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.

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.

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.

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.

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.

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.

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.

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.

Elevated TSH Levels: A Database Study of General Practitioners' Course of Action.

OBJECTIVE: To investigate general practitioners' course of action after detection of elevated thyroid stimulating hormone (TSH) levels regarding repeat testing, direct levothyroxine replacement, or neither. METHODS: We conducted a retrospective study of adults without prior evidence of thyroid disease and with a first detection of elevated TSH levels from January 1, 2015, to December 31, 2020, using data from electronic medical records of a Swiss primary care database. We determined the occurrence of either repeat TSH testing or direct levothyroxine initiation in primary care during 12-month follow-up and determined associations with demographic and clinical factors. RESULTS: Of the 1 591 patients included (median age 65 years, 64.4% female, median TSH 5.7 mIU/L), 34.3% received repeat TSH testing and 12.4% received direct levothyroxine replacement in primary care during follow-up. Repeat TSH testing showed the strongest association with overt hypothyroidism and was more common among patients with high primary care utilization and among patients aged 40-64 years compared to patients aged <40 years. Direct levothyroxine initiation was more likely for TSH levels >7 mIU/L, overt hypothyroidism, female patients, and nonurban practices. CONCLUSIONS: While the degree of thyroid dysfunction was the main driver of follow-up, we identified important gaps in the primary care-based monitoring of elevated TSH levels in young patients and in patients with infrequent consultations. We also observed potential overtreatment of women and patients in nonurban areas. Our findings highlight the need for standardization and dissemination of guidelines for the management of elevated TSH levels among general practitioners.

Incidence of Diabetes Mellitus and Its Impact on Outcomes in Patients Undergoing Surgical Pancreatectomy for Non-Malignant and Malignant Pancreatobiliary Diseases-A Retrospective Analysis.

Diabetes mellitus (DM) is a prominent risk factor for malignant and non-malignant pancreatic diseases. Furthermore, the presence of DM predicts an unfavourable outcome in people with pancreatic cancer. This retrospective observational study investigated 370 patients who underwent pancreatic resection surgery for various indications (84.3% in malignant indication) in a single surgery centre in Graz, Austria. The preoperative and postoperative diabetes statuses were evaluated according to surgery method and disease entity and predictors for diabetes development after surgery, as well as outcomes (survival and cancer recurrence) according to diabetes status, were analysed. In the entire cohort, the postoperative diabetes (postopDM) incidence was 29%. PostopDM occurred significantly more frequently in malignoma patients than in those with benign diseases (31.3% vs. 16.7%; p = 0.040, OR = 2.28). In the malignoma population, BMI, longer surgery duration, and prolonged ICU and hospital stay were significant predictors of diabetes development. The 1- and 2-year follow-ups showed a significantly increased mortality of people with postopDM in comparison to people without diabetes (HR 1-year = 2.02, p = 0.014 and HR 2-years = 1.56, p = 0.034). Local cancer recurrence was not influenced by the diabetes status. Postoperative new-onset diabetes seems to be associated with higher mortality of patients with pancreatic malignoma undergoing pancreatobiliary surgery.

Three decades of rust surveys in the United States reveal drastic virulence changes in oat crown rust.

To better understand how the pathogenicity of the oat crown rust pathogen, Puccinia coronata f. sp. avenae (Pca), has changed in the United States, 30 years of USDA survey isolates (n=5,456) tested on 30-40 differential lines were analyzed for overall and Pc resistance gene specific virulence trends and correlations. Pca is incredibly pathologically diverse with 88% of races represented by a single isolate. There are a slightly higher proportion of unique races from the Northern region of the United States and for one fourth of the years, Northern region isolates were significantly more virulent than Southern isolates which supports the idea that sexual recombination in this region is mediated by the alternate host as a major factor in creating new races. However, there is also support for regular isolate movement between North and South regions as isolates in the United States are steadily accumulating virulences at a rate of 0.35 virulences per year. Virulence significantly increased for 23 and decreased for 4 of the 40 differential lines. In the past few years, virulence has reached 90% or greater for 16 differential lines. There were also strong correlations in virulence for certain Pc genes that are likely identical, allelic, or target the same or closely linked pathogen effectors (e.g. Pc39, Pc55, and Pc71), and the results were largely in concordance with recent GWAS effector studies using USDA isolate subsets. Understanding changes in Pca pathogenicity is essential for the responsible deployment and management of Pc resistance genes for sustainable and profitable oat production.

A promoterless AAV6.2FF-based lung gene editing platform for the correction of surfactant protein B deficiency.

Surfactant protein B (SP-B) deficiency is a rare genetic disease that causes fatal respiratory failure within the first year of life. Currently, the only corrective treatment is lung transplantation. Here, we co-transduced the murine lung with adeno-associated virus 6.2FF (AAV6.2FF) vectors encoding a SaCas9-guide RNA nuclease or donor template to mediate insertion of promoterless reporter genes or the (murine) Sftpb gene in frame with the endogenous surfactant protein C (SP-C) gene, without disrupting SP-C expression. Intranasal administration of 3 × 1011 vg donor template and 1 × 1011 vg nuclease consistently edited approximately 6% of lung epithelial cells. Frequency of gene insertion increased in a dose-dependent manner, reaching 20%-25% editing efficiency with the highest donor template and nuclease doses tested. We next evaluated whether this promoterless gene editing platform could extend survival in the conditional SP-B knockout mouse model. Administration of 1 × 1012 vg SP-B-donor template and 5 × 1011 vg nuclease significantly extended median survival (p = 0.0034) from 5 days in the untreated off doxycycline group to 16 days in the donor AAV and nuclease group, with one gene-edited mouse living 243 days off doxycycline. This AAV6.2FF-based gene editing platform has the potential to correct SP-B deficiency, as well as other disorders of alveolar type II cells.

Solution-State 2D NMR Spectroscopy of Mixtures HyperpolarizedUsing Optically Polarized Crystals.

The HYPNOESYS method (Hyperpolarized NOE System), which relies on the dissolution of optically polarized crystals, has recently emerged as a promising approach to enhance the sensitivity of NMR spectroscopy in the solution state. However, HYPNOESYS is a single-shot method that is not generally compatible with multidimensional NMR. Here we show that 2D NMR spectra can be obtained from HYPNOESYS-polarized samples, using single-scan acquisition methods. The approach is illustrated with a mixture of terpene molecules and a benchtop NMR spectrometer, paving the way to a sensitive, information-rich and affordable analytical method.

Importance of different electronic medical record components for chronic disease identification in a Swiss primary care database: a cross-sectional study.

BACKGROUND: Primary care databases collect electronic medical records with routine data from primary care patients. The identification of chronic diseases in primary care databases often integrates information from various electronic medical record components (EMR-Cs) used by primary care providers. This study aimed to estimate the prevalence of selected chronic conditions using a large Swiss primary care database and to examine the importance of different EMR-Cs for case identification. METHODS: Cross-sectional study with 120,608 patients of 128 general practitioners in the Swiss FIRE ("Family Medicine Research using Electronic Medical Records") primary care database in 2019. Sufficient criteria on three individual EMR-Cs, namely medication, clinical or laboratory parameters and reasons for encounters, were combined by logical disjunction into definitions of 49 chronic conditions; then prevalence estimates and measures of importance of the individual EMR-Cs for case identification were calculated. RESULTS: A total of 185,535 cases (i.e. patients with a specific chronic condition) were identified. Prevalence estimates were 27.5% (95% CI: 27.3-27.8%) for hypertension, 13.5% (13.3-13.7%) for dyslipidaemia and 6.6% (6.4-6.7%) for diabetes mellitus. Of all cases, 87.1% (87.0-87.3%) were identified via medication, 22.1% (21.9-22.3%) via clinical or laboratory parameters and 19.3% (19.1-19.5%) via reasons for encounters. The majority (65.4%) of cases were identifiable solely through medication. Of the two other EMR-Cs, clinical or laboratory parameters was most important for identifying cases of chronic kidney disease, anorexia/bulimia nervosa and obesity whereas reasons for encounters was crucial for identifying many low-prevalence diseases as well as cancer, heart disease and osteoarthritis. CONCLUSIONS: The EMR-C medication was most important for chronic disease identification overall, but identification varied strongly by disease. The analysis of the importance of different EMR-Cs for estimating prevalence revealed strengths and weaknesses of the disease definitions used within the FIRE primary care database. Although prioritising specificity over sensitivity in the EMR-C criteria may have led to underestimation of most prevalences, their sex- and age-specific patterns were consistent with published figures for Swiss general practice.

Malignant Proliferating Pilar Tumor: Clinicopathologic, Immunohistochemical, and Molecular Study of 17 Cases.

Proliferating pilar tumors are rare neoplasms that differentiate toward the outer sheath near the isthmus and can rarely undergo malignant transformation. We performed histopathologic evaluation on 26 benign proliferating pilar tumor (BPPT) and 17 malignant proliferating pilar tumor (MPPT). Ki-67 and p53 immunostains were performed on 13 BPPT and 10 MPPT. Six MPPT cases were successfully analyzed by a next-generation sequencing platform which surveyed exonic DNA sequences of 447 cancer genes and 191 regions across 60 genes for rearrangement detection. Patient demographics and clinical characteristics were similar between the BPPT and MPPT groups. Follow-up data of 16 of 17 MPPT (median, 25 mo) showed metastasis in 1 MPPT. The histologic features associated with MPPT include size >2.5 cm, adjacent desmoplastic stroma, small nests or cords of atypical epithelium in surrounding stroma, irregular infiltration or borders, abnormal keratinization, large hyperchromatic nuclei, prominent nucleoli, severe cytologic atypia, nuclear pleomorphism, necrosis, and increased mitotic figures. MPPT harbors copy number gains of 15q and losses of 6p and 6q, findings previously reported in BPPT. However, MPPT harbors frequent TP53 mutations as molecular markers of progression. Different from cutaneous squamous cell carcinoma, MPPT more frequently demonstrates low tumor mutational burden and typically lacks a UV signature, suggestive of a different etiologic pathway than squamous cell carcinoma. In summary, with a median follow-up of 25 months, this study shows that MPPT is a biologically indolent carcinoma with rare metastasis. Molecular analyses suggest a non-UV-related pathogenesis with frequent TP53 aberration.

Regenerative Engineering of a Biphasic Patient-Fitted Temporomandibular Joint Condylar Prosthesis.

Regenerative medicine approaches to restore the mandibular condyle of the temporomandibular joint (TMJ) may fill an unmet patient need. In this study, a method to implant an acellular regenerative TMJ prosthesis was developed for orthotopic implantation in a pilot goat study. The scaffold incorporated a porous, polycaprolactone-hydroxyapatite (PCL-HAp, 20wt% HAp) 3D printed condyle with a cartilage-matrix-containing hydrogel. A series of material characterizations was used to determine the structure, fluid transport, and mechanical properties of 3D printed PCL-HAp. To promote marrow uptake for cell seeding, a scaffold pore size of 152 ± 68 µm resulted in a whole blood transport initial velocity of 3.7 ± 1.2 mm·s-1 transported to the full 1 cm height. The Young's modulus of PCL was increased by 67% with the addition of HAp, resulting in a stiffness of 269 ± 20 MPa for etched PCL-HAp. In addition, the bending modulus increased by 2.06-fold with the addition of HAp to 470 MPa for PCL-HAp. The prosthesis design with an integrated hydrogel was compared with unoperated contralateral control and no-hydrogel group in a goat model for 6 months. A guide was used to make the condylectomy cut, and the TMJ disc was preserved. MicroCT assessment of bone suggested variable tissue responses with some regions of bone growth and loss, although more loss may have been exhibited by the hydrogel group than the no-hydrogel group. A benchtop load transmission test suggested that the prosthesis was not shielding load to the underlying bone. Although variable, signs of neocartilage formation were exhibited by Alcian blue and collagen II staining on the anterior, functional surface of the condyle. Overall, this study demonstrated signs of functional TMJ restoration with an acellular prosthesis. There were apparent limitations to continuous, reproducible bone formation, and stratified zonal cartilage regeneration. Future work may refine the prosthesis design for a regenerative TMJ prosthesis amenable to clinical translation.

Quantification of cross-vendor variation in ADC measurements in vendor-specific prostate MRI-protocols.

PURPOSE: The purpose of this study was to quantify the variability of Apparent Diffusion Coefficient (ADC) and test if there were statistically significant differences in ADC between MRI systems and sequences. METHOD: With a two-chamber cylindrical ADC phantom with fixed ADC values (1,000 and 1,600x10-6 mm2/s) a single-shot (ss) Echo Planar Imaging (EPI), a multi-shot EPI, a reduced field of view DWI (zoom) and a Turbo Spin Echo DWI sequence were tested in six MRI systems from three vendors at 1.5 T and 3 T. Technical parameters were according to Prostate Imaging Reporting and Data System Version 2.1. ADC maps were calculated by vendor specific algorithms. Absolute and relative differences in ADC from the phantom-ADC were calculated and differences between sequences were tested. RESULTS: At 3 T absolute differences from phantom given ADC (∼1,000 and âˆ¼ 1,600x10-6 mm2/s) were -83 - 42x10-6 mm2/s (-8.3%-4.2%) and -48 - 15x10-6 mm2/s (-3%-0.9%), respectively and at 1.5 T absolute differences were -81 - 26x10-6 mm2/s (-2.6%-8.1%) and -74 - 67x10-6 mm2/s (-4.6%-4.2%), respectively. Significant statistical differences in ADC measurements were identified between vendors in all sequences except for ssEPI and zoom at 3 T in the 1,600x10-6 mm2/s phantom chamber. Significant differences were also identified between ADC measurements at 1.5 T and 3 T in some of the sequences and vendors, but not all. CONCLUSION: The variation of ADC between different MRI systems and prostate specific DWI sequences is limited in this phantom study and without apparent clinical relevance. However, prospective multicenter studies of prostate cancer patients are needed for further investigation.