dementia (hazard ratio (HR) = 1.07, 95% confidence interval (CI) = 1.02-1.13). Grand multiparity (five or more parities) increased the risk of dementia by 30% compared to 1-4 parities (HR = 1.30, 95% CI = 1.02-1.67). The risk of NAD increased by 12% for every parity (HR = 1.12, 95% CI = 1.02-1.23) and by 60% for grand multiparity (HR = 1.60, 95% CI = 1.00-2.55), but the risk of AD was not significantly associated with parity. CONCLUSIONS: Grand multiparity is a significant risk factor for dementia in women. This may have particularly important implications for women in low and middle-income countries where the fertility rate and prevalence of grand multiparity are high.

Dissociable dopaminergic and pavlovian influences in goal-trackers and sign-trackers on a model of compulsive checking in OCD.

RATIONALE: Checking is a functional behaviour that provides information to guide behaviour. However, in obsessive-compulsive disorder (OCD), checking may escalate to dysfunctional levels. The processes underpinning the transition from functional to dysfunctional checking are unclear but may be associated with individual differences that support the development of maladaptive behaviour. We examined one such predisposition, sign-tracking to a pavlovian conditioned stimulus, which we previously found associated with dysfunctional checking. How sign-tracking interacts with another treatment with emerging translational validity for OCD-like checking, chronic administration of the dopamine D2 receptor agonist quinpirole, is unknown. OBJECTIVES: We tested how functional and dysfunctional checking in the rat observing response task (ORT) was affected by chronic quinpirole administration in non-autoshaped controls and autoshaped animals classified as sign-trackers or goal-trackers. METHODS: Sign-trackers or goal-trackers were trained on the ORT before the effects of chronic quinpirole administration on checking were assessed. Subsequently, the effects on checking of different behavioural challenges, including reward omission and the use of unpredictable reinforcement schedules, were tested. RESULTS: Prior autoshaping increased checking. Sign-trackers and goal-trackers responded differently to quinpirole sensitization, reward omission and reinforcement uncertainty. Sign-trackers showed greater elevations in dysfunctional checking, particularly during uncertainty. By contrast, goal-trackers predominantly increased functional checking responses, possibly in response to reduced discrimination accuracy in the absence of cues signalling which lever was currently active. CONCLUSIONS: The results are discussed in terms of how pavlovian associations influence behaviour that becomes compulsive in OCD and how this may be dependent on striatal dopamine D2 receptors.

Single-Cell Analysis of the Periodontal Immune Niche in Type 2 Diabetes.

Periodontitis (PD) is a common source of uncontrolled inflammation in obesity-associated type 2 diabetes (T2D). PD apparently fuels the inflammation of T2D and associates with poor glycemic control and increased T2D morbidity. New therapeutics are critically needed to counter the sources of periodontal infection and inflammation that are accelerated in people with T2D. The precise mechanisms underlying the relationship between PD and T2D remain poorly understood. Every major immune cell subset has been implicated in the unresolved inflammation of PD, regardless of host metabolic health. However, analyses of inflammatory cells in PD with human periodontal tissue have generally focused on mRNA quantification and immunohistochemical analyses, both of which provide limited information on immune cell function. We used a combination of flow cytometry for cell surface markers and enzyme-linked immunospot methods to assess the subset distribution and function of immune cells isolated from gingiva of people who had PD and were systemically healthy, had PD and T2D (PD/T2D), or, for flow cytometry, were systemically and orally healthy. T-cell subsets dominated the cellular immune compartment in gingiva from all groups, and B cells were relatively rare. Although immune cell frequencies were similar among groups, a higher proportion of CD11b+ or CD4+ cells secreted IFNγ/IL-10 or IL-8, respectively, in cells from PD/T2D samples as compared with PD-alone samples. Our data indicate that fundamental differences in gingival immune cell function between PD and T2D-potentiated PD may account for the increased risk and severity of PD in subjects with T2D. Such differences may suggest unexpected therapeutic targets for alleviating periodontal inflammation in people with T2D.

