Associations between ambient air pollution and daily mortality in a cohort of congestive heart failure: Case-crossover and nested case-control analyses using a distributed lag nonlinear model.

BACKGROUND: Persons with congestive heart failure may be at higher risk of the acute effects related to daily fluctuations in ambient air pollution. To meet some of the limitations of previous studies using grouped-analysis, we developed a cohort study of persons with congestive heart failure to estimate whether daily non-accidental mortality were associated with spatially-resolved, daily exposures to ambient nitrogen dioxide (NO2) and ozone (O3), and whether these associations were modified according to a series of indicators potentially reflecting complications or worsening of health. METHODS: We constructed the cohort from the linkage of administrative health databases. Daily exposure was assigned from different methods we developed previously to predict spatially-resolved, time-dependent concentrations of ambient NO2 (all year) and O3 (warm season) at participants' residences. We performed two distinct types of analyses: a case-crossover that contrasts the same person at different times, and a nested case-control that contrasts different persons at similar times. We modelled the effects of air pollution and weather (case-crossover only) on mortality using distributed lag nonlinear models over lags 0 to 3 days. We developed from administrative health data a series of indicators that may reflect the underlying construct of "declining health", and used interactions between these indicators and the cross-basis function for air pollutant to assess potential effect modification. RESULTS: The magnitude of the cumulative as well as the lag-specific estimates of association differed in many instances according to the metric of exposure. Using the back-extrapolation method, which is our preferred exposure model, we found for the case-crossover design a cumulative mean percentage changes (MPC) in daily mortality per interquartile increment in NO2 (8.8 ppb) of 3.0% (95% CI: -0.4, 6.6%) and for O3 (16.5 ppb) 3.5% (95% CI: -4.5, 12.1). For O3 there was strong confounding by weather (unadjusted MPC = 7.1%; 95% CI: 1.7, 12.7%). For the nested case-control approach the cumulative MPC for NO2 in daily mortality was 2.9% (95% CI: -0.9, 6.9%) and for O3 7.3% (95% CI: 3.0, 11.9%). We found evidence of effect modification between daily mortality and cumulative NO2 and O3 according to the prescribed dose of furosemide in the nested case-control analysis, but not in the case-crossover analysis. CONCLUSIONS: Mortality in congestive heart failure was associated with exposure to daily ambient NO2 and O3 predicted from a back-extrapolation method using a land use regression model from dense sampling surveys. The methods used to assess exposure can have considerable influence on the estimated acute health effects of the two air pollutants

Early Diagnosis of HIV Infection in Infants - One Caribbean and Six Sub-Saharan African Countries, 2011-2015.

Pediatric human immunodeficiency virus (HIV) infection remains an important public health issue in resource-limited settings. In 2015, 1.4 million children aged 50% decline. The most common challenges for access to testing for early infant diagnosis included difficulties in specimen transport, long turnaround time between specimen collection and receipt of results, and limitations in supply chain management. Further reductions in HIV mortality in children can be achieved through continued expansion and improvement of services for early infant diagnosis in PEPFAR-supported countries, including initiatives targeted to reach HIV-exposed infants, ensure access to programs for early infant diagnosis of HIV, and facilitate prompt linkage to treatment for children diagnosed with HIV infection

Radiation Dosimetry in 177 Lu-PSMA-617 Therapy

Radionuclide therapy using the small molecule PSMA bound to the beta-emitting radionuclide, Lutetium-177 (177Lu-PSMA) has demonstrated efficacy and survival benefit castrate resistant metastatic disease and represents a novel new line of therapy. Whilst dosimetry was critical for early development, it was not incorporated into either the TheraP or VISION randomized studies, highlighting the difficulty of adopting dosimetry in routine clinical practice. Accumulated clinical experience has also shown that the common (and generally low grade) toxicities such as nausea, xerostomia, and cytopenias are not readily predicted on the basis of dosimetry estimates. The majority of dosimetry and clinical literature deals with the radiopharmaceutical 177Lu-PSMA-617 which displays relatively consistent patterns of retention among normal tissues and high specificity for metastatic prostate cancer phenotypes. Population dosimetry incorporating estimates to the kidneys, salivary glands, and bone marrow have been widely reported the typical range of doses is becoming well established. There is growing interest on tumor dosimetry in 177Lu-PSMA-617 therapy as an overall modest side-effect profile from primary organ retention has been observed. A focus away from normal organ dosimetry to whole body tumor dosimetry may enable early prediction of treatment failure. Given the safety of 177Lu-PSMA there is also potential to escalate administered radioactivity to further improve outcomes. Importantly, the variability of uptake between individuals, both to tumor and normal organs, has also been highlighted which provides some rationale for the utility of personalized radiation analysis to optimize treatment based on potential toxicity thresholds or tumor control. Methods to perform dosimetry using serial post treatment imaging may incorporate planar, 3D SPECT, or hybrid datasets. Reliable measurements may be obtained through either method, however, continued developments in computational analysis are better suited to fully 3D imaging; particularly in conjunction with volumetric CT to assist with alignment and contouring. Dose analysis over sequential treatment cycles is vital to understand the radiobiology of these treatments which is unique compared to external beam therapy due to dose rate, fractionation scheme, and potential for intratumoral nonuniformity

Quantitative calibration of Tb-161 SPECT/CT in view of personalised dosimetry assessment studies

Abstract Background Terbium-161 (161Tb)-based radionuclide therapy poses an alternative to current Lutetium-177 (177Lu) approaches with the additional benefit of secondary Auger and conversion electron emissions capable of delivering high doses of localised damage to micro-metastases including single cells. Quantitative single-photon emission computed tomography, paired with computed tomography (SPECT/CT), enables quantitative measurement from post-therapy imaging. In view of dosimetry extrapolations, a Tb-161 sensitivity SPECT/CT camera calibration was performed using a method previously validated for 177Lu. Methods Serial imaging of a NEMA/IEC body phantom with Tb-161 was performed on SPECT/CT with low-energy high-resolution collimators employing a photopeak of 75 keV with a 20% width. Quantitative stability and recovery coefficients were investigated over a sequence of 19 scans with buffered 161Tb solution at total phantom activity ranging from 70 to 4990 MBq. Results Sphere recovery coefficients were 0.60 ± 0.05, 0.52 ± 0.07, 0.45 ± 0.07, 0.39 ± 0.07, 0.28 ± 0.08, and 0.20 ± 0.08 for spheres 37, 28, 22, 17, 13, and 10mm, respectively, when considered across all activity and scan durations with dual-energy window scatter correction. Whole-field reconstructed sensitivity was calculated as 1.42E−5 counts per decay. Qualitatively, images exhibited no visual artefacts and were comparable to 177Lu SPECT/CT. Conclusions Quantitative SPECT/CT of 161Tb is feasible over a range of activities enabling dosimetry analogous to 177Lu whilst also producing suitable imaging for clinical review. This has been incorporated into a prospective trial of 161Tb-PSMA for men with metastatic prostate cancer

A Systematic Review of the Variability in Performing and Reporting Intraprostatic Prostate-specific Membrane Antigen Positron Emission Tomography in Primary Staging Studies

Context: Prostate cancer (PCa) remains one of the leading causes of cancer-related deaths in men worldwide. Men at risk are typically offered multiparametric magnetic resonance imaging and, if suspicious, a targeted biopsy. However, false-negative rates of magnetic resonance imaging are consistently 18%; therefore, there is growing interest in improving the diagnostic performance of imaging through novel technologies. Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is being utilised for PCa staging and, more recently, for intraprostatic tumour localisation. However, significant variability has been observed in how PSMA PET is performed and reported. Objective: In this review, we aim to evaluate how pervasive this variability is in trials investigating the performance of PSMA PET in primary PCa workup. Evidence acquisition: Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, we performed an optimal search in five different databases. After removing duplicates, 65 studies were included in our review. Evidence synthesis: Studies dated back as early as 2016, with numerous different source countries. There was variation in the reference standard for PSMA PET, with some using biopsy specimens or surgical specimens, and in some cases, a combination of the two. Similar inconsistencies were noted when studies selected histological definitions of clinically significant PCa, while some omitted their definition altogether. The most significant variations in performing PSMA PET were the radiotracer type, dose, acquisition time after injection, and the PET camera being utilised. Substantial variation in the reporting of PSMA PET was noted, with no consistency in defining what constitutes a positive intraprostatic lesion. Across 65 studies, four different definitions were used. Conclusions: This systematic review has highlighted considerable variation in obtaining and performing a PSMA PET study in the context of primary PCa diagnosis. Given the discrepancy in how PSMA PET was performed and reported, it questions the homogony of studies from centre to centre. Standardisation of PSMA PET is required for this to become a consistently useful and reproducible modality in the diagnosis of PCa. Patient summary: Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is being utilised for staging and localisation of prostate cancer (PCa); however, there is significant variability in performing and reporting PSMA PET. Standardisation of PSMA PET is required for results to be consistently useful and reproducible for the diagnosis of PCa

Comparison of dual-energy CT with positron emission tomography for lung perfusion imaging in patients with non-small cell lung cancer

Objective. Functional lung avoidance (FLA) radiotherapy treatment aims to spare lung regions identified as functional from imaging. Perfusion contributes to lung function and can be measured from the determination of pulmonary blood volume (PBV). An advantageous alternative to the current determination of PBV from positron emission tomography (PET) may be from dual energy CT (DECT), due to shorter examination time and widespread availability. This study aims to determine the correlation between PBV determined from DECT and PET in the context of FLA radiotherapy. Approach. DECT and PET acquisitions at baseline of patients enrolled in the HI-FIVE clinical trial (ID: NCT03569072) were reviewed. Determination of PBV from PET imaging ( PBV PET ), from DECT imaging generated from a commercial software (Syngo.via, Siemens Healthineers, Forchheim, Germany) with its lowest ( PBV syngo R = 1 ) and highest ( PBV syngo R = 10 ) smoothing level parameter value (R), and from a two-material decomposition (TMD) method ( PBV TMD L ) with variable median filter kernel size (L) were compared. Deformable image registration between DECT images and the CT component of the PET/CT was applied to PBV maps before resampling to the PET resolution. The Spearman correlation coefficient (r s) between PBV determinations was calculated voxel-wise in lung subvolumes. Main results. Of this cohort of 19 patients, 17 had a DECT acquisition at baseline. PBV maps determined from the commercial software and the TMD method were very strongly correlated [r s( PBV syngo R = 1 , PBV TMD L = 1 ) = 0.94 ± 0.01 and r s( PBV syngo R = 10 , PBV TMD L = 9 ) = 0.94 ± 0.02]. PBV PET was strongly correlated with PBV TMD L [r s( PBV PET , PBV TMD L = 28 ) = 0.67 ± 0.11]. Perfusion patterns differed along the posterior-anterior direction [r s( PBV PET , PBV TMD L = 28 ) = 0.77 ± 0.13/0.57 ± 0.16 in the anterior/posterior region]. Significance. A strong correlation between DECT and PET determination of PBV was observed. Streak and smoothing effects in DECT and gravitational artefacts and misregistration in PET reduced the correlation posteriorly

Additional file 1 of Quantitative calibration of Tb-161 SPECT/CT in view of personalised dosimetry assessment studies

Additional file 1. Figure S1: VOI placement of NEMA spheres and two cylindrical regions (turquoise) used as background measurement. Figure S2: Example distribution of background VOI counts over a range of activity concentration levels (0.011, 0.088, and 0.618 MBq/mL) and scan durations (2, 8, and 16 seconds). Figure S3: NEMA sphere RC and CNR as a function of post-processing Gaussian smoothing from single acquisition with 1.2 GBq in FOV with 8 second frame duration. Figure S4: Gamma spectrum obtained from Siemens Intevo-BOLD gamma camera with 990 MBq in NEMA IEC NU2 phantom over 2-minute analyser acquisition. Vertical lines indicate peaked energy windows (red = photopeak [64-79 keV], yellow = lower scatter [60-64 keV], blue = upper scatter [79-83 keV])

The PRIMARY Score: Using Intraprostatic 68Ga-PSMA PET/CT Patterns to Optimize Prostate Cancer Diagnosis.

Multiparametric MRI (mpMRI) is validated for the diagnosis of clinically significant prostate cancer (csPCa). 68Ga-PSMA-11 PET/CT (68Ga-PSMA PET/CT) combined with mpMRI has improved negative predictive value over mpMRI alone for csPCa. The aim of this post hoc analysis of the PRIMARY study was to evaluate the clinical significance of patterns of intraprostatic PSMA activity, proposing a 5-point PRIMARY score to optimize the accuracy of 68Ga-PSMA PET/CT for csPCa in a low-prevalence population. Methods: The PRIMARY trial was a prospective multicenter phase II imaging trial that enrolled men with suspected PCa, no prior biopsy, and a recent mpMRI examination (6 mo) and for whom prostate biopsy was planned. In total, 291 men underwent mpMRI, 68Ga-PSMA PET/CT, and systematic biopsy with or without targeted biopsy. The mpMRI was read separately using the Prostate Imaging Reporting and Data System (PI-RADS) (version 2). 68Ga-PSMA PET/CT (pelvis only) was acquired a minimum of 60 min after injection. 68Ga-PSMA PET/CT was centrally read for pattern (diffuse transition zone [TZ], symmetric central zone [CZ], focal TZ, or focal peripheral zone [PZ]) and intensity (SUVmax). In this post hoc analysis, a 5-level PRIMARY score was assigned on the basis of analysis of the central read: no pattern (score of 1), diffuse TZ or CZ (not focal) (score of 2), focal TZ (score of 3), focal PZ (score of 4), or an SUVmax of at least 12 (score of 5). Two further readers independently assigned a PRIMARY score to 118 scans to determine interrater agreement. Associations between PRIMARY score and csPCa (International Society of Urological Pathology grade group ≥ 2) were evaluated. Results: Of the 291 men enrolled, 162 (56%) had csPCa. A PRIMARY score of 1 was present in 16% (47); a score of 2, in 19% (55); a score of 3, in 10% (29); a score of 4 in 40% (117); and a score of 5, in 15% (43). The proportion of patients with csPCa and a PRIMARY score of 1, 2, 3, 4, and 5 was 8.5% (4/47), 27% (15/55), 38% (11/29), 76% (89/117), and 100% (43/43), respectively. Sensitivity, specificity, positive predictive value, and negative predictive value for a PRIMARY score of 1 or 2 (low-risk patterns) versus a PRIMARY score of 3-5 (high-risk patterns) were 88%, 64%, 76%, and 81%, respectively, compared with 83%, 53%, 69%, and 72%, respectively, for a PI-RADS score of 2 versus 3-5 on mpMRI. The Cohen κ for a PRIMARY score of 1 of 2 versus a PRIMARY score of 3-5 was 0.76 (95% CI, 0.64-0.88) for reader 1 and 0.64 (95% CI, 0.49-0.78) for reader 2. Conclusion: A PRIMARY score incorporating intraprostatic pattern and intensity on 68Ga-PSMA PET/CT shows potential, with high diagnostic accuracy for csPCa. Further validation is warranted before implementation

A Novel Risk Calculator Incorporating Clinical Parameters, Multiparametric Magnetic Resonance Imaging, and Prostate-Specific Membrane Antigen Positron Emission Tomography for Prostate Cancer Risk Stratification Before Transperineal Prostate Biopsy

Background: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) can detect multiparametric magnetic resonance imaging (mpMRI)-invisible prostate tumours and improve the sensitivity of detection of prostate cancer (PCa) in comparison to mpMRI alone. Numerous risk calculators have been validated as tools for stratification of men at risk of being diagnosed with clinically significant (cs)PCa. Objective: To develop a novel risk calculator using clinical parameters and imaging parameters from mpMRI and PSMA PET/CT in a cohort of patients undergoing mpMRI and PSMA PET/CT before biopsy. Design, setting, and participants: A total of 291 men from the PRIMARY prospective trial underwent mpMRI and PSMA PET/CT before transperineal prostate biopsy with sampling of systematic and targeted cores. Outcome measurements and statistical analysis: Novel risk calculators were developed using multivariable logistic regression analysis to predict detection of overall PCa (International Society of Urological Pathology grade group [GG] ≥1) and csPCa (GG ≥2). The risk calculators were then compared with the European Randomised Study of Screening for Prostate Cancer risk calculator incorporating mpMRI (ERSPC-MRI). Resampling methods were used to evaluate the discrimination and calibration of the risk calculators and to perform decision curve analysis. Results and limitations: Age, prostate-specific antigen, prostate volume, and mpMRI Prostate Imaging-Reporting and Data System scores were included in the MRI risk calculator, resulting in area under the receiver operating characteristic curve (AUC) values of 0.791 for overall PCa (GG ≥1) and 0.812 for csPCa (GG ≥2). Addition of the maximum standardised uptake value (SUVmax) on PSMA PET/CT for the prostate lesion, and of SUVmax for the mpMRI lesions for the MRI-PSMA risk calculator resulted in AUCs of 0.831 for overall PCa and 0.876 for csPCa (≥ISUP2).The ERSPC-MRI risk calculator had AUCs of 0.758 (p = 0.02) for overall PCa and 0.805 (p = 0.001) for csPCa. Both the MRI and MRI-PSMA risk calculators were superior to the ERSPC-MRI for both overall PCa and csPCa. Conclusions: These novel risk calculators incorporate clinical and radiological parameters for stratification of men at risk of csPCa. The risk calculator including PSMA PET/CT data is superior to a calculator incorporating mpMRI data alone. Patient summary: We evaluated a new risk calculator that uses clinical information and results from two types of scan to predict the risk of clinically significant prostate cancer on prostate biopsy. This risk model can guide patients and clinicians in shared decision-making and may help in avoiding unnecessary prostate biopsies

The diverse roles of protein kinase C in pancreatic β-cell function

Abstract Members of the serine/threonine PKC (protein kinase C) family perform diverse functions in multiple cell types. All members of the family are activated in signalling cascades triggered by occupation of cell surface receptors, but the cPKC (conventional PKC) and nPKC (novel PKC) isoforms are also responsive to fatty acid metabolites. PKC isoforms are involved in various aspects of pancreatic β-cell function, including cell proliferation, differentiation and death, as well as regulation of secretion in response to glucose and muscarinic receptor agonists. Recently, the nPKC isoform, PKCε, has also been implicated in the loss of insulin secretory responsiveness that underpins the development of Type 2 diabetes