Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation.

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10-15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10-8) and mtDNA replication (p = 1.2 × 10-7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10-4).

Racism and Older Black Americans' Health: a Systematic Review.

We reviewed research that examines racism as an independent variable and one or more health outcomes as dependent variables in Black American adults aged 50 years and older in the USA. Of the 43 studies we reviewed, most measured perceived interpersonal racism, perceived institutional racism, or residential segregation. The only two measures of structural racism were birth and residence in a "Jim Crow state." Fourteen studies found associations between racism and mental health outcomes, five with cardiovascular outcomes, seven with cognition, two with physical function, two with telomere length, and five with general health/other health outcomes. Ten studies found no significant associations in older Black adults. All but six of the studies were cross-sectional. Research to understand the extent of structural and multilevel racism as a social determinant of health and the impact on older adults specifically is needed. Improved measurement tools could help address this gap in science.

Identification of IgG1 isotype phosphorylcholine antibodies for the treatment of inflammatory cardiovascular diseases.

BACKGROUND: Phosphorylcholine (PC) is an important pro-inflammatory damage-associated molecular pattern. Previous data have shown that natural IgM anti-PC protects against cardiovascular disease. We aimed to develop a monoclonal PC IgG antibody with anti-inflammatory and anti-atherosclerotic properties. METHODS: Using various techniques PC antibodies were validated and optimized. In vivo testing was performed in a femoral artery cuff model in ApoE3*Leiden mice. Safety studies are performed in rats and cynomolgus monkeys. RESULTS: A chimeric anti-PC (PC-mAb(T15), consisting of a human IgG1 Fc and a mouse T15/E06 Fab) was produced, and this was shown to bind specifically to epitopes in human atherosclerotic tissues. The cuff model results in rapid induction of inflammatory genes and altered expression of genes associated with ER stress and choline metabolism in the lesions. Treatment with PC-mAb(T15) reduced accelerated atherosclerosis via reduced expression of endoplasmic reticulum stress markers and CCL2 production. Recombinant anti-PC Fab fragments were identified by phage display and cloned into fully human IgG1 backbones creating a human monoclonal IgG1 anti-PC (PC-mAbs) that specifically bind PC, apoptotic cells and oxLDL. Based on preventing macrophage oxLDL uptake and CCL2 production, four monoclonal PC-mAbs were selected, which to various extent reduced vascular inflammation and lesion development. Additional optimization and validation of two PC-mAb antibodies resulted in selection of PC-mAb X19-A05, which inhibited accelerated atherosclerosis. Clinical grade production of this antibody (ATH3G10) significantly attenuated vascular inflammation and accelerated atherosclerosis and was tolerated in safety studies in rats and cynomolgus monkeys. CONCLUSIONS: Chimeric anti-PCs can prevent accelerated atherosclerosis by inhibiting vascular inflammation directly and through reduced macrophage oxLDL uptake resulting in decreased lesions. PC-mAb represents a novel strategy for cardiovascular disease prevention.

Cats' Internal Exposure to Selected Brominated Flame Retardants and Organochlorines Correlated to House Dust and Cat Food.

Pet cats may be used as a biomarker for assessing exposures to organohalogen compounds (OHCs) adsorbed to household dust in home environments. This study explores two exposure routes of OHCs, ingestion of OHCs (i) via house dust and (ii) via cat food. House dust from 17 Swedish homes and serum from the participating families' pet cats were collected, and cat food was purchased matching the diet reported. Paired samples of cat serum, house dust, and cat food were analyzed for brominated flame retardants/natural products (polybrominated diphenyl ethers (PBDEs), decabromobiphenyl (BB-209), decabromodiphenyl ethane (DBDPE), 2,4,6-tribromophenol (2,4,6-TBP), OH-PBDEs) and organochlorines (polychlorinated biphenyls (PCBs), 1,1-bis(4,4'-dichlorodiphenyl)-2,2,2-trichloroethane (4,4'-DDT), 1,1-bis(4,4'-dichlorodiphenyl)-2,2-dichloroethene (4,4'-DDE), hexachlorobenzene (HCB), pentachlorophenol (PCP)). Significant correlations were found between serum and dust samples from the living rooms for BDE-47 (p < 0.035), BDE-99 (p < 0.035), and BDE-153 (p < 0.039), from the adult's bedroom for BDE-99 (p < 0.019) and from all rooms for BDE-99 (p < 0.020) and BB-209 (p < 0.048). This is the first time a correlation between cat serum levels and household dust has been established, a finding that supports the hypothesis that dust is a significant exposure route for cats. Serum levels were also significantly correlated with concentrations found in cat food for 6-OH-BDE47 (p < 0.002), 2,4,6-TBP (p < 0.035), and BB-209 (p < 0.007). DBDPE was found in high concentrations in all dust (median 154 pmol/g) and food samples (median 0.7 pmol/g lw) but was below detection in serum samples, suggesting low or no bioavailability for DBDPE in cats.

High spatial resolution, low-noise Brillouin dynamic gratings reflectometry based on digital pulse compression.

Digital pulse compression was used to enhance the performance of optical time-domain reflectometry, employing Brillouin dynamic gratings (BDGs) in polarization-maintaining fibers. The fundamental and unique issues in BDG field-reflection are addressed, and rules for proper selection of the coding and detection techniques are formulated. While coding in BDG applications generally requires coherent processing of the reflection, conditions are established for use of direct detection. A 256-bit Golay complementary unipolar probe code is used to demonstrate an eightfold signal-to-noise ratio enhancement in the measurement of the Brillouin gain spectrum (BGS), with a spatial resolution of 2 cm and a full-BGS acquisition rate of 133⅓ kHz, resulting in an equivalent reduction in the estimation error of small Brillouin frequency shifts.

Effects of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus.

AIMS: To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus (T2DM). METHODS: Patients were randomized to oral PF-06291874 or placebo on a background of either metformin (Part A, Cohorts 1-5: 5-150 mg once daily), or metformin and sulphonylurea (Part B, Cohorts 1-2: 15 or 30 mg once daily) for 14-28 days. A mixed-meal tolerance test (MMTT) was administered on days -1 (baseline), 14 and 28. Assessments were conducted with regard to pharmacokinetics, various pharmacodynamic variables, safety and tolerability. Circulating amino acid concentrations were also measured. RESULTS: PF-06291874 exposure was approximately dose-proportional with a half-life of ∼19.7-22.7 h. Day 14 fasting plasma glucose and mean daily glucose values were reduced from baseline in a dose-dependent manner, with placebo-corrected decreases of 34.3 and 42.4 mg/dl, respectively, at the 150 mg dose. After the MMTT, dose-dependent increases in glucagon and total glucagon-like peptide-1 (GLP-1) were observed, although no meaningful changes were noted in insulin, C-peptide or active GLP-1 levels. Small dose-dependent increases in LDL cholesterol were observed, along with reversible increases in serum aminotransferases that were largely within the laboratory reference range. An increase in circulating gluconeogenic amino acids was also observed on days 2 and 14. All dose levels of PF-06291874 were well tolerated. CONCLUSION: PF-06291874 was well tolerated, has a pharmacokinetic profile suitable for once-daily dosing, and results in reductions in glucose with minimal risk of hypoglycaemia.

Comparison between MRI and CT in prediction of peritoneal carcinomatosis index (PCI) in patients undergoing cytoreductive surgery in relation to the experience of the radiologist.

BACKGROUND: To compare CT and MRI for peritoneal carcinomatosis index (PCI) assessment and to compare assessments made by the radiologist based on their experiences. METHOD AND MATERIALS: MRI and CT of abdomen and pelvis were performed on 39 prospectively followed by surgery directly. Two blinded radiologists with different experience levels evaluated PCI separately on different occasions on 19 cases initially and later on the remaining 20. The agreement between the radiologists' assessment and surgical findings in total and per site were recorded. RESULTS: Total PCI: The experienced radiologist was able to assess total tumor burden correctly on both CT and MRI (kappa = 1.0). For the inexperienced radiologist the assessment was better on CT (kappa = 0.73) compared to MRI (kappa = 0.58). Different sites: The experienced radiologist showed high agreement with kappa = 0.77 for MRI and 0.80 for CT. Corresponding figures were 0.39 and 0.60 for the inexperienced radiologist. For the second phase the agreement levels increased for the inexperienced radiologist increased to 0.80 and 0.70, respectively. CONCLUSION: CT and MRI are equal when read by experienced radiologist. CT shows better results when read by an inexperienced radiologist compared to MRI, however the results of the latter can easily be improved.

Risk factors for tibial stress injuries: a case-control study.

OBJECTIVE: To identify physical and behavioral characteristics related to the incidence of tibial stress injuries (TSIs). DESIGN: Case-control study. No clinical care was conducted. SETTING: Research laboratories in the San Francisco (the United States) and Gold Coast (Australia) areas. PARTICIPANTS: Forty-eight patients (21 men and 27 women) with acute TSI, and 36 (16 men and 20 women) age-matched, sex-matched, height-matched, weight-matched, and activity-matched controls with no history of TSI. INDEPENDENT VARIABLES: Height, weight, body mass index, bone, lean and fat mass, lower limb alignment anomalies, foot type, orthotics, calcium, recent weight change, menstrual history, oral contraceptive use, medications, smoking, alcohol, sleep, training type, and intensity. Differences in continuous variables were tested using 1-way analysis of variance. Categorical variable comparisons were performed with Fisher exact test. MAIN OUTCOME MEASURE: Tibial stress injury. RESULTS: Tibial stress injury cases had 2.7% more fat (P < 0.001) and 2.6% less muscle (P < 0.001) as well as lower trochanteric bone mineral content (BMC) (P < 0.001), lumbar spine (LS) area (P < 0.001), femoral neck BMC (P < 0.001), length (P < 0.05), area (P < 0.001), cortical width (P < 0.01), cross-sectional moment of inertia (P < 0.001), and index of bending strength (P < 0.001) than controls. Controls had lower LS BMC (P < 0.01), length (P < 0.001), and broadband ultrasound attenuation (P < 0.001). The use of orthotic insoles was more prevalent in TSI cases than controls (25% vs 5.6%, respectively; P < 0.02), as were foot anomalies (56.3% vs 27.8%, respectively; P = 0.01). CONCLUSIONS: Tibial stress injury cases had lower lean and higher fat mass, a tendency for smaller bones, and for foot anomalies compared with uninjured matched controls. bone mineral density was normal for both groups. CLINICAL RELEVANCE: Enhancing lean mass and limiting gains in fat may provide some protection against TSI. Individuals with small skeletal frames are advised to increase training loads particularly gradually and to reduce training intensity at the first sign of pain in the shins.

Zero-field magnetic skyrmions in exchange-biased ferromagnetic-antiferromagnetic bilayers.

We report on the stabilization of ferromagnetic skyrmions in zero external magnetic fields, in exchange-biased systems composed of ferromagnetic-antiferromagnetic (FM-AFM) bilayers. By performing atomistic spin dynamics simulations, we study cases of compensated, uncompensated, and partly uncompensated FM-AFM interfaces, and investigate the impact of important parameters such as temperature, inter-plane exchange interaction, Dzyaloshinskii-Moriya interaction, and magnetic anisotropy on the skyrmions appearance and stability. The model with an uncompensated FM-AFM interface leads to the stabilization of individual skyrmions and skyrmion lattices in the FM layer, caused by the effective field from the AFM instead of an external magnetic field. Similarly, in the case of a fully compensated FM-AFM interface, we show that FM skyrmions can be stabilized. We also demonstrate that accounting for interface roughness leads to stabilization of skyrmions both in compensated and uncompensated interface. Moreover, in bilayers with a rough interface, skyrmions in the FM layer are observed for a wide range of exchange interaction values through the FM-AFM interface, and the chirality of the skyrmions depends critically on the exchange interaction.

Coupled atomistic spin-lattice simulations of ultrafast demagnetization in 3d ferromagnets.

Despite decades of research, the role of the lattice and its coupling to the magnetisation during ultrafast demagnetisation processes is still not fully understood. Here we report on studies of both explicit and implicit lattice effects on laser induced ultrafast demagnetisation of bcc Fe and fcc Co. We do this using atomistic spin- and lattice dynamics simulations following a heat-conserving three-temperature model. We show that this type of Langevin-based simulation is able to reproduce observed trends of the ultrafast magnetization dynamics of fcc Co and bcc Fe. The parameters used in our models are all obtained from electronic structure theory, with the exception of the lattice dynamics damping term, where a range of parameters were investigated. It was found that while the explicit spin-lattice coupling in the studied systems does not impact the demagnetisation process notably, the lattice damping has a large influence on the details of the magnetization dynamics. The dynamics of Fe and Co following the absorption of a femtosecond laser pulse are compared with previous results for Ni and similarities and differences in the materials' behavior are analysed. For all elements investigated so far with this model, we obtain a linear relationship between the value of the maximally demagnetized state and the fluence of the laser pulse , which is in agreement with experiments. Moreover, we demonstrate that the demagnetization amplitude is largest for Ni and smallest for Co. This holds over a wide range of the reported electron-phonon couplings, and this demagnetization trend is in agreement with recent experiments.

Combined Cabazitaxel and Carboplatin Treatment of Metastatic Castration Resistant Prostate Cancer Patients, With Innate or Acquired Resistance to Cabazitaxel Monotherapy.

BACKGROUND: There is new interest in platinum-based treatment of patients with metastatic castration resistant prostate cancer (mCRPC), to which a subgroup responds. Although platinum sensitivity is suggested to be associated with aggressive disease features and distinct molecular profiles, identification of responders is a clinical challenge. In this study, we selected patients who displayed PSA progression during cabazitaxel monotherapy, for combined cabazitaxel and carboplatin treatment. METHODS: In this retrospective study, mCRPC patients received carboplatin and cabazitaxel after biochemical progression following at least 2 cabazitaxel monotherapy cycles. We assessed PSA response, Time to PSA Progression (TTpsa) and Time to Radiographic Progression (TTrad). For a subset of patients, mutational analysis of BRCA-1, BRCA-2, ATM, PTEN, P53 and RB1 was performed. RESULTS: Forty-five patients were included, after a median of 4 (3-6) cycles of cabazitaxel monotherapy. Patients received a median of 3 (2-5) cycles of combined cabazitaxel and carboplatin, on which 12 (26.6%) patients had a PSA decline ≥ 50% from baseline. TTpsa was 2 (1-5) months and TTrad 3 (2-6) months. Adverse events were predominantly grade 1-2. Of the 29 (64.4%) patients evaluable for molecular signature, 6 (13.3%) had BRCA1, BRCA2 or ATM mutations and 12 (26.7%) had a PTEN, P53 or RB1 mutations. The occurrence of these mutations was not associated with any clinical outcome measure. CONCLUSIONS: In this study we showed that patients with PSA progression during cabazitaxel monotherapy could benefit from the addition of carboplatin to cabazitaxel, while prospective identification of these patients remains a clinical challenge.

Exploring HIV disease indicators at MDR-TB treatment initiation in South Africa.

BACKGROUND: Understanding relationships between HIV and multidrug-resistant TB (MDR-TB) is crucial for ensuring successful MDR-TB outcomes.METHODS: We used a cross-sectional analysis to evaluate sociodemographic and clinical characteristics as correlates of antiretroviral therapy (ART) use, having an HIV viral load (VL) result, and HIV viral suppression in a cross-sectional sample of people with HIV (PWH) and MDR-TB enrolled in a cluster-randomized trial of nurse case management to improve MDR-TB outcomes.RESULTS: Among 1,479 PWH, the mean age was 37.1 years; 809 (54.7%) were male, and 881 (59.6%) were taking ART. Housing location, employment status, and CD4 count differed significantly between those taking vs. those not taking ART. Among the 881 taking ART, 681 (77.3%) had available HIV VL results. Housing location, CD4 count, and prior history of TB differed significantly between those with and without a VL result. Among the 681 with a VL result, 418 (61.4%) were virally suppressed. Age, education level, CD4 count, TB history, housing location, and ART type differed significantly between those with and without viral suppression.CONCLUSION: PWH presenting for MDR-TB treatment with a history of TB, taking a protease inhibitor, or living in a township may risk poor MDR-TB outcomes.

Prospective Longitudinal Assessment of Quality of Life After Stereotactic Ablative Radiotherapy for Oligometastases: Analysis of the Population-based SABR-5 Phase II Trial.

AIMS: To evaluate longitudinal patient-reported quality of life (QoL) in patients treated with stereotactic ablative radiotherapy (SABR) for oligometastases. MATERIALS AND METHODS: The SABR-5 trial was a population-based single-arm phase II study of SABR to up to five sites of oligometastases, conducted in six regional cancer centres in British Columbia, Canada from 2016 to 2020. Prospective QoL was measured using treatment site-specific QoL questionnaires at pre-treatment baseline and at 3, 6, 9, 12, 15, 18, 21, 24, 30 and 36 months after treatment. Patients with bone metastases were assessed with the Brief Pain Inventory (BPI). Patients with liver, adrenal and abdominopelvic lymph node metastases were assessed with the Functional Assessment of Chronic Illness Therapy-Abdominal Discomfort (FACIT-AD). Patients with lung and intrathoracic lymph node metastases were assessed with the Prospective Outcomes and Support Initiative (POSI) lung questionnaire. The two one-sided test procedure was used to assess equivalence between the worst QoL score and the baseline score of individual patients. The mean QoL at all time points was used to determine the trajectory of QoL response after SABR. The proportion of patients with 'stable', 'improved' or 'worsened' QoL was determined for all time points based on standard minimal clinically important differences (MCID; BPI worst pain = 2, BPI functional interference score [FIS] = 0.5, FACIT-AD Trial Outcome Index [TOI] = 8, POSI = 3). RESULTS: All enrolled patients with baseline QoL assessment and at least one follow-up assessment were analysed (n = 133). On equivalence testing, the patients' worst QoL scores were clinically different from baseline scores and met MCID (BPI worst pain mean difference: 1.8, 90% confidence interval 1.19 to 2.42]; BPI FIS mean difference: 1.68, 90% confidence interval 1.15 to 2.21; FACIT-AD TOI mean difference: -8.76, 90% confidence interval -11.29 to -6.24; POSI mean difference: -4.61, 90% confidence interval -6.09 to -3.14). However, the mean FIS transiently worsened at 9, 18 and 21 months but eventually returned to stable levels. The mean FACIT and POSI scores also worsened at 36 months, albeit with a limited number of responses (n = 4 and 8, respectively). Most patients reported stable QoL at all time points (range: BPI worst pain 71-82%, BPI FIS 45-78%, FACIT-AD TOI 50-100%, POSI 25-73%). Clinically significant stability, worsening and improvement were seen in 70%/13%/18% of patients at 3 months, 53%/28%/19% at 18 months and 63%/25%/13% at 36 months. CONCLUSIONS: Transient decreases in QoL that met MCID were seen between patients' worst QoL scores and baseline scores. However, most patients experienced stable QoL relative to pre-treatment levels on long-term follow-up. Further studies are needed to characterise patients at greatest risk for decreased QoL.

Predictors of Quality of Life Decline in Patients with Oligometastases treated with Stereotactic Ablative Radiotherapy: Analysis of the Population-Based SABR-5 Phase II Trial.

AIMS: Most patients experience stable quality of life (QoL) after stereotactic ablative radiotherapy (SABR) treatment for oligometastases. However, a subset of patients experience clinically relevant declines in QoL on post-treatment follow-up. This study aimed to identify risk factors for QoL decline. MATERIALS AND METHODS: The SABR-5 trial was a population-based single-arm phase II study of SABR to up to five sites of oligometastases. Prospective QoL was measured using treatment site-specific tools at pre-treatment baseline and 3, 6, 9, 12, 15, 18, 21, 24, 30 and 36 months after treatment. The time to persistent QoL decline was calculated as the time from SABR to the first decline in QoL score meeting minimum clinically important difference with no improvement to baseline score on subsequent assessments. Univariable and multivariable logistic regression analyses were carried out to determine factors associated with QoL decline. RESULTS: One hundred and thirty-three patients were included with a median follow-up of 32 months (interquartile range 25-43). Thirty-five patients (26%) experienced a persistent decline in QoL. The median time until persistent QoL decline was not reached. The cumulative incidence of QoL decline at 2 and 3 years were 22% (95% confidence interval 14.0-29.6) and 40% (95% confidence interval 28.0-51.2), respectively. In multivariable analysis, disease progression (odds ratio 5.23, 95% confidence interval 1.59-17.47, P = 0.007) and adrenal metastases (odds ratio 9.70, 95% confidence interval 1.41-66.93, P = 0.021) were associated with a higher risk of QoL decline. Grade 3 or higher (odds ratio 3.88, 95% confidence interval 0.92-16.31, P = 0.064) and grade 2 or higher SABR-associated toxicity (odds ratio 2.24, 95% confidence interval 0.85-5.91, P = 0.10) were associated with an increased risk of QoL decline but did not reach statistical significance. CONCLUSIONS: Disease progression and adrenal lesion site were associated with persistent QoL decline following SABR. The development of grade 3 or higher toxicities was also associated with an increased risk, albeit not statistically significant. Further studies are needed, focusing on the QoL impact of metastasis-directed therapies.

Interatomic exchange interactions for finite-temperature magnetism and nonequilibrium spin dynamics.

We derive ab inito exchange parameters for general noncollinear magnetic configurations, in terms of a multiple scattering formalism. We show that the general exchange formula has an anisotropiclike term even in the absence of spin-orbit coupling, and that this term is large, for instance, for collinear configuration in bcc Fe, whereas for fcc Ni it is quite small. We demonstrate that keeping this term leads to what one should consider a biquadratic effective spin Hamiltonian even in the case of collinear arrangement. In noncollinear systems this term results in new tensor elements that are important for exchange interactions at finite temperatures, but they have less importance at low temperature. To illustrate our results in practice, we calculate for bcc Fe magnon spectra obtained from configuration-dependent exchange parameters, where the configurations are determined by finite-temperature effects. Our theory results in the same quantitative results as the finite-temperature neutron scattering experiments.

Tibial stress injury: relationship of radiographic, nuclear medicine bone scanning, MR imaging, and CT Severity grades to clinical severity and time to healing.

PURPOSE: To examine the relationship between severity grade for radiography, triple-phase technetium 99m nuclear medicine bone scanning, magnetic resonance (MR) imaging, and computed tomography (CT); clinical severity; and recovery time from a tibial stress injury (TSI), as well as to evaluate interassessor grading reliability. MATERIALS AND METHODS: This protocol was approved by the Griffith University Human Research Ethics Committee, the Stanford University Panel on Human Subjects in Medical Research, the U.S. Army Human Subjects Research Review Board, and the Australian Defense Human Research Ethics Committee. Informed consent was obtained from all subjects. Forty subjects (17 men, 23 women; mean age, 26.2 years ± 6.9 [standard deviation]) with TSI were enrolled. Subjects were examined acutely with standard anteroposterior and lateral radiography, nuclear medicine scanning, MR imaging, and CT. Each modality was graded by four blinded clinicians. Mixed-effects models were used to examine associations between image severity, clinical severity, and time to healing, with adjustments for image modality and assessor. Grading reliability was evaluated with the Cronbach α coefficient. RESULTS: Image assessment reliability was high for all grading systems except radiography, which was moderate (α = 0.565-0.895). Clinical severity was negatively associated with MR imaging severity (P ≤ .001). There was no significant relationship between time to healing and severity score for any imaging modality, although a positive trend existed for MR imaging (P = .07). CONCLUSION: TSI clinical severity was negatively related to MR imaging severity. Radiographic, bone scan, and CT severity were not related to time to healing, but there was a positive trend for MR imaging.

Can acute abdominal CT prioritize patients with suspected diverticulitis for a subsequent clean colonic examination?

AIM: The aim of this study was to investigate whether patients with diverticulitis can be prioritized with higher urgency for a subsequent full colonic examination based upon the emergency abdominal CT scan performed at the time of presentation. METHOD: All patients with a diagnosis of diverticulitis, hospitalized during 2006 and having a CT scan on admission and a subsequent 'clean colon' examination, were reviewed. The CT scan was reviewed by two independent and blinded senior radiologists (Radiologist A and Radiologist B) for signs inconsistent with diverticulitis and suggestive of malignancy. The patients were classified on the CT scan results into group 1 (normal findings, nontumour pathology or benign polyps < 1 cm) or group 2 (benign polyps ≥ 1 cm and cancer). RESULTS: Ninety-three patients (83 in group 1 and 10 in group 2) were reviewed. Radiologist A suggested high-priority colonic examination in 18% and 50% of patients in groups 1 and 2, respectively, and Radiologist B in 63% and 90% of patients, respectively. There was a statistically significant interobserver difference, and also lower accuracy of Radiologist B compared with Radiologist A in predicting a subsequent 'clean colon' examination. CONCLUSION: Use of an emergency acute CT scan at the time of diagnosis of diverticulitis to predict a clean colon examination for neoplasia is not reliable because there is a considerable degree of interobserver difference between radiologists.

Dose-dependent toxicological effects in rats following a 90-day dietary exposure to PCB-156 include retinoid disruption.

The toxicity of PCB-156 (2,3,3',4,4',5-hexachlorobiphenyl) was investigated in rats following subchronic dietary exposure. Groups of 10 male and female Sprague-Dawley rats were administered PCB-156 in the diet at 0, 0.01, 0.1, 1 or 10 ppm for 90 days. Dose-dependent increases were detected for the liver, lung and kidney weights, as well as for the liver EROD, PROD and UDPGT enzyme activities and liver uroporphyrin concentration. Dose-dependent decreases were observed in final body weight, body weight gain, and thymus weight. Apolar retinoid concentrations were decreased in the liver and lungs and increased in the kidneys. Histopathological examination of the liver, thyroid, and thymus showed mild to moderate dose-related changes. A LOAEL of 0.01 ppm was established, based on reduced apolar liver retinoid concentration. Benchmark dose-modelling corroborated the sensitivity of liver retinoid endpoints. The lower confidence limits (BMDL) for a 5% decrease in apolar liver retinoid concentrations were 0.0009 and 0.0007 ppm, respectively, in males and females, corresponding to a daily dose of 0.06 µg PCB-156 per kg body weight. Organizing dose-response data for the individual hepatic endpoints along the PCB-156 dosing scale revealed a sequence of events compatible with a causal link between depletion of apolar retinoids and the other liver biochemistry and pathology findings. Taken together, data suggest that the retinoid endpoints should be further evaluated for a causal relationship to PCB-induced liver toxicity and that retinoid system endpoints are identified and characterized to support health risk assessment in the emerging research fields of endocrine disruption and mixture toxicology.

Validation of the Prognostic Utility of ESTRO/EORTC Oligometastatic Disease Classification: A Secondary Analysis From the Population-Based Phase II SABR-5 Trial.

PURPOSE: The recently developed European Society for Radiotherapy and Oncology (ESTRO)/European Organization for Research and Treatment of Cancer (EORTC) oligometastatic disease (OMD) classification has not been validated in terms of its prognostic significance. This study stratified patients from the phase II SABR-5 trial based on ESTRO/EORTC criteria and compared progression-free survival (PFS) and overall survival (OS) to determine the prognostic significance of the classification scheme. METHODS AND MATERIALS: The SABR-5 trial was a single arm phase II study conducted at the 6 regional cancer centers across British Columbia (BC), Canada, where SABR for oligometastases was only offered on trial. Patients with up to 5 oligometastases (total or not controlled by prior treatment and including induced OMD) underwent SABR to all lesions. Patients were 18 years of age or older, Eastern Cooperative Oncology Group 0 to 2, and life expectancy ≥6 months. PFS and OS were calculated using the Kaplan-Meier method and differences between OMD groups were assessed with log-rank tests. Univariable and multivariable analyses were performed using Cox regression modeling. RESULTS: Between November 2016 and July 2020, 381 patients underwent SABR on trial. Median follow-up was 27 months (interquartile range, 18-36). The most frequent OMD group was de novo OMD (69%), followed by repeat (16%) and induced (13%). OMD groups differed significantly in PFS (P < .001) but not OS (P = .069). The OMD classification was an independent predictor of both PFS (P = .005) and OS (P = .002). Of the 5 classification factors, only chronicity (synchronous, hazard ratio, 0.52; P = .027) and oligoprogression (hazard ratio, 2.05; P = .004) were independently prognostic for OS. CONCLUSIONS: In this large prospective cohort, the ESTRO/EORTC classification was an independent predictor of PFS and OS and should be used to identify specific patient groups for clinical trials. In this trial population, the prognostic power is largely attributable to chronicity and oligoprogression. Simplification of the framework may be possible in the future and allow for greater ease of use; however, further data on underrepresented OMD groups and histologies will be required.

Staging of uterine cervical cancer with MRI: guidelines of the European Society of Urogenital Radiology.

OBJECTIVE: To design clear guidelines for the staging and follow-up of patients with uterine cervical cancer, and to provide the radiologist with a framework for use in multidisciplinary conferences. METHODS: Guidelines for uterine cervical cancer staging and follow-up were defined by the female imaging subcommittee of the ESUR (European Society of Urogenital Radiology) based on the expert consensus of imaging protocols of 11 leading institutions and a critical review of the literature. RESULTS: The results indicated that high field Magnetic Resonance Imaging (MRI) should include at least two T2-weighted sequences in sagittal, axial oblique or coronal oblique orientation (short and long axis of the uterine cervix) of the pelvic content. Axial T1-weighted sequence is useful to detect suspicious pelvic and abdominal lymph nodes, and images from symphysis to the left renal vein are required. The intravenous administration of Gadolinium-chelates is optional but is often required for small lesions (<2 cm) and for follow-up after treatment. Diffusion-weighted sequences are optional but are recommended to help evaluate lymph nodes and to detect a residual lesion after chemoradiotherapy. CONCLUSIONS: Expert consensus and literature review lead to an optimized MRI protocol to stage uterine cervical cancer. MRI is the imaging modality of choice for preoperative staging and follow-up in patients with uterine cervical cancer.