Does complexity relate to compensation? A comparison of relative value units in initial versus recurrent inguinal hernia repair.

PURPOSE: Work relative value units (wRVUs) can be used as a compensation model based on the effort required for providing a service and helps to determine adequate compensation for physicians. Thus, more complex surgical procedures that require greater technical skills and time should yield greater compensation. There are limited data comparing wRVUs and operative times within common general surgery procedures such as inguinal hernia repair. This study aims to compare mean operative times and wRVUs per minute between primary and recurrent inguinal hernia repairs, the latter being considered as a more difficult procedure to perform. METHODS: A retrospective analysis of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was performed to identify all patients undergoing primary inguinal hernia repair and recurrent inguinal hernia repair by general surgeons over a 6-year period (2012-2017). Calculation and comparison of mean operative times, wRVUs, and wRVU per minute were performed. RESULTS: A total of 134,391 patients were included in the analysis. 121,235 underwent primary inguinal repair and 13,156 patients underwent repair of recurrent inguinal hernia. Patients were distributed within open/reducible, open/incarcerated and laparoscopy groups. Mean operative time and RVUs were greater for recurrent inguinal procedures (p < 0.0001). Consistently, RVU per minute was also found to be higher for recurrent procedures within the different groups analyzed. CONCLUSION: Appropriately, general surgeons are reimbursed at a higher rate per minute in recurrent cases, regardless of the technique used.

Suppressed immune microenvironment and repertoire in brain metastases from patients with resected non-small-cell lung cancer.

BACKGROUND: The tumor immune microenvironment (TIME) of lung cancer brain metastasis is largely unexplored. We carried out immune profiling and sequencing analysis of paired resected primary tumors and brain metastases of non-small-cell lung carcinoma (NSCLC). PATIENTS AND METHODS: TIME profiling of archival formalin-fixed and paraffin-embedded specimens of paired primary tumors and brain metastases from 39 patients with surgically resected NSCLCs was carried out using a 770 immune gene expression panel and by T-cell receptor beta repertoire (TCRß) sequencing. Immunohistochemistry was carried out for validation. Targeted sequencing was carried out to catalog hot spot mutations in cancer genes. RESULTS: Somatic hot spot mutations were mostly shared between both tumor sites (28/39 patients; 71%). We identified 161 differentially expressed genes, indicating inhibition of dendritic cell maturation, Th1, and leukocyte extravasation signaling pathways, in brain metastases compared with primary tumors (P < 0.01). The proinflammatory cell adhesion molecule vascular cell adhesion protein 1 was significantly suppressed in brain metastases compared with primary tumors. Brain metastases exhibited lower T cell and elevated macrophage infiltration compared with primary tumors (P < 0.001). T-cell clones were expanded in 64% of brain metastases compared with their corresponding primary tumors. Furthermore, while TCR repertoires were largely shared between paired brain metastases and primary tumors, T-cell densities were sparse in the metastases. CONCLUSION: We present findings that suggest that the TIME in brain metastases from NSCLC is immunosuppressed and comprises immune phenotypes (e.g. immunosuppressive tumor-associated macrophages) that may help guide immunotherapeutic strategies for NSCLC brain metastases.

Exogenous ß-mannanase supplementation improved immunological and metabolic responses in lactating dairy cows.

Exogenous enzymes have been used to improve nutrient utilization in several species of livestock, particularly swine and poultry. In addition, improved immunological and metabolic traits have been reported in nonruminants. The objective of this study was to determine the effects of ß-mannanase supplementation on milk yield and composition, and immunological and metabolic responses in lactating Holstein dairy cows. Two weeks after calving, 20 Holstein cows (10 multiparous and 10 primiparous) were blocked by parity and assigned to 1 of 2 diets for 182 d. All cows were housed in the same environment and fed the same basal diet. The basal diet of the treatment group was supplemented with ß-mannanase (CTCBio Inc., Seoul, South Korea) at 0.1% of concentrate dry matter. No differences were detected between the control and enzyme supplement groups in milk yield parameters or milk composition. Supplementation of ß-mannanase enzyme reduced blood haptoglobin levels in supplemented multiparous cows compared with controls. Furthermore, nonesterified fatty acid concentration levels tended to be lower in cows fed ß-mannanase, regardless of parity. Neither immunoglobulin G nor milk somatic cell count was affected by ß-mannanase supplementation, regardless of parity. The number of insemination services tended to be lower in cows fed diets supplemented with ß-mannanase. Results from this study suggest that supplementation of ß-mannanase exogenous enzyme could help to reduce instances of systemic inflammation and decrease fat mobilization in lactating Holstein cows. Multiparous cows are considered susceptible to acute infections and inflammation; thus, the enzyme had a greater effect in multiparous cows.

A luminescence-based assay for evaluating bactericidal antibody to Borrelia burgdorferi in vaccinated horses' serum.

BACKGROUND: Current serological tests cannot discriminate between bactericidal Borrelia burgdorferi antibodies from others that are merely a response to Borrelia antigenic stimulation. OBJECTIVE: To develop a sensitive and convenient luminescence-based serum bactericidal assay (L-SBA) to identify serum borreliacidal activity. STUDY DESIGN: Prospective validation study and method comparison. METHODS: Serum samples were obtained either from archives of the Animal Health Diagnostic Center at Cornell University (N = 7) or from a vaccination trial (N = 238). Endogenous complement-inactivated serum sample was incubated with exogenic complement and B. burgdorferi ML23 pBBE22luc, which is able to process luciferin with luciferase and produce luminescence in viable Borrelia. After incubation, a light signal can be detected by using a luminometer to calculate the borreliacidal antibody titre. RESULTS: Components of the reaction mixture including spirochetes and complement from various sources and concentrations were tested to identify a reliable recipe for our complement-mediated L-SBA. We also applied this L-SBA on measuring bactericidal antibody activities and calculated the half inhibitory concentration (IC50 ) of serum samples from clinical collections. Furthermore, we analysed the L-SBA titres and anti-outer surface protein A (OspA) antibody levels from vaccinated horses using the multiplex assays and found that there is a relationship between results generated using these two different assays. The increases of L-SBA titres correlated with increases of anti-OspA antibody titre in sera (r = 0.423). MAIN LIMITATIONS: Immunoreactivity of commercial complement may differ from different batches. Clinical protection of borreliacidal antibody levels has not been determined. CONCLUSIONS: The L-SBA provided a sensitive and easy-operating platform for the evaluation of bactericidal antibody to B. burgdorferi, and we anticipated L-SBA would function well as an evaluation tool of vaccine efficiency in the future.

Weekly paclitaxel, carboplatin, cetuximab, and cetuximab, docetaxel, cisplatin, and fluorouracil, followed by local therapy in previously untreated, locally advanced head and neck squamous cell carcinoma.

BACKGROUND: The survival advantage of induction chemotherapy (IC) followed by locoregional treatment is controversial in locally advanced head and neck squamous cell carcinoma (LAHNSCC). We previously showed feasibility and safety of cetuximab-based IC (paclitaxel/carboplatin/cetuximab-PCC, and docetaxel/cisplatin/5-fluorouracil/cetuximab-C-TPF) followed by local therapy in LAHNSCC. The primary end point of this phase II clinical trial with randomization to PCC and C-TPF followed by combined local therapy in patients with LAHNSCC stratified by human papillomavirus (HPV) status and T-stage was 2-year progression-free survival (PFS) compared with historical control. PATIENTS AND METHODS: Eligible patients were ≥18 years with squamous cell carcinoma of the oropharynx, oral cavity, nasopharynx, hypopharynx, or larynx with measurable stage IV (T0-4N2b-2c/3M0) and known HPV by p16 status. Stratification was by HPV and T-stage into one of the two risk groups: (i) low-risk: HPV-positive and T0-3 or HPV-negative and T0-2; (ii) intermediate/high-risk: HPV-positive and T4 or HPV-negative and T3-4. Patient reported outcomes were carried out. RESULTS: A total of 136 patients were randomized in the study, 68 to each arm. With a median follow up of 3.2 years, the 2-year PFS in the PCC arm was 89% in the overall, 96% in the low-risk and 67% in the intermediate/high-risk groups; in the C-TPF arm 2-year PFS was 88% in the overall, 88% in the low-risk and 89% in the intermediate/high-risk groups. CONCLUSION: The observed 2-year PFS of PCC in the low-risk group and of C-TPF in the intermediate/high-risk group showed a 20% improvement compared with the historical control derived from RTOG-0129, therefore reaching the primary end point of the trial.

Larotrectinib in adult patients with solid tumours: a multi-centre, open-label, phase I dose-escalation study.

BACKGROUND: NTRK1, NTRK2 and NTRK3 gene fusions (NTRK gene fusions) occur in a range of adult cancers. Larotrectinib is a potent and highly selective ATP-competitive inhibitor of TRK kinases and has demonstrated activity in patients with tumours harbouring NTRK gene fusions. PATIENTS AND METHODS: This multi-centre, phase I dose escalation study enrolled adults with metastatic solid tumours, regardless of NTRK gene fusion status. Key inclusion criteria included evaluable and/or measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function. Larotrectinib was administered orally once or twice daily, on a continuous 28-day schedule, in increasing dose levels according to a standard 3 + 3 dose escalation scheme. The primary end point was the safety of larotrectinib, including dose-limiting toxicity. RESULTS: Seventy patients (8 with tumours with NTRK gene fusions; 62 with tumours without a documented NTRK gene fusion) were enrolled to 6 dose cohorts. There were four dose-limiting toxicities; none led to study drug discontinuation. The maximum tolerated dose was not reached. Larotrectinib-related adverse events were predominantly grade 1; none were grade 4 or 5. The most common grade 3 larotrectinib-related adverse event was anaemia [4 (6%) of 70 patients]. A dose of 100 mg twice daily was recommended for phase II studies based on tolerability and antitumour activity. In patients with evaluable TRK fusion cancer, the objective response rate by independent review was 100% (eight of the eight patients). Eight (12%) of the 67 assessable patients overall had an objective response by investigator assessment. Median duration of response was not reached. Larotrectinib had limited activity in tumours with NTRK mutations or amplifications. Pharmacokinetic analysis showed exposure was generally proportional to administered dose. CONCLUSIONS: Larotrectinib was well tolerated, demonstrated activity in all patients with tumours harbouring NTRK gene fusions, and represents a new treatment option for such patients. CLINCALTRIALS.GOV NUMBER: NCT02122913.

Bone mineral density as a dose-response predictor for osteoporosis: a propensity score analysis of longitudinal incident study (KCIS no. 39).

BACKGROUND: Osteoporosis is a global disease burden for aging society. The role of quantitative ultrasound (QUS) in the prediction for osteoporosis in a dose-response manner is hardly addressed. AIM: We aimed to show the dose-response of QUS measurement in the prediction for osteoporosis by a community-based study. DESIGN: A prospective cohort study. METHODS: Participants were recruited between 2000 and 2004. Demographic data and heel QUS measurement were collected at baseline. Diagnosis of osteoporosis was ascertained by the follow-up of this cohort over time. In order to reduce the imbalance of baseline characteristics in the observational study, we applied propensity score by using proportional odds regression analysis to match the quintiles of QUS T-score. RESULTS: A total of 44 957 subjects composed of 17 678 men (39.3%) and 27 279 women (69.7%) were recruited. After adjustments for propensity score, an increase in one unit of QUB T-score led to 7% reduction in the risk for osteoporosis [adjusted odds ratio (OR) = 0.93, 95% confidence interval (CI): 0.89-0.96, P < 0.0001]. Higher quintile of QUS T-score yielded a lower risk of osteoporosis with a gradient relationship [OR: 0.82 (95%CI: 0.72-0.92); OR: 0.81 (95%CI: 0.71-0.91); OR: 0.77 (95%CI: 0.68-0.87) and OR: 0.76 (95%CI: 0.67-0.86)] from the second to highest quintile opposed to first quintile (P < 0.0001). The cumulative incidence of osteoporosis was higher in the lower quintile during follow-up (log-rank test, P < 0.001). CONCLUSION: QUS is an independent predictor for osteoporosis in a dose-response manner using a large population-based cohort. Due to the lower cost and portability of QUS measurement, the pre-screening for osteoporosis by QUS can be considered in the area with limited resources can be a feasible and alternative method.

Genetic interaction is associated with lower metabolic connectivity and memory impairment in clinically mild Alzheimer's disease.

Metabolic connectivity as showed by [18F] fluorodeoxyglucose (FDG) positron emission tomography (FDG-PET) reflects neuronal connectivity. The aim of this study was to investigate the genetic impact on metabolic connectivity in default mode subnetworks and its clinical-pathological relationships in patients with Alzheimer's disease (AD). We separately investigated the modulation of 2 default mode subnetworks, as identified with independent component analysis, by comparing APOE-ε4 carriers to noncarriers with AD. We further analyzed the interaction effects of APOE (APOE-ε4 carriers vs noncarriers) with PICALM (rs3851179-GG vs rs3851179-A-allele carriers) on episodic memory (EM) deficits, reduction in cerebral metabolic rate for glucose (CMRgl) and decreased metabolic connectivity in default mode subnetworks. The metabolic connectivity in the ventral default mode network (vDMN) was positively correlated with EM scores (ß =0.441, P < .001). The APOE-ε4 carriers had significantly lower metabolic connectivity in the vDMN than the APOE-ε4 carriers (t(96) = -2.233, P = .028). There was an effect of the APOE-PICALM (rs3851179) interactions on reduced CMRgl in regions of vDMN (P < .001), and on memory deficits (F3,93 =5.568, P = .020). This study identified that PICALM may modulates memory deficits, reduced CMRgl and decreased metabolic connectivity in the vDMN in APOE-ε4 carriers. [18F] FDG-PET-based metabolic connectivity may serve a useful tool to elucidate the neural networks underlying clinical-pathological relationships in AD.

Hemodynamic Impairment Measured by Positron-Emission Tomography Is Regionally Associated with Decreased Cortical Thickness in Moyamoya Phenomenon.

BACKGROUND AND PURPOSE: Impaired cerebrovascular reactivity has been associated with decreased cortical thickness in patients with arterial occlusive diseases. This study tests the hypothesis that severe hemodynamic impairment, indicated by increased oxygen extraction fraction ratios on positron-emission tomography with 15O tracers, is associated with decreased cortical thickness in patients with Moyamoya phenomenon. MATERIALS AND METHODS: Patients with unilateral or bilateral idiopathic Moyamoya phenomenon were recruited. Oxygen extraction fraction ratio maps were generated from cerebral images of O[15O] counts divided by H2[15O] counts with normalization by corresponding cerebellar counts. The normal range of the oxygen extraction fraction ratio was estimated from historically available healthy control subjects. Cortical thickness was estimated from T1-weighted MR imaging and FreeSurfer. Regional samples of oxygen extraction fraction ratios and cortical thicknesses were drawn using FreeSurfer parcellations, retaining only parcellations from the vascular territory of the middle cerebral artery. RESULTS: Complete MR imaging and PET datasets were available in 35 subjects, including 23 women; the mean age at scanning was 44 years. Patients with Moyamoya phenomenon had a significantly increased regional oxygen extraction fraction ratio compared with 15 healthy control subjects (P < .001). Regional oxygen extraction fraction ratio and age were significant predictors of cortical thickness (P < .001 for each) in a generalized linear mixed-effects model. Using hemisphere averages and patient averages, we found that only age was a significant predictor of cortical thickness (P < .001). CONCLUSIONS: Chronic hemodynamic impairment, as indicated by a higher regional oxygen extraction fraction ratio, was significantly predictive of reduced cortical thickness in mixed-effects analysis of FreeSurfer regions. This phenomenon may be related to reversible metabolic down-regulation